increase in anchorage-independent growth [302]. In H1975 cells, the exposure to PM<sub>2.5</sub> induced approximately 5-fold increase in colony formation ability, but in PC9 and A549 cells PM<sub>2.5</sub> exposure caused a less than 2-fold increase [302]. These data suggest that PM<sub>2.5</sub> stimulates EGFR activation and cell proliferation in a variety of lung cancer cell lines, but the responses were considerably enhanced in cells harboring both the L858R and T790M mutations [302], which both are common in ADC from never smokers [38].

PM<sub>2.5</sub>-exposure has also been shown to induce an AhR-dependent transcriptional activation of transmembrane serine protease 2 (TMPRSS2) and subsequent expression of the IL-1 family member IL-18 that may promote cancer progression. AhR nuclear expression also correlated with TMPRSS2 and IL18 expression and cancer stage in human lung cancer tissue [302]. Although the link between the AhR-TMPRSS2-IL18 pathway and EGFR activation was not specifically explored, the study provides a potential link between AhR activation and ADC with EGFR driver mutations. On the other hand, AhR expression has been reported to suppress lung cancer metastasis after orthotopic implantation of human adenocarcinoma cell lines (H1975, A549 and H1299) in SCID CB.17 mice, suggesting that AhR suppresses lung carcinogenesis irrespective of the dominant oncogenic driver [303]. Low AhR expression levels were also associated with faster cancer progression and reduced survival in lung ADC patients [303]. A likely explanation for this apparent contradiction could be the differences in effects of constitutive AhR activity versus PAH-induced AhR activation. There is a considerable diversity in AhR-regulated responses induced by different ligands [191], and the native AhR in unstimulated cells appears to affect the regulation of different gene clusters than those regulated upon ligand activation [304]. Importantly, while PAH exposure activated EGFR, this was not the case for dioxins, which underscores the variability in effects induced by different ligands [233].

Based on the above, we suggest that AhR may induce proliferation of lung cancer cells through mechanisms involving both non-genomic activation of EGFR, and genomic activation of NF-κB and its target genes such as TMPRSS2, leading to inflammatory responses regulated by members of the IL-1 cytokine family, such as IL-1β and IL-18. It seems that these effects may be enhanced in EGFR-driven adenocarcinoma, especially by the L858R mutation in exon 21, and that the involvement of AhR is restricted to PAH-mediated activation, since dioxins may not activate EGFR to a similar extent and unliganded constitutive AhR appears to suppress lung tumor progression independent of the driver mutation.

### 9.3. Extracellular vesicles and miRNA

Extracellular vesicles (EVs) are nanostructures produced by all cells, mediating cell-to-cell communication by exchanging proteins, nucleic acids and lipids or organelles (e.g. mitochondria) [305-307]. They constitute a heterogeneous population including exosomes (Exo; less than 200 nm), microvesicles (MV; 100-1000 nm) and apoptotic bodies. EVs are detected in various biological fluids [308], and suggested to participate in the maintenance of cellular homeostasis and intercellular communication including immune responses, cell proliferation, tissue repair and angiogenesis. EVs contribute to inflammation by containing cytokines, accordingly EVs containing high concentrations of biologically active TNF-α produced by alveolar macrophages was detected in bronchoalveolar lavage fluids (BALFs) during lung injury [309,310]. Damaged epithelial cells may also produce EVs that recruited pro-inflammatory M1 macrophages [311]. These nanostructures are also suggested to contribute to the growth and worsening of cancers. EVs produced by lung cancer cells are reported to stimulate the production of the pro-angiogenic factor vascular endothelial growth factor (VEGF) and increase vascular permeability and extracellular matrix remodeling [312]. Furthermore, an increase in EVs containing cell death protein ligand-1 (PD-L1) suggested to be involved in tumor immune evasion observed in patients with non-small cell lung cancers, who were non-

responders to treatment [313]. Notably, PD-L1 is known to be under the control of AhR [301].

An increasing amount of evidence suggests that environmental pollutants can modify the production of EVs, and that they are involved in the appearance or progression of diseases linked to environmental exposures including lung cancer [314]. Tobacco-smoke, PM<sub>2.5</sub> and PAHs have been shown to trigger EV release from different lung cell types (macrophages, bronchial epithelial cells, endothelial cells, platelets) [315]. PAHs such as B[a]P, dibenz[a,h]anthracene, or benz[a]anthracene, have been shown to increase EVs production by endothelial cells [316]. However, until now only limited data exist concerning the role of AhR in EVs production and content, especially upon exposure to air pollutants such as tobacco-smoke, PM<sub>2.5</sub> or PAHs. Recently, it was demonstrated, using endothelial and hepatic cell models, that PAHs such as B[a]P may increase exosome production through AhR activation [316,317]. The inhibitory effect of naringenin (a flavonoid targeting AhR pathway) on EV production in BEAS-2B cells exposed to cigarette smoke extract could indicate a role for AhR also in lung epithelial cells [318]. Furthermore, pyrene, a weak agonist of canonical AhR signaling but potent inducer of AhR non-genomic Ca<sup>2+</sup> signaling [214], increased exosome production using constitutive androstane receptor (CAR) pathway [317].

EVs may also contain miRNAs/ncRNA, a class of RNAs that regulate gene expression by interacting with their target mRNAs to induce their silencing, thereby influencing the cell response [319]. Via regulation of oncogenes or tumor suppressors, miRNAs can modulate tumor formation and contribute to lung cancer development [320-323]. Interestingly, several experimental and epidemiological studies report that exposure to various sources of combustion PM such as DEP, industrial/biomass combustion and cigarette smoking alter miRNA levels [324]. For example, DEP exposure in human lung cells upregulated miR-21 which has previously been identified as an 'oncomir' candidate by targeting cell proliferation and EMT through regulation of the PTEN/AKT signaling pathway [325]. Furthermore, loss of miR-29a is associated with cdc7 kinase accumulation and has been suggested as a mechanism to acquire resistance to cigarette smoke-induced DNA damage allowing the cells to proliferate [326].

The miRNAs have also been studied as biomarkers of interest in lung cancer [327] as diagnostic and/or prognostic tools [328,329]. More recently, EV-derived from biological fluids and their miRNAs have been proposed as a potential source of biomarkers for exposure and effects of environmental pollutants. Changes in extracellular miRNAs have been correlated to different sources of PM including DEP [330,331], traffic-related air pollution [332] and cigarette smoke [333-336]. Some miRNAs are commonly deregulated in lung cancers and as a result of exposure to air pollution, and they have been suggested as interesting biomarkers for the detection of sensitive human populations [337]. Furthermore, miRNAs following exposure to cigarette smoke are also suggested to contribute to a modification of the tumor microenvironment towards a pro-inflammatory response [338] and to be pro-angiogenic [339,340].

Finally, an increasing number of studies have shown that some miRNAs target AhR and vice versa, that AhR regulate miRNAs following oncogenic changes induced by PAHs [341,342]. In fact, AhR has been proposed as a key regulator in controlling miRNA levels in lung [343]. Accordingly, without activation, AhR suppressed the expression of the cancer-associated miR-96, whereas chronic cigarette smoke markedly increased its level by a mechanism independent of classic AhR activation by ligands [343]. Such ligand-independent regulation of miR-196a by AhR has been described by Hetch et al. [344] in lung fibroblasts controlling their apoptosis and potentially regulating the hallmarks of cancer as previously suggested [345]. By contrast, we and others recently reported the ligand-dependent AhR activation of miR-132 expression in blood cells [346,347]. This miRNA may possess pro- or anti-tumor functions depending on cancer [348]. Altogether, these elements reveal the interest and the complexity of miRNAs in air pollution-
induced lung cancers and underline the need to further explore biological importance of the AhR in miRNA-induced processes, notably in link with EVs.

# 10. Role of PAHs and AhR in regulating the tumor microenvironment (TME)

## 10.1. Tumor microenvironment - Immune cells and stromal cells

Tumor cells are surrounded by non-malignant stromal cells which play a critical role for the survival, growth, progression, and metastasis of cancer cells. It is important to note that the development of metastasis is the cause of more than 90% of cancer mortality, and that the metastasis of tumor cells depends on the support of their microenvironment. Non-malignant stromal cells are a heterogeneous cell population forming the structure of the tumor microenvironment (TME) and include cancer associated fibroblasts (CAFs), endothelial cells, adipocytes and pericytes. Interestingly, a recent study showed that elevation of the protein fibroblast growth factor 2 (FGF-2) expression involves AhR signaling resulting in pericyte proliferation in the TME. Consequently, increased FGF-2 signaling and proliferation of pericytes leads to accumulation of tumor associated macrophages (TAMs) and metastasis [349].

Moreover, infiltrating adaptive and innate immune cells play a critical role in the TME and exert an anti- or pro-tumorigenic effect on the development of cancer. For instance, regulatory B cells producing IL-10 may contribute to immunosuppression in the tumor microenvironment. Regulatory B cells differentiation is promoted by the key tryptophan metabolite L-kynurenine (L-Kyn) in an indoleamine 2,3-dioxygenase (IDO) and AhR-dependent mechanism [350]. In addition to B cells, recent studies have shown that AhR activation by TCDD leads to accumulation of tumor associated myeloid cells (TAMs) including myeloid derived suppressor cells (MDSCs) or TAMs [351]. The importance of immunosuppressive TAMs and the central role of the TME has been demonstrated for the progression and metastasis of various malignancies including lung and breast cancer [352,353].

Furthermore, recent reports have shown a critical role of AhR in the recruitment of MDSCs and TAMs in adipose tissue of TCDD-treated mice [354] and during the development of glioblastoma [355,356]. The AhR has been found to induce the expression of immunoregulatory enzymes and factors such as arginase 1 (Arg1), IDO, IL-10 and the S100 calcium binding protein S100A9 which are important for the immunosuppressive function of TAMs by creating a tumor-promoting microenvironment [357–360]. Additionally, cytokines, chemokines, and growth factors are soluble factors and important components of the TME since they regulate the recruitment and migration of immune cells as well as tumor cells [361]. The important role of IL-1β has also been demonstrated in AhR-mediated (TCDD-induced) development of lymphoma [96]. These studies indicate that IL-1β signaling creates a tumor-promoting microenvironment contributing to tumor growth and metastasis as reported previously [362,363]. Additionally, numerous studies confirmed the AhR-dependent upregulation of IL-1β in macrophages and other cell types after treatment with PM, PAHs and TCDD [352,353].

In summary, the literature supports the conclusion that activation of AhR generates a pro-tumorigenic microenvironment that tumors evolve to escape the immune response, enabling progressive tumor growth and metastasis. Consequently, the AhR may play a critical role in the TME of various cancer types by modulating the recruitment and function of infiltrating immune cells. Because AhR can be regulated by small molecules, the AhR has been suggested to be an attractive target for the tumor microenvironment and immunotherapy to treat cancer [113,364,365].

## 10.2. Angiogenesis and tumor growth

Formation of new blood vessels, neo-angiogenesis, is an essential part of tumor development in lung cancer and other cancers [366]. Development of different AhR knockout mouse models in the 1990s revealed that AhR deficiency caused cardiac hypertrophy, vascular abnormalities in multiple organs and altered blood pressure [367]. These studies pointed towards a central role of AhR in angiogenesis. The central role of AhR cardiovascular development and homeostasis has been extensively reviewed elsewhere [367–370] and will therefore not be discussed in detail here. Among the angiogenic factors affected by AhR activation is the vascular endothelial growth factor (VEGF), which is a key regulator of angiogenesis.

In vitro exposure of a coculture of eosinophilic (EoL-1) cells and human umbilical vein endothelial cells (HUVECs) to B[a]P, was reported to promote HUVEC growth through ERK1/2 mediated VEGF expression and release from the EoL-1 cells [371]. Similarly, benzyl butyl phtalate induced VEGF release, stimulation angiogenesis in vitro and in vivo through AhR non-genomic activation of ERK1/2 in hepatocarcinoma (Huh7) cells [372]. AhR has been reported to induce VEGF expression in HepG2 cells through activating transcription factor 4 (ATF4), which may be under regulation of the ERK172 pathway [373]. Thus, the angiogenic VEGF-signal appears to arise from activation of AhR in both immune cells and cancer cells, which in the case of lung cancer would be bronchial and alveolar epithelial cells. However, AhR knockdown has also been shown to impair angiogenesis and compromise tumor xenograft growth in mice, by a mechanism involving AhR-dependent VEGF activation in endothelial cells [374]. VEGF is also regulated by the hypoxia-inducible factor-α (HIF-1 α), a PAS family member [375]. Angiogenesis as well as upregulation of the expression of HIF-1 α, ARNT, and VEGF induced by ischemia are enhanced in AhR knockout mice [376]. Indeed, HIF-1 α and AhR crosstalk has been shown to impact both hypoxia-driven gene expression and AhR target genes, presumably via competition for their common dimerization partner, Arnt, as well as by additional mechanisms relevant e.g. for immune cell regulation [377]. Moreover, the role of AhR in VEGF and angiogenesis regulation could be significantly affected by metabolism of PAHs. In fish cell models, both benzo[k]fluoranthene and B[a]P have been shown to alter expression of hypoxia reporter gene, presumably via their metabolites [378]. Interestingly, in human lung adenocarcinoma A549 cells, B[a]P has been found to promote induction of HIF-1 α target genes, including VEGF and carbonic anhydrase IX (CA IX) [379]. Another study indicated that a metabolite of B[a]P, B[a]P-3,6-dione, can induce HIF-1 α degradation in A549 cells [380]. By contrast BPDE and dihydrodiol epoxide metabolite of chrysene have both been reported to stimulate VEGF induction independently of HIF-1 α [381]. Thus, effects of PAHs on HIF-1α-driven angiogenesis in tumor cells could be regulated not only by their AhR activity but they could be directed also by a pattern of their metabolites being formed in target cells.

# 11. Role of PAHs and AhR in regulation of cancer cell stemness and metastasis

Acquisition of stem cell-like tumor phenotype (cancer stemness) and cancer stem cells are playing an important role in chemoresistance, tumor progression and metastasis. Cancer stem cells have been found to be multidrug-resistant (MDR) based on high expression of the multidrug transporter ATP-binding cassette super-family G member 2 (ABCG2) which is an efflux protein, also called the breast cancer resistance protein (BCRP) [382]. Interestingly, ABCG2 has been identified as a direct transcriptional target of AhR [383]. Consequently, the AhR has been implicated in cancer stemness serving as a sensor and molecular bridge between environmental exposure to PM and PAHs and an increased risk to develop metastases. In the lung, AhR has been shown to induce the expression of ABCG2 and other critical genes involved in cancer stemness [384] which has been found to be associated with an increase of
induced lung cancers and underline the need to further explore biological importance of the AhR in miRNA-induced processes, notably in link with EVs.

# 10. Role of PAHs and AhR in regulating the tumor microenvironment (TME)

## 10.1. Tumor microenvironment - Immune cells and stromal cells

Tumor cells are surrounded by non-malignant stromal cells which play a critical role for the survival, growth, progression, and metastasis of cancer cells. It is important to note that the development of metastasis is the cause of more than 90% of cancer mortality, and that the metastasis of tumor cells depends on the support of their microenvironment. Non-malignant stromal cells are a heterogeneous cell population forming the structure of the tumor microenvironment (TME) and include cancer associated fibroblasts (CAFs), endothelial cells, adipocytes and pericytes. Interestingly, a recent study showed that elevation of the protein fibroblast growth factor 2 (FGF-2) expression involves AhR signaling resulting in pericyte proliferation in the TME. Consequently, increased FGF-2 signaling and proliferation of pericytes leads to accumulation of tumor associated macrophages (TAMs) and metastasis [349].

Moreover, infiltrating adaptive and innate immune cells play a critical role in the TME and exert an anti- or pro-tumorigenic effect on the development of cancer. For instance, regulatory B cells producing IL-10 may contribute to immunosuppression in the tumor microenvironment. Regulatory B cells differentiation is promoted by the key tryptophan metabolite L-kynurenine (L-Kyn) in an indoleamine 2,3-dioxygenase (IDO) and AhR-dependent mechanism [350]. In addition to B cells, recent studies have shown that AhR activation by TCDD leads to accumulation of tumor associated myeloid cells (TAMs) including myeloid derived suppressor cells (MDSCs) or TAMs [351]. The importance of immunosuppressive TAMs and the central role of the TME has been demonstrated for the progression and metastasis of various malignancies including lung and breast cancer [352,353].

Furthermore, recent reports have shown a critical role of AhR in the recruitment of MDSCs and TAMs in adipose tissue of TCDD-treated mice [354] and during the development of glioblastoma [355,356]. The AhR has been found to induce the expression of immunoregulatory enzymes and factors such as arginase 1 (Arg1), IDO, IL-10 and the S100 calcium binding protein S100A9 which are important for the immunosuppressive function of TAMs by creating a tumor-promoting microenvironment [357–360]. Additionally, cytokines, chemokines, and growth factors are soluble factors and important components of the TME since they regulate the recruitment and migration of immune cells as well as tumor cells [361]. The important role of IL-1β has also been demonstrated in AhR-mediated (TCDD-induced) development of lymphoma [96]. These studies indicate that IL-1β signaling creates a tumor-promoting microenvironment contributing to tumor growth and metastasis as reported previously [362,363]. Additionally, numerous studies confirmed the AhR-dependent upregulation of IL-1β in macrophages and other cell types after treatment with PM, PAHs and TCDD [352,353].

In summary, the literature supports the conclusion that activation of AhR generates a pro-tumorigenic microenvironment that tumors evolve to escape the immune response, enabling progressive tumor growth and metastasis. Consequently, the AhR may play a critical role in the TME of various cancer types by modulating the recruitment and function of infiltrating immune cells. Because AhR can be regulated by small molecules, the AhR has been suggested to be an attractive target for the tumor microenvironment and immunotherapy to treat cancer [113,364,365].

## 10.2. Angiogenesis and tumor growth

Formation of new blood vessels, neo-angiogenesis, is an essential part of tumor development in lung cancer and other cancers [366]. Development of different AhR knockout mouse models in the 1990s revealed that AhR deficiency caused cardiac hypertrophy, vascular abnormalities in multiple organs and altered blood pressure [367]. These studies pointed towards a central role of AhR in angiogenesis. The central role of AhR cardiovascular development and homeostasis has been extensively reviewed elsewhere [367–370] and will therefore not be discussed in detail here. Among the angiogenic factors affected by AhR activation is the vascular endothelial growth factor (VEGF), which is a key regulator of angiogenesis.

In vitro exposure of a coculture of eosinophilic (EoL-1) cells and human umbilical vein endothelial cells (HUVECs) to B[a]P, was reported to promote HUVEC growth through ERK1/2 mediated VEGF expression and release from the EoL-1 cells [371]. Similarly, benzyl butyl phtalate induced VEGF release, stimulation angiogenesis in vitro and in vivo through AhR non-genomic activation of ERK1/2 in hepatocarcinoma (Huh7) cells [372]. AhR has been reported to induce VEGF expression in HepG2 cells through activating transcription factor 4 (ATF4), which may be under regulation of the ERK172 pathway [373]. Thus, the angiogenic VEGF-signal appears to arise from activation of AhR in both immune cells and cancer cells, which in the case of lung cancer would be bronchial and alveolar epithelial cells. However, AhR knockdown has also been shown to impair angiogenesis and compromise tumor xenograft growth in mice, by a mechanism involving AhR-dependent VEGF activation in endothelial cells [374]. VEGF is also regulated by the hypoxia-inducible factor-α (HIF-1 α), a PAS family member [375]. Angiogenesis as well as upregulation of the expression of HIF-1 α, ARNT, and VEGF induced by ischemia are enhanced in AhR knockout mice [376]. Indeed, HIF-1 α and AhR crosstalk has been shown to impact both hypoxia-driven gene expression and AhR target genes, presumably via competition for their common dimerization partner, Arnt, as well as by additional mechanisms relevant e.g. for immune cell regulation [377]. Moreover, the role of AhR in VEGF and angiogenesis regulation could be significantly affected by metabolism of PAHs. In fish cell models, both benzo[k]fluoranthene and B[a]P have been shown to alter expression of hypoxia reporter gene, presumably via their metabolites [378]. Interestingly, in human lung adenocarcinoma A549 cells, B[a]P has been found to promote induction of HIF-1 α target genes, including VEGF and carbonic anhydrase IX (CA IX) [379]. Another study indicated that a metabolite of B[a]P, B[a]P-3,6-dione, can induce HIF-1 α degradation in A549 cells [380]. By contrast BPDE and dihydrodiol epoxide metabolite of chrysene have both been reported to stimulate VEGF induction independently of HIF-1 α [381]. Thus, effects of PAHs on HIF-1α-driven angiogenesis in tumor cells could be regulated not only by their AhR activity but they could be directed also by a pattern of their metabolites being formed in target cells.

# 11. Role of PAHs and AhR in regulation of cancer cell stemness and metastasis

Acquisition of stem cell-like tumor phenotype (cancer stemness) and cancer stem cells are playing an important role in chemoresistance, tumor progression and metastasis. Cancer stem cells have been found to be multidrug-resistant (MDR) based on high expression of the multidrug transporter ATP-binding cassette super-family G member 2 (ABCG2) which is an efflux protein, also called the breast cancer resistance protein (BCRP) [382]. Interestingly, ABCG2 has been identified as a direct transcriptional target of AhR [383]. Consequently, the AhR has been implicated in cancer stemness serving as a sensor and molecular bridge between environmental exposure to PM and PAHs and an increased risk to develop metastases. In the lung, AhR has been shown to induce the expression of ABCG2 and other critical genes involved in cancer stemness [384] which has been found to be associated with an increase of
stem population in osteosarcoma cells [385]. Further, the stabilization and activation of AhR has been associated with the expression of deubiquitinase UCHL3 promoting cancer stemness in non-small cell lung carcinoma [386]. The role of AhR in metastasis and cancer stemness seems to be rather complex and may involve various signaling pathways and cell types. Nonetheless, there is increasing evidence that chronic and sustained activation of AhR by environmental toxins (e.g. dioxins and PAHs) promotes carcinogenesis by supporting cancer stemness, chemoresistance and metastasis [364,387].

Atmospheric PM and associated pollutants have been also shown to alter EMT in lung epithelial and bronchial epithelial cell models. EMT plays a central role in various lung diseases, including pulmonary fibrosis and lung cancer. Effects of PM and other particles on EMT have been reviewed extensively in a recent work of Cochard and colleagues [388]. EMT is defined as a process by which cells lose their epithelial phenotype and acquire mesenchymal traits, which include increased ability to migrate and invade. As such, it plays a central role in cancer metastasis. This physiological process occurring during embryogenesis and organ development, which is usually defined by a loss of expression of E-cadherin and acquisition of expression of N-cadherin and vimentin, consists of numerous transition steps, which are only partially recapitulated in cancer cells [389–391]. Nevertheless, already partially executed EMT program may drive cancer metastasis and affects plasticity of tumor cells [389].

Regarding the impact of PM (and PAHs) on EMT in pulmonary cells, numerous studies have been carried out *in vitro* during recent years, and the cellular models used included both bronchial and alveolar epithelial cell models. The treatments included ambient PM<sub>2.5</sub>, DEP, PM derived from biomass burning and a number of standard reference materials (SRM), in both particulate forms and applied as their organic extracts [388]. There is a significant variability in dosing regimens or exposure times, but in general, a wide spectrum of PMs, or their extracts, have been shown to cause EMT in cell models derived from respiratory cells [388]. Studies using PM, DEP and/or individual PAHs as model PAH have indicated that these treatments may cause EMT-like phenotype in alveolar epithelial A549 or in human immortalized bronchial epithelial cells [281,392–395]. Their effects were mostly associated with the loss of E-cadherin expression and increased motility of target cells; nevertheless, the mechanisms underlying these effects remain only partially understood. Interestingly, a two-week exposure to B[a]P, but not TCDD, promoted mesenchymal-like phenotype in A549 cells. While TCDD increased the proliferative rate of A549 cells, exposure to B[a]P decreased cell proliferation and induced EMT-like phenotype, which was associated with enhanced cell migration, invasion, and altered cell morphology. These changes were mediated by the p21<sup>Cip1</sup>-dependent delay in cell cycle progression [281]. Thus, activation of the AhR alone was not sufficient to elicit EMT in this cell model.

In human bronchial BEAS-2B cells, a short-term exposure to PM induced matrix metalloproteinase MMP1, extracellular matrix (ECM) remodeling genes, and several other genes related to EMT [392]. PM, cigarette smoke condensate and B[a]P have induced EMT in human bronchial epithelial cells (HBEC). However, twelve weeks of chronic exposure to these mixtures or to B[a]P were necessary to establish mesenchymal-like phenotype [396]. Deregulation of serpin family B member 2 (SERPINB2) expression is another mechanism that has been suggested to link EMT and PM exposure in human bronchial cells [397]. The upregulation of SERPINB2 via AhR-dependent mechanism [398] induced morphological alterations but it reduced cell migration after short-term exposure to PM2.5; in contrast, in transformed mesenchymal-like HBEC has been strongly SERPINB2 down-regulated. The over-expression of SERPINB2 in PM-exposed bronchial cells might be interpreted as an initial protective mechanism, helping to maintain the epithelial character of the cells [397].

Comparative HPLC-MS/MS analysis of parental HBEC-12KT and B[a]P-transformed HBEC-12KT-B1 (the cells with acquired mesenchymal-like phenotype) has revealed significant changes in sphingolipid (SL)

and glycosphingolipid (GSL) profiles, favoring those SLs and GSLs which have been reported to act as positive modulators of EMT and other pro-carcinogenic processes [399]. Being both intracellular signaling molecules and important integral components of membrane lipid signaling domains, specific SLs and GSLs have been reported to be involved in cancer development, via playing multiple roles in promoting cancer cell growth and survival, as well as in EMT, cell migration and invasion [400–402]. Interestingly, exosomes isolated from mesenchymal-like HBEC-12KT-B1 cells contained similarly altered SL/GSL profiles indicating a possibility that exosomes derived from transformed mesenchymal-like cells might contribute to cancer progression also in recipient cells [399].

Taken together, multiple mechanisms leading to EMT in airway epithelial cells (both normal and cancer cells) have been reported after exposures to PM, DEP, their extracts or to individual PAHs. The AhR-dependent action of PAHs could also be modified by toxic effects of other PM components [388], leading to generation of oxidative stress, inflammatory responses or disruption of DNA integrity and cell proliferation. Together, these effects may lead to activation of transcription factors regulating EMT response. Overall, the mechanisms underlying induction of mesenchymal-like phenotype in lung epithelium will require further attention, as this mechanism may significantly contribute to dissemination of lung cancer cells and formation of metastases. Another line of evidence supporting this comes from the experiments with cigarette smoke, which contains large quantities of PAHs and AhR ligands, and which has been documented to induce EMT in lung adenocarcinoma A549 cells [403]. The cigarette smoke extract-induced intracellular ROS increased expression of runt-related transcription factor 2 (RUNX-2) and galectin-3, a novel mechanism likely to contribute to EMT induction [403]. The effects of PAHs and their mixtures on EMT are mostly non-genotoxic. They might be relevant for normal cells of respiratory epithelium, during early stages of cell transformation, as well as during cancer progression, where they promote cancer cell dissemination.

## 12. Framework for development of adverse outcome pathways (AOPs) for air pollution induced lung cancer

Recently, an adverse outcome pathway (AOP) was proposed for breast-cancer related cell death, with AhR as the molecular initiating event (MIE), decreased apoptosis and increased motility, inflammation, and endothelial migration as cellular key events (KE) [29]. As discussed in the present review, AhR and PAHs appear to affect many of the same responses in the lungs and a corresponding AOP could likely be developed for lung cancer development from PM<sub>2.5</sub> and combustion particles. However, the AOP for AhR-induced breast cancer, which was based on an artificial intelligence tool, provides limited molecular insight into the KEs induced by AhR activation in breast cancer cells [29]. By contrast, the recent studies on air pollution induced lung cancer discussed in this review provide a more detailed mapping of the molecular and cellular events contributing to adenocarcinoma development from ambient air PM<sub>2.5</sub> exposure. Air pollution induced lung cancer in never-smokers appear primarily to be due to promotion of AT2 cells harboring naturally acquired EGFR mutations. The collective evidence suggest that AhR plays a central role by regulating proinflammatory cytokines in various lung cells. Additional evidence for a central role of AhR in EGFR driven lung cancers from combustion particle exposure comes from the well-established link between AhR non-genomic signaling and activation of EGFR, and the observations that AhR nuclear translocation, a marker of AhR activation, is common in lung cancer from never-smokers. Based on this we suggest a framework for the role of AhR in lung cancer development from air pollution and other low concentrations of combustion PM, were AhR activation in macrophages and epithelial cells may represent the MIE leading release of IL-1 family cytokines such as IL-1 β and IL-18, and activation of EGFR which both contributes to induce proliferation of AT2 cells with EGFR driver
stem population in osteosarcoma cells [385]. Further, the stabilization and activation of AhR has been associated with the expression of deubiquitinase UCHL3 promoting cancer stemness in non-small cell lung carcinoma [386]. The role of AhR in metastasis and cancer stemness seems to be rather complex and may involve various signaling pathways and cell types. Nonetheless, there is increasing evidence that chronic and sustained activation of AhR by environmental toxins (e.g. dioxins and PAHs) promotes carcinogenesis by supporting cancer stemness, chemoresistance and metastasis [364,387].

Atmospheric PM and associated pollutants have been also shown to alter EMT in lung epithelial and bronchial epithelial cell models. EMT plays a central role in various lung diseases, including pulmonary fibrosis and lung cancer. Effects of PM and other particles on EMT have been reviewed extensively in a recent work of Cochard and colleagues [388]. EMT is defined as a process by which cells lose their epithelial phenotype and acquire mesenchymal traits, which include increased ability to migrate and invade. As such, it plays a central role in cancer metastasis. This physiological process occurring during embryogenesis and organ development, which is usually defined by a loss of expression of E-cadherin and acquisition of expression of N-cadherin and vimentin, consists of numerous transition steps, which are only partially recapitulated in cancer cells [389–391]. Nevertheless, already partially executed EMT program may drive cancer metastasis and affects plasticity of tumor cells [389].

Regarding the impact of PM (and PAHs) on EMT in pulmonary cells, numerous studies have been carried out *in vitro* during recent years, and the cellular models used included both bronchial and alveolar epithelial cell models. The treatments included ambient PM<sub>2.5</sub>, DEP, PM derived from biomass burning and a number of standard reference materials (SRM), in both particulate forms and applied as their organic extracts [388]. There is a significant variability in dosing regimens or exposure times, but in general, a wide spectrum of PMs, or their extracts, have been shown to cause EMT in cell models derived from respiratory cells [388]. Studies using PM, DEP and/or individual PAHs as model PAH have indicated that these treatments may cause EMT-like phenotype in alveolar epithelial A549 or in human immortalized bronchial epithelial cells [281,392–395]. Their effects were mostly associated with the loss of E-cadherin expression and increased motility of target cells; nevertheless, the mechanisms underlying these effects remain only partially understood. Interestingly, a two-week exposure to B[a]P, but not TCDD, promoted mesenchymal-like phenotype in A549 cells. While TCDD increased the proliferative rate of A549 cells, exposure to B[a]P decreased cell proliferation and induced EMT-like phenotype, which was associated with enhanced cell migration, invasion, and altered cell morphology. These changes were mediated by the p21<sup>Cip1</sup>-dependent delay in cell cycle progression [281]. Thus, activation of the AhR alone was not sufficient to elicit EMT in this cell model.

In human bronchial BEAS-2B cells, a short-term exposure to PM induced matrix metalloproteinase MMP1, extracellular matrix (ECM) remodeling genes, and several other genes related to EMT [392]. PM, cigarette smoke condensate and B[a]P have induced EMT in human bronchial epithelial cells (HBEC). However, twelve weeks of chronic exposure to these mixtures or to B[a]P were necessary to establish mesenchymal-like phenotype [396]. Deregulation of serpin family B member 2 (SERPINB2) expression is another mechanism that has been suggested to link EMT and PM exposure in human bronchial cells [397]. The upregulation of SERPINB2 via AhR-dependent mechanism [398] induced morphological alterations but it reduced cell migration after short-term exposure to PM2.5; in contrast, in transformed mesenchymal-like HBEC has been strongly SERPINB2 down-regulated. The over-expression of SERPINB2 in PM-exposed bronchial cells might be interpreted as an initial protective mechanism, helping to maintain the epithelial character of the cells [397].

Comparative HPLC-MS/MS analysis of parental HBEC-12KT and B[a]P-transformed HBEC-12KT-B1 (the cells with acquired mesenchymal-like phenotype) has revealed significant changes in sphingolipid (SL)

and glycosphingolipid (GSL) profiles, favoring those SLs and GSLs which have been reported to act as positive modulators of EMT and other pro-carcinogenic processes [399]. Being both intracellular signaling molecules and important integral components of membrane lipid signaling domains, specific SLs and GSLs have been reported to be involved in cancer development, via playing multiple roles in promoting cancer cell growth and survival, as well as in EMT, cell migration and invasion [400–402]. Interestingly, exosomes isolated from mesenchymal-like HBEC-12KT-B1 cells contained similarly altered SL/GSL profiles indicating a possibility that exosomes derived from transformed mesenchymal-like cells might contribute to cancer progression also in recipient cells [399].

Taken together, multiple mechanisms leading to EMT in airway epithelial cells (both normal and cancer cells) have been reported after exposures to PM, DEP, their extracts or to individual PAHs. The AhR-dependent action of PAHs could also be modified by toxic effects of other PM components [388], leading to generation of oxidative stress, inflammatory responses or disruption of DNA integrity and cell proliferation. Together, these effects may lead to activation of transcription factors regulating EMT response. Overall, the mechanisms underlying induction of mesenchymal-like phenotype in lung epithelium will require further attention, as this mechanism may significantly contribute to dissemination of lung cancer cells and formation of metastases. Another line of evidence supporting this comes from the experiments with cigarette smoke, which contains large quantities of PAHs and AhR ligands, and which has been documented to induce EMT in lung adenocarcinoma A549 cells [403]. The cigarette smoke extract-induced intracellular ROS increased expression of runt-related transcription factor 2 (RUNX-2) and galectin-3, a novel mechanism likely to contribute to EMT induction [403]. The effects of PAHs and their mixtures on EMT are mostly non-genotoxic. They might be relevant for normal cells of respiratory epithelium, during early stages of cell transformation, as well as during cancer progression, where they promote cancer cell dissemination.

## 12. Framework for development of adverse outcome pathways (AOPs) for air pollution induced lung cancer

Recently, an adverse outcome pathway (AOP) was proposed for breast-cancer related cell death, with AhR as the molecular initiating event (MIE), decreased apoptosis and increased motility, inflammation, and endothelial migration as cellular key events (KE) [29]. As discussed in the present review, AhR and PAHs appear to affect many of the same responses in the lungs and a corresponding AOP could likely be developed for lung cancer development from PM<sub>2.5</sub> and combustion particles. However, the AOP for AhR-induced breast cancer, which was based on an artificial intelligence tool, provides limited molecular insight into the KEs induced by AhR activation in breast cancer cells [29]. By contrast, the recent studies on air pollution induced lung cancer discussed in this review provide a more detailed mapping of the molecular and cellular events contributing to adenocarcinoma development from ambient air PM<sub>2.5</sub> exposure. Air pollution induced lung cancer in never-smokers appear primarily to be due to promotion of AT2 cells harboring naturally acquired EGFR mutations. The collective evidence suggest that AhR plays a central role by regulating proinflammatory cytokines in various lung cells. Additional evidence for a central role of AhR in EGFR driven lung cancers from combustion particle exposure comes from the well-established link between AhR non-genomic signaling and activation of EGFR, and the observations that AhR nuclear translocation, a marker of AhR activation, is common in lung cancer from never-smokers. Based on this we suggest a framework for the role of AhR in lung cancer development from air pollution and other low concentrations of combustion PM, were AhR activation in macrophages and epithelial cells may represent the MIE leading release of IL-1 family cytokines such as IL-1 β and IL-18, and activation of EGFR which both contributes to induce proliferation of AT2 cells with EGFR driver
mutations subsequently leading to tumor growth and lung ADC devel-
opment (Fig. 2a). Although the role of AhR non-genomic signaling in
EGFR activation is well established, it still remains unclear whether and
how PM2.5 contribute to activation of EGFR with oncogenic mutations.
Furthermore, additional AhR-regulated mechanisms clearly contribute
to cancer progression through enhancing cell survival/suppression of
apoptosis, altered tumor microenvironment, reduction of contact inhi-
bition and increased angiogenesis (Fig. 2a). At higher combustion PM
exposure doses, AhR-induced PAH metabolism and mutations in
particular in TP53 and KRAS, become more important (Fig. 2b).

Additional effects of AhR activation on inflammation, tumor microen-
vironment, cell-to-cell communication, cell proliferation and survival,
are likely to occur also in these cases. However, it should be noted that
proliferation and colony formation of lung cancer cells with KRAS mu-
tations may be less affected by PM2.5 exposure than lung cancer cells
harboring tEGFR mutations, and AhR has also been reported to suppress
KRAS-driven NSCLC. It should also be considered that other combustion-
derived mutagens not discussed in this review (e.g. aldehydes, nitrosa-
mine, metals, and ultrafine-/nanoparticles as such) may contribute
significantly to lung cancer development at high combustion PM

<figure><img src="image_4.png" /><figcaption>Fig. 2. A framework for development of Adverse Outcome Pathways (AOPs) for AhR in lung cancer from air pollution and combustion PM. The figure presents a framework for development of AOPs for the link between AhR activation in different lung cell types and development of lung cancer after exposure of low levels of combustion PM and PAHs from outdoor air (A) and high-level exposures from smoking or occupational settings (B). At low-level exposure (A), AhR activation is primarily suggested to induce lung cancer by tumor promotion, through release of proinflammatory IL-1 family cytokines and nongenomic activation of EGFR. At high-level exposure (B) AhR induced CYP1 expression with subsequent PAH metabolism, formation of genotoxic metabolites and mutations in TP53 and KRAS is believed to be a central, early key events. AhR induced tumor promotion likely also affects cancer development in the high-level exposure scenario, but the role is less clear and suppressive effects of AhR on KRAS-driven cancers have been reported. It should be noted that some of MIE like VEGF release resulting in increased angiogenesis are first of importance in the later stage of cancer development; while key events like release of immunomodulating factors, DNA damage/ mutations, increased cell survival, disrupted cell-to-cell-communication are of importance during a much longer period of cancer development than indicated in the figures. Well documented connections between AhR activation as the molecular initiating event, different key events, and the adverse outcome (lung cancer) are highlighted by solid lines on green background. Dotted lines represent connections that are indicated in the literature but where more uncertainty still exists.</figcaption></figure>
mutations subsequently leading to tumor growth and lung ADC devel-
opment (Fig. 2a). Although the role of AhR non-genomic signaling in
EGFR activation is well established, it still remains unclear whether and
how PM2.5 contribute to activation of EGFR with oncogenic mutations.
Furthermore, additional AhR-regulated mechanisms clearly contribute
to cancer progression through enhancing cell survival/suppression of
apoptosis, altered tumor microenvironment, reduction of contact inhi-
bition and increased angiogenesis (Fig. 2a). At higher combustion PM
exposure doses, AhR-induced PAH metabolism and mutations in
particular in TP53 and KRAS, become more important (Fig. 2b).

Additional effects of AhR activation on inflammation, tumor microen-
vironment, cell-to-cell communication, cell proliferation and survival,
are likely to occur also in these cases. However, it should be noted that
proliferation and colony formation of lung cancer cells with KRAS mu-
tations may be less affected by PM2.5 exposure than lung cancer cells
harboring tEGFR mutations, and AhR has also been reported to suppress
KRAS-driven NSCLC. It should also be considered that other combustion-
derived mutagens not discussed in this review (e.g. aldehydes, nitrosa-
mine, metals, and ultrafine-/nanoparticles as such) may contribute
significantly to lung cancer development at high combustion PM

<figure><img src="image_4.png" /><figcaption>Fig. 2. A framework for development of Adverse Outcome Pathways (AOPs) for AhR in lung cancer from air pollution and combustion PM. The figure presents a framework for development of AOPs for the link between AhR activation in different lung cell types and development of lung cancer after exposure of low levels of combustion PM and PAHs from outdoor air (A) and high-level exposures from smoking or occupational settings (B). At low-level exposure (A), AhR activation is primarily suggested to induce lung cancer by tumor promotion, through release of proinflammatory IL-1 family cytokines and nongenomic activation of EGFR. At high-level exposure (B) AhR induced CYP1 expression with subsequent PAH metabolism, formation of genotoxic metabolites and mutations in TP53 and KRAS is believed to be a central, early key events. AhR induced tumor promotion likely also affects cancer development in the high-level exposure scenario, but the role is less clear and suppressive effects of AhR on KRAS-driven cancers have been reported. It should be noted that some of MIE like VEGF release resulting in increased angiogenesis are first of importance in the later stage of cancer development; while key events like release of immunomodulating factors, DNA damage/ mutations, increased cell survival, disrupted cell-to-cell-communication are of importance during a much longer period of cancer development than indicated in the figures. Well documented connections between AhR activation as the molecular initiating event, different key events, and the adverse outcome (lung cancer) are highlighted by solid lines on green background. Dotted lines represent connections that are indicated in the literature but where more uncertainty still exists.</figcaption></figure>
exposure.

Conclusive evidence for the role of AhR and PAHs in many of these processes is still lacking. However, this suggested framework for AhR signaling in lung cancer may provide a guidance for future studies and development of AOPs for AhR in lung cancer from exposure to ambient air PM<sub>2.5</sub> and combustion PM. For instance, there is a need to explore how AhR knockdown or pharmacological inhibition would affect PM<sub>2.5</sub> induced tumor promotion in lung AT2 cells with EGFR driver mutations and to compare the impact of PM<sub>2.5</sub> with high or low PAH content on these responses. It is, however, important to consider that the role of AhR in lung cancer development is highly complex and, as is often the case in AhR research, that contrasting findings have been reported. The key to understanding the apparent multifaceted role of AhR in tumor development may lie in the diversity of responses regulated by unli-ganded constitutively active AhR, and upon distinct modes of AhR activation being elicited by its different ligands. Activation of AhR by PAHs and other ligands does not merely function as an on-off switch for transcription of target genes. AhR rather appears to bind and regulate a large number of gene clusters in unstimulated cells, and ligand-dependent activation causes considerable qualitative shifts in the genes regulated by the receptor [304]. A similar ligand promiscuity has also been described for the non-genomic effects of AhR [214,233]. These qualitative shifts in signaling and responses could likely explain some of the apparent contradictory results reported from studies on AhR in lung cancer based on knockout or overexpression models versus those based on exposure to different AhR ligands. Moreover, AhR could play specific roles in different types of lung cancers, where some express high AhR levels and others do not, and some are induced by AhR, while others are suppressed by AhR activity. Clarifying the underlying mechanisms for this "Janus-faced" role of AhR in lung cancer will be important. Another central question relates to the dose-response (or concentration-effect) relationship between PM or PAH exposure and different responses regulated by the AhR. The wide range of cellular processes regulated by AhR are presumably activated at somewhat different dose levels. Iden-tifying the most sensitive biological responses induced by AhR may provide important information on the main mechanisms driving lung cancer development at relatively low PM-exposure levels encountered in outdoor air. After all, activation of AhR appears to be among the most sensitive endpoints reported from *in vitro* exposure of lung cell models to PM or DEP [111,112].

## 13. Conclusion

After more than half a century of research originating from studies on PAH metabolism, our understanding of the role of AhR in cancer development has expanded dramatically. For lung cancer, as for many other cancer types, AhR has been implicated at all stages of tumor development including initiation, promotion, progression, invasion, and metastasis.

We propose that lung cancer from smoking (and occupational and domestic exposure to high combustion PM levels) and lung cancer from air pollution (and secondhand smoke) in never-smokers represent the two ends of a dose-response continuum (Fig. 2a and b). In the case of lung adenocarcinomas (ADC) development in never-smokers from PM<sub>2.5</sub> exposure from air pollution, tumor promotion appears to be a key mechanism acting on lung cells with EGFR driver-mutations acquired naturally through ageing. PAHs from combustion PM are likely candidate components contributing to these responses, through AhR-mediated activation of IL-1 family cytokines such as IL-1β and IL-18 induced through genomic pathways, and possibly also through non-genomic activation of EGFR. Moreover, AhR signaling upregulates immune-regulatory factors and can generate a pro-tumorigenic micro-environment enabling tumor promotion as discussed in this review. For lung squamous cell carcinoma (SCC) development in the central airways induced by higher exposure levels of combustion PM from smoking, occupational exposure, or indoor coal combustion, the initiation step

appears to be a key mechanism driven by mutagenic PAH-metabolites through the classical AhR:Arnt-CYP pathway, acting in combination with other combustion-derived mutagens. The tumor promoting effects of AhR may also be involved in SCC, but they might be less prominent here. Accordingly, AhR has been reported to suppress some lung cancers, including those with KRAS-driver mutations characteristic of PAH-induced genotoxicity and smoking.

Clarifying the role of AhR in lung cancer development associated with air pollution and combustion PM may provide tools for detecting vulnerable populations and give a deeper understanding of essential risk factors. Hopefully this will lead to more efficient measures to reduce exposure to the most harmful air pollutants which can help to intervene and mitigate the development of cancer, especially for people at higher risk through environmental exposure to air pollution.

## Funding

JØ has received funding from the European Union's Horizon 2020 research and innovation program through the ULTRHAS project, Ultrafine Particles from Transportation - Health Assessment of Sources, under grant agreement No 955390. CV is supported in part by the Molecular Oncology Program at the UC Davis Comprehensive Cancer Center and the National Institute of Environmental Health Sciences of the United States National Institutes of Health under Award Number R01ES029126 and R01ES032827. JV and MM are supported by the Czech Science Foundation (project no. 21-00533S). JV acknowledges institutional support of the Institute of Biophysics of the Czech Academy of Sciences (RVO: 68081707).

## CRediT authorship contribution statement

**Jørn A. Holme:** Conceptualization, Writing – original draft, Writing – review & editing.
**Jan Vondráček:** Writing – original draft, Writing – review & editing.
**Miroslav Machala:** Writing – original draft, Writing – review & editing.
**Dominique Lagadic-Gossmann:** Writing – original draft, Writing – review & editing.
**Christoph F.A. Vogel:** Writing – original draft, Writing – review & editing.
**Eric Le Ferrec:** Writing – original draft, Writing – review & editing.
**Lydie Sparfel:** Writing – original draft, Writing – review & editing.
**Johan Øvrevik:** Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Visualization.

## Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## References

[1] S.H. Landis, T.Murray, S. Bolden, P.A.Wingo. Cancer statistics, 1999. CA Cancer J. Clin. 1999;49(1):8-31, 1.

[2] A. Jemal, M.J. Thun, L.A. Ries, H.L. Howe, H.K. Weir, M.M. Center, et al., Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control, J. Natl Cancer Inst. 100 (23) (2008) 1672-1694.

[3] H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 71 (3) (2021) 209-249.

[4] American Cancer Society Trusted Source A, Lung cancer and age: statistics, risk factors, and more, Healthline. (2021). https://www.healthline.com/health/lung-cancer/lung-cancer-age.

[5] W.H. Goodson 3rd, L. Lowe, D.O. Carpenter, M. Gilbertson, A. Manaf Ali, L. de Cerain, A. Salsamendi, et al., Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead, Carcinogenesis 36 Suppl 1 (Suppl 1) (2015) S254-S296.

[6] S. Sun, J.H. Schiller, A.F. Gazdar, Lung cancer in never smokers — a different disease, Nat. Rev. Cancer 7 (10) (2007) 778-790.

[7] H.E. Institute, H., State of global air 2020, Health Effects Institute, Boston, MA, US, 2020.
exposure.

Conclusive evidence for the role of AhR and PAHs in many of these
processes is still lacking. However, this suggested framework for AhR
signaling in lung cancer may provide a guidance for future studies and
development of AOPs for AhR in lung cancer from exposure to ambient
air PM<sub>2.5</sub> and combustion PM. For instance, there is a need to explore
how AhR knockdown or pharmacological inhibition would affect PM<sub>2.5</sub>
induced tumor promotion in lung AT2 cells with EGFR driver mutations
and to compare the impact of PM<sub>2.5</sub> with high or low PAH content on
these responses. It is, however, important to consider that the role of
AhR in lung cancer development is highly complex and, as is often the
case in AhR research, that contrasting findings have been reported. The
key to understanding the apparent multifaceted role of AhR in tumor
development may lie in the diversity of responses regulated by unli-
ganded constitutively active AhR, and upon distinct modes of AhR
activation being elicited by its different ligands. Activation of AhR by
PAHs and other ligands does not merely function as an on-off switch for
transcription of target genes. AhR rather appears to bind and regulate a
large number of gene clusters in unstimulated cells, and ligand-
dependent activation causes considerable qualitative shifts in the
genes regulated by the receptor [304]. A similar ligand promiscuity has
also been described for the non-genomic effects of AhR [214,233]. These
qualitative shifts in signaling and responses could likely explain some of
the apparent contradictory results reported from studies on AhR in lung
cancer based on knockout or overexpression models versus those based
on exposure to different AhR ligands. Moreover, AhR could play specific
roles in different types of lung cancers, where some express high AhR
levels and others do not, and some are induced by AhR, while others are
suppressed by AhR activity. Clarifying the underlying mechanisms for
this "Janus-faced" role of AhR in lung cancer will be important. Another
central question relates to the dose-response (or concentration-effect)
relationship between PM or PAH exposure and different responses
regulated by the AhR. The wide range of cellular processes regulated by
AhR are presumably activated at somewhat different dose levels. Iden-
tifying the most sensitive biological responses induced by AhR may
provide important information on the main mechanisms driving lung
cancer development at relatively low PM-exposure levels encountered in
outdoor air. After all, activation of AhR appears to be among the most
sensitive endpoints reported from *in vitro* exposure of lung cell models to
PM or DEP [111,112].

13. Conclusion

After more than half a century of research originating from studies on
PAH metabolism, our understanding of the role of AhR in cancer
development has expanded dramatically. For lung cancer, as for many
other cancer types, AhR has been implicated at all stages of tumor
development including initiation, promotion, progression, invasion, and
metastasis.

We propose that lung cancer from smoking (and occupational and
domestic exposure to high combustion PM levels) and lung cancer from
air pollution (and secondhand smoke) in never-smokers represent the
two ends of a dose-response continuum (Fig. 2a and b). In the case of
lung adenocarcinomas (ADC) development in never-smokers from PM2.5
exposure from air pollution, tumor promotion appears to be a key
mechanism acting on lung cells with EGFR driver-mutations acquired
naturally through ageing. PAHs from combustion PM are likely candi-
date components contributing to these responses, through AhR-
mediated activation of IL-1 family cytokines such as IL-1β and IL-18
induced through genomic pathways, and possibly also through non-
genomic activation of EGFR. Moreover, AhR signaling upregulates
immune-regulatory factors and can generate a pro-tumorigenic micro-
environment enabling tumor promotion as discussed in this review. For
lung squamous cell carcinoma (SCC) development in the central airways
induced by higher exposure levels of combustion PM from smoking,
occupational exposure, or indoor coal combustion, the initiation step

appears to be a key mechanism driven by mutagenic PAH-metabolites
through the classical AhR:Arnt-CYP pathway, acting in combination
with other combustion-derived mutagens. The tumor promoting effects
of AhR may also be involved in SCC, but they might be less prominent
here. Accordingly, AhR has been reported to suppress some lung can-
cers, including those with KRAS-driver mutations characteristic of PAH-
induced genotoxicity and smoking.

Clarifying the role of AhR in lung cancer development associated
with air pollution and combustion PM may provide tools for detecting
vulnerable populations and give a deeper understanding of essential risk
factors. Hopefully this will lead to more efficient measures to reduce
exposure to the most harmful air pollutants which can help to intervene
and mitigate the development of cancer, especially for people at higher
risk through environmental exposure to air pollution.

Funding

JØ has received funding from the European Union's Horizon 2020 research and innovation program through the ULTRHAS project, Ultrafine Particles from Transportation - Health Assessment of Sources, under grant agreement No 955390. CV is supported in part by the Molecular Oncology Program at the UC Davis Comprehensive Cancer Center and the National Institute of Environmental Health Sciences of the United States National Institutes of Health under Award Number R01ES029126 and R01ES032827. JV and MM are supported by the Czech Science Foundation (project no. 21-00533S). JV acknowledges institutional support of the Institute of Biophysics of the Czech Academy of Sciences (RVO: 68081707).

CRediT authorship contribution statement

**Jørn A. Holme:** Conceptualization, Writing – original draft, Writing – review & editing. **Jan Vondráček:** Writing – original draft, Writing – review & editing. **Miroslav Machala:** Writing – original draft, Writing – review & editing. **Dominique Lagadic-Gossmann:** Writing – original draft, Writing – review & editing. **Christoph F.A. Vogel:** Writing – original draft, Writing – review & editing. **Eric Le Ferrec:** Writing – original draft, Writing – review & editing. **Lydie Sparfel:** Writing – original draft, Writing – review & editing. **Johan Øvrevik:** Conceptualization, Supervision, Writing – original draft, Writing – review & editing, Visualization.

Declaration of Competing Interest

The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.

References

[1] S.H. Landis, T.Murray, S. Bolden, P.A.Wingo. Cancer statistics, 1999. CA Cancer J. Clin. 1999;49(1):8-31, 1.

[2] A. Jemal, M.J. Thun, L.A. Ries, H.L. Howe, H.K. Weir, M.M. Center, et al., Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control, J. Natl Cancer Inst. 100 (23) (2008) 1672-1694.

[3] H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin. 71 (3) (2021) 209-249.

[4] American Cancer Society Trusted Source A, Lung cancer and age: statistics, risk factors, and more, Healthline. (2021). https://www.healthline.com/health/lung-cancer/lung-cancer-age.

[5] W.H. Goodson 3rd, L. Lowe, D.O. Carpenter, M. Gilbertson, A. Manaf Ali, L. de Cerain, A. Salsamendi, et al., Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead, Carcinogenesis 36 Suppl 1 (Suppl 1) (2015) S254-S296.

[6] S. Sun, J.H. Schiller, A.F. Gazdar, Lung cancer in never smokers — a different disease, Nat. Rev. Cancer 7 (10) (2007) 778–790.

[7] H.E. Institute, H., State of global air 2020, Health Effects Institute, Boston, MA, US, 2020.
[8] Iarc, Outdoor air pollution, IARC Monogr. Eval. Carcinog. Risks Hum. 109 (2016) 33-444.

[9] Iarc, Diesel and gasoline engine exhausts and some nitroarenes, IARC Monogr. Eval. Carcinog. Risks Hum. 105 (2014) 9-699.

[10] IARC. Tobacco smoking., IARC Monogr. Eval. Carcinog. Risk Chem. Hum. 38 (1986) 35-394.

[11] Iarc, Tobacco smoke and involuntary smoking, IARC Monogr. Eval. Carcinog. Risks Hum. 83 (2004) 1-1438.

[12] Iarc, Household use of solid fuels and high-temperature frying, IARC Monogr. Eval. Carcinog. Risks Hum. 95 (2010) 1-430.

[13] L.C. Vinikoor-Imler, J.A. Davis, T.J. Luben, An ecologic analysis of county-level PM2.5 concentrations and lung cancer incidence and mortality, Int. J. Environ. Res. Public Health 8 (6) (2011) 1865-1871.

[14] S.P. Eckel, M. Cockburn, Y.H. Shu, H. Deng, F.W. Lurmann, L. Liu, et al., Air pollution affects lung cancer survival, Thorax 71 (10) (2016) 891-898.

[15] Bidoli E, Pappagallo M, Birri S, Frova L, Zanier L, Serraino D. Residential proximity to major roadways and lung cancer mortality. Italy. 2010-2016: An observational study. Int J Environ Res Public Health. 2016;13(2):191.

[16] Y. Shao, Y. Wang, H. Yu, Y. Zhang, F. Xiang, Y. Yang, et al., Geographical variation in lung cancer risk associated with road traffic in Jiading District, Shanghai. Sci Total Environ. 652 (2019) 729-735.

[17] S. Cakmak, C. Hebbern, J. Vanos, D.L. Crouse, M. Tjepkema, Exposure to traffic and mortality risk in the 1991-2011 Canadian Census Health and Environment Cohort (CanCHEC), Environ. Int. 124 (2019) 16-24.

[18] P. Vineis, G. Hoek, M. Krzyzanowski, F. Vigna-Taglianti, F. Veglia, L. Airoldi, et al., Lung cancers attributable to environmental tobacco smoke and air pollution in non-smokers in different European countries: a prospective study, Environ. Health 6 (2007) 7.

[19] S.N. Gowda, A.J. DeRoos, R.P. Hunt, A.J. Gassett, M.C. Mirabelli, C.E. Bird, et al., Ambient air pollution and lung cancer risk among never-smokers in the Women's Health Initiative, Environ Epidemiol. 3 (6) (2019) e076.

[20] L.D. Glaxton, G.M. Woodall Jr., A review of the mutagenicity and rodent carcinogenicity of ambient air, Mutat. Res. 636 (1-3) (2007) 36-94.

[21] C.C. Cho, W.Y. Hsieh, C.H. Tsai, C.Y. Chen, H.F. Chang, C.S. Lin, In vitro and in vivo experimental studies of PM(2.5) on disease progression, Int. J. Environ. Res. Public Health 15 (7) (2018).

[22] A. Nemmar, J.A. Holme, I. Rosas, P.E. Schwarze, E. Alfaro-Moreno, Recent advances in particulate matter and nanoparticle toxicology: a review of the in vivo and in vitro studies, Biomed Res. Int. 2013 (2013) 279371.

[23] F.R. Cassee, M.E. Héroux, M.E. Gerlofs-Nijland, F.J. Kelly, Particulate matter beyond mass: recent health evidence on the role of fractions, chemical constituents and sources of emission, Inhal. Toxicol. 25 (14) (2013) 802-812.

[24] D.M. DeMarini, W.P. Linak, Mutagenicity and carcinogenicity of combustion emissions are impacted more by comburstor technology than by fuel composition: a brief review, Environ. Mol. Mutagen. 63 (3) (2022) 135-150.

[25] C.E. Boström, P. Gerde, A. Hanberg, B. Jernström, C. Johansson, T. Kyrklund, et al., Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air, Environ. Health Perspect. 110 Suppl 3(Suppl 3) (2002) 451-488.

[26] K. Dreij, Å. Mattsson, I.W.H. Jarvis, H. Lim, J. Hurkmans, J. Gustafsson, et al., Cancer risk assessment of airborne PAHs based on in vitro mixture potency factors, Environ. Sci. Tech. 51 (15) (2017) 8805-8814.

[27] J. Vondracek, M. Machala, The role of metabolism in toxicity of polycyclic aromatic hydrocarbons and their non-genotoxic modes of action, Curr. Drug Metab. 22 (8) (2021) 584-595.

[28] M. Lag, J. Ovrevik, M. Refsnes, J.A. Holme, Potential role of polycyclic aromatic hydrocarbons in air pollution-induced non-malignant respiratory diseases, Respir. Res. 21 (1) (2020) 299.

[29] L. Benoit, F. Jornod, E. Zgheib, C. Tomkiewicz, M. Koual, T. Coustillet, et al., Adverse outcome pathway from activation of the AhR to breast cancer-related death, Environ. Int. 165 (2022), 107323.

[30] W.A. Cooper, D.C. Lam, S.A. O'Toole, J.D. Minna, Molecular biology of lung cancer, J. Thorac. Dis. 5 Suppl 5(Suppl 5) (2013) S479-S490.

[31] D.W. Nebert, T.P. Dalton, The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis, Nat. Rev. Cancer 6 (12) (2006) 947-960.

[32] J.J. Tsay, K.M. Tchou-Wong, A.K. Greenberg, H. Pass, W.N. Rom, Aryl hydrocarbon receptor and lung cancer, Anticancer Res 33 (4) (2013) 1247-1256.

[33] B. Shivanna, C. Chu, B. Moorthy, The aryl hydrocarbon receptor (AHR): A novel therapeutic target for pulmonary diseases? Int. J. Mol. Sci. 23 (3) (2022).

[34] M. Moserová, V. Kotrbová, D. Aimová, M. Sulc, E. Frei, M. Stiborová, Analysis of benzo[a]pyrene metabolites formed by rat hepatic microsomes using high pressure liquid chromatography: optimization of the method, Interdiscip. Toxicol. 2 (4) (2009) 239-244.

[35] D.W. Nebert, T.P. Dalton, A.B. Okey, F.J. Gonzalez, Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer, J. Biol. Chem. 279 (23) (2004) 23847-23850.

[36] Y. Shimizu, Y. Nakatsuru, M. Ichinose, Y. Takahashi, H. Kume, J. Mimura, et al., Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor, PNAS 97 (2) (2000) 779-782.

[37] T. Zhang, P. Joubert, N. Ansari-Pour, W. Zhao, P.H. Hoang, R. Lokanga, et al., Genomic and evolutionary classification of lung cancer in never smokers, Nat. Genet. 53 (9) (2021) 1348-1359.

[38] W. Hill, E.L. Lim, C.E. Weeden, C. Lee, M. Augustine, K. Chen, et al., Lung adenocarcinoma promotion by air pollutants, Nature 616 (7955) (2023) 159-167.

[39] H.C. Pitot, T. Goldsworthy, H.A. Campbell, A. Poland, Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine, Cancer Res. 40 (10) (1980) 3616-3620.

[40] A. Poland, D. Palen, E. Glover, Tumour promotion by TCDD in skin of HRS/J hairless mice, Nature 300 (5889) (1982) 271-273.

[41] H.P. Shu, D.J. Paustenbach, F.J. Murray, A critical evaluation of the use of mutagenesis, carcinogenesis, and tumor promotion data in a cancer risk assessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin, Regul. Toxicol. Pharm. 7 (1) (1987) 57-88.

[42] L.E. Beebe, M.R. Anver, C.W. Riggs, L.W. Fornwald, L.M. Anderson, Promotion of N-nitrosodimethylamine-initiated mouse lung tumors following single or multiple low dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin, Carcinogenesis 16 (6) (1995) 1345-1349.

[43] Z. Wang, M. Snyder, J.E. Kenison, K. Yang, B. Lara, E. Lydell, et al., How the AHR became important in cancer: The role of chronically active AHR in cancer aggression, Int. J. Mol. Sci. 22 (1) (2020).

[44] P. Xue, J. Fu, Y. Zhou, The aryl hydrocarbon receptor and tumor immunity, Front. Immunol. 9 (2018) 286.

[45] J. Øvrevik, M. Refsnes, M. Låg, J.A. Holme, P.E. Schwarze, Activation of proinflammatory responses in cells of the airway mucosa by particulate matter: oxidant- and non-oxidant-mediated triggering mechanisms, Biomolecules 5 (3) (2015) 1399-1440.

[46] NTP. Diesel exhaust particulates. 2011.

[47] A.I. Totlandsdal, J. Øvrevik, R.E. Cochran, J.I. Herseth, A.K. Bølling, M. Låg, et al., The occurrence of polycyclic aromatic hydrocarbons and their derivatives and the proinflammatory potential of fractionated extracts of diesel exhaust and wood smoke particles, J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng. 49 (4) (2014) 383-396.

[48] Y.-y. Li, D. Liang, H. Shen, An analysis of background interference on fire debris, Procedia Eng. 52 (2013) 664-670.

[49] R. Avagyan, R. Nyström, R. Lindgren, C. Boman, R. Westerholm, Particulate hydroxy-PAH emissions from a residential wood log stove using different fuels and burning conditions, Atmos. Environ. 140 (2016) 1-9.

[50] G.M. Karavalakis, T. Robledo, A. Miguel. A review of polycyclic aromatic hydrocarbon and polycyclic aromatic hydrocarbon derivative emissions from off-road, light-duty, heavy-duty, and stationary sources. University of California, Riverside, and Bourns College of Engineering-Center for Environmental Research and Technology (CE-CERT); 2020.

[51] A.H. Hartikainen, M. Ihalainen, P. Yli-Pirilä, L. Hao, M. Kortelainen, S.M. Pieber, et al., Photochemical transformation and secondary aerosol formation potential of Euro6 gasoline and diesel passenger car exhaust emissions, J. Aerosol Sci 171 (2023), 106159.

[52] S.M. Platt, I. El Haddad, S.M. Pieber, A.A. Zardini, R. Suarez-Bertoa, M. Clairotte, et al., Gasoline cars produce more carbonaceous particulate matter than modern filter-equipped diesel cars, Sci. Rep. 7 (1) (2017) 4926.

[53] T. Skuland, V.S. Grytting, M. Låg, R.B. Jørgensen, B. Snilsberg, D. Leseman, et al., Road tunnel-derived coarse, fine and ultrafine particulate matter: physical and chemical characterization and pro-inflammatory responses in human bronchial epithelial cells, Part. Fibre Toxicol. 19 (1) (2022) 45.

[54] J.A. Holme, M. Låg, T. Skuland, M. Parenicová, M. Ciganek, K. Pencíková, et al., Characterization of elements, PAHs, AhR-activity and pro-inflammatory responses of road tunnel-derived particulate matter in human hepatocyte-like and bronchial epithelial cells, Toxicol. In Vitro 90 (2023), 105611.

[55] A. Feilberg, M.W.B. Poulsen, T. Nielsen, H. Skov, Occurrence and sources of particulate nitro-polycyclic aromatic hydrocarbons in ambient air in Denmark, Atmos. Environ. 35 (2001) 353-366.

[56] K. Pěncíková, M. Ciganek, J. Neča, P. Illés, Z. Dvorák, J. Vondráček, et al., Modulation of endocrine nuclear receptor activities by polyaromatic compounds present in fractionated extracts of diesel exhaust particles, Sci. Total Environ. 677 (2019) 626-636.

[57] Y.-Y. Lee, Y.-K. Hsieh, B.-W. Huang, J.K. Mutuku, G.-P. Chang-Chien, S. Huang, An overview: PAH and nitro-PAH emission from the stationary sources and their transformations in the atmosphere, Aerosol Air Qual. Res. 22 (7) (2022), 220164.

[58] P.T. Scheepers, M.H. Martens, D.D. Velders, M. Fijneman, M. van Kerkhoven, J. Noordhoek, et al., 1-Nitropyrene as a marker for the mutagenicity of diesel exhaust-derived particulate matter in workplace atmospheres, Environ. Mol. Mutagen. 25 (2) (1995) 134-147.

[59] L. Páková, J. Vondráček, L. Trilecová, M. Ciganek, K. Pěncíková, J. Neča, et al., The aryl hydrocarbon receptor-mediated and genotoxic effects of fractionated extract of standard reference diesel exhaust particle material in pulmonary, liver and prostate cells, Toxicol. In Vitro 29 (3) (2015) 438-448.

[60] M. Gualtieri, J. Øvrevik, J.A. Holme, M.G. Perrone, E. Bolzacchini, P.E. Schwarze, et al., Differences in cytotoxicity versus pro-inflammatory potency of different PM fractions in human epithelial lung cells, Toxicol. In Vitro 24 (1) (2010) 29-39.

[61] T. Hu, J. Zhang, X. Xing, C. Zhan, L. Zhang, H. Liu, et al., Seasonal variation and health risk assessment of atmospheric PM2.5-bound polycyclic aromatic hydrocarbons in a classic agglomeration industrial city, central China, Air Qual. Atmos. Health 11 (6) (2018) 683-694.

[62] Y. Ishihara, S.Y. Kado, K.J. Bein, Y. He, A.A. Pouraryan, A. Urban, et al., Aryl hydrocarbon receptor signaling synergizes with TLR/NF-κB-signaling for induction of IL-22 through canonical and non-canonical AhR pathways, Front Toxicol. 3 (2021), 787360.

[63] T.M. Young, G.P. Black, L. Wong, C.S. Bloszies, O. Fiehn, G. He, et al., Identifying toxicologically significant compounds in urban wildfire ash using In vitro bioassays and high-resolution mass spectrometry, Environ. Sci. Tech. 55 (6) (2021) 3657-3667.
[8] Iarc, Outdoor air pollution, IARC Monogr. Eval. Carcinog. Risks Hum. 109 (2016) 33-444.

[9] Iarc, Diesel and gasoline engine exhausts and some nitroarenes, IARC Monogr. Eval. Carcinog. Risks Hum. 105 (2014) 9-699.

[10] IARC. Tobacco smoking., IARC Monogr. Eval. Carcinog. Risk Chem. Hum. 38 (1986) 35-394.

[11] Iarc, Tobacco smoke and involuntary smoking, IARC Monogr. Eval. Carcinog. Risks Hum. 83 (2004) 1-1438.

[12] Iarc, Household use of solid fuels and high-temperature frying, IARC Monogr. Eval. Carcinog. Risks Hum. 95 (2010) 1-430.

[13] L.C. Vinikoor-Imler, J.A. Davis, T.J. Luben, An ecologic analysis of county-level PM2.5 concentrations and lung cancer incidence and mortality, Int. J. Environ. Res. Public Health 8 (6) (2011) 1865-1871.

[14] S.P. Eckel, M. Cockburn, Y.H. Shu, H. Deng, F.W. Lurmann, L. Liu, et al., Air pollution affects lung cancer survival, Thorax 71 (10) (2016) 891-898.

[15] Bidoli E, Pappagallo M, Birri S, Frova L, Zanier L, Serraino D. Residential proximity to major roadways and lung cancer mortality. Italy. 2010-2016: An observational study. Int J Environ Res Public Health. 2016;13(2):191.

[16] Y. Shao, Y. Wang, H. Yu, Y. Zhang, F. Xiang, Y. Yang, et al., Geographical variation in lung cancer risk associated with road traffic in Jiading District, Shanghai. Sci Total Environ. 652 (2019) 729-735.

[17] S. Cakmak, C. Hebbern, J. Vanos, D.L. Crouse, M. Tjepkema, Exposure to traffic and mortality risk in the 1991-2011 Canadian Census Health and Environment Cohort (CanCHEC), Environ. Int. 124 (2019) 16-24.

[18] P. Vineis, G. Hoek, M. Krzyzanowski, F. Vigna-Taglianti, F. Veglia, L. Airoldi, et al., Lung cancers attributable to environmental tobacco smoke and air pollution in non-smokers in different European countries: a prospective study, Environ. Health 6 (2007) 7.

[19] S.N. Gowda, A.J. DeRoos, R.P. Hunt, A.J. Gassett, M.C. Mirabelli, C.E. Bird, et al., Ambient air pollution and lung cancer risk among never-smokers in the Women's Health Initiative, Environ Epidemiol. 3 (6) (2019) e076.

[20] L.D. Glaxton, G.M. Woodall Jr., A review of the mutagenicity and rodent carcinogenicity of ambient air, Mutat. Res. 636 (1-3) (2007) 36-94.

[21] C.C. Cho, W.Y. Hsieh, C.H. Tsai, C.Y. Chen, H.F. Chang, C.S. Lin, In vitro and in vivo experimental studies of PM(2.5) on disease progression, Int. J. Environ. Res. Public Health 15 (7) (2018).

[22] A. Nemmar, J.A. Holme, I. Rosas, P.E. Schwarze, E. Alfaro-Moreno, Recent advances in particulate matter and nanoparticle toxicology: a review of the in vivo and in vitro studies, Biomed Res. Int. 2013 (2013) 279371.

[23] F.R. Cassee, M.E. Héroux, M.E. Gerlofs-Nijland, F.J. Kelly, Particulate matter beyond mass: recent health evidence on the role of fractions, chemical constituents and sources of emission, Inhal. Toxicol. 25 (14) (2013) 802-812.

[24] D.M. DeMarini, W.P. Linak, Mutagenicity and carcinogenicity of combustion emissions are impacted more by combustor technology than by fuel composition: a brief review, Environ. Mol. Mutagen. 63 (3) (2022) 135-150.

[25] C.E. Boström, P. Gerde, A. Hanberg, B. Jernström, C. Johansson, T. Kyrklund, et al., Cancer risk assessment, indicators, and guidelines for polycyclic aromatic hydrocarbons in the ambient air, Environ. Health Perspect. 110 Suppl 3(Suppl 3) (2002) 451-488.

[26] K. Dreij, Å. Mattsson, I.W.H. Jarvis, H. Lim, J. Hurkmans, J. Gustafsson, et al., Cancer risk assessment of airborne PAHs based on in vitro mixture potency factors, Environ. Sci. Tech. 51 (15) (2017) 8805-8814.

[27] J. Vondracek, M. Machala, The role of metabolism in toxicity of polycyclic aromatic hydrocarbons and their non-genotoxic modes of action, Curr. Drug Metab. 22 (8) (2021) 584-595.

[28] M. Lag, J. Ovrevik, M. Refsnes, J.A. Holme, Potential role of polycyclic aromatic hydrocarbons in air pollution-induced non-malignant respiratory diseases, Respir. Res. 21 (1) (2020) 299.

[29] L. Benoit, F. Jornod, E. Zgheib, C. Tomkiewicz, M. Koual, T. Coustillet, et al., Adverse outcome pathway from activation of the AhR to breast cancer-related death, Environ. Int. 165 (2022), 107323.

[30] W.A. Cooper, D.C. Lam, S.A. O'Toole, J.D. Minna, Molecular biology of lung cancer, J. Thorac. Dis. 5 Suppl 5(Suppl 5) (2013) S479-S490.

[31] D.W. Nebert, T.P. Dalton, The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis, Nat. Rev. Cancer 6 (12) (2006) 947-960.

[32] J.J. Tsay, K.M. Tchou-Wong, A.K. Greenberg, H. Pass, W.N. Rom, Aryl hydrocarbon receptor and lung cancer, Anticancer Res 33 (4) (2013) 1247-1256.

[33] B. Shivanna, C. Chu, B. Moorthy, The aryl hydrocarbon receptor (AHR): A novel therapeutic target for pulmonary diseases? Int. J. Mol. Sci. 23 (3) (2022).

[34] M. Moserová, V. Kotrbová, D. Aimová, M. Sulc, E. Frei, M. Stiborová, Analysis of benzo[a]pyrene metabolites formed by rat hepatic microsomes using high pressure liquid chromatography: optimization of the method, Interdiscip. Toxicol. 2 (4) (2009) 239-244.

[35] D.W. Nebert, T.P. Dalton, A.B. Okey, F.J. Gonzalez, Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer, J. Biol. Chem. 279 (23) (2004) 23847-23850.

[36] Y. Shimizu, Y. Nakatsuru, M. Ichinose, Y. Takahashi, H. Kume, J. Mimura, et al., Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor, PNAS 97 (2) (2000) 779-782.

[37] T. Zhang, P. Joubert, N. Ansari-Pour, W. Zhao, P.H. Hoang, R. Lokanga, et al., Genomic and evolutionary classification of lung cancer in never smokers, Nat. Genet. 53 (9) (2021) 1348-1359.

[38] W. Hill, E.L. Lim, C.E. Weeden, C. Lee, M. Augustine, K. Chen, et al., Lung adenocarcinoma promotion by air pollutants, Nature 616 (7955) (2023) 159-167.

[39] H.C. Pitot, T. Goldsworthy, H.A. Campbell, A. Poland, Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine, Cancer Res. 40 (10) (1980) 3616-3620.

[40] A. Poland, D. Palen, E. Glover, Tumour promotion by TCDD in skin of HRS/J hairless mice, Nature 300 (5889) (1982) 271-273.

[41] H.P. Shu, D.J. Paustenbach, F.J. Murray, A critical evaluation of the use of mutagenesis, carcinogenesis, and tumor promotion data in a cancer risk assessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin, Regul. Toxicol. Pharm. 7 (1) (1987) 57-88.

[42] L.E. Beebe, M.R. Anver, C.W. Riggs, L.W. Fornwald, L.M. Anderson, Promotion of N-nitrosodimethylamine-initiated mouse lung tumors following single or multiple low dose exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin, Carcinogenesis 16 (6) (1995) 1345-1349.

[43] Z. Wang, M. Snyder, J.E. Kenison, K. Yang, B. Lara, E. Lydell, et al., How the AHR became important in cancer: The role of chronically active AHR in cancer aggression, Int. J. Mol. Sci. 22 (1) (2020).

[44] P. Xue, J. Fu, Y. Zhou, The aryl hydrocarbon receptor and tumor immunity, Front. Immunol. 9 (2018) 286.

[45] J. Øvrevik, M. Refsnes, M. Låg, J.A. Holme, P.E. Schwarze, Activation of proinflammatory responses in cells of the airway mucosa by particulate matter: oxidant- and non-oxidant-mediated triggering mechanisms, Biomolecules 5 (3) (2015) 1399-1440.

[46] NTP. Diesel exhaust particulates. 2011.

[47] A.I. Totlandsdal, J. Øvrevik, R.E. Cochran, J.I. Herseth, A.K. Bølling, M. Låg, et al., The occurrence of polycyclic aromatic hydrocarbons and their derivatives and the proinflammatory potential of fractionated extracts of diesel exhaust and wood smoke particles, J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng. 49 (4) (2014) 383-396.

[48] Y.-y. Li, D. Liang, H. Shen, An analysis of background interference on fire debris, Procedia Eng. 52 (2013) 664-670.

[49] R. Avagyan, R. Nyström, R. Lindgren, C. Boman, R. Westerholm, Particulate hydroxy-PAH emissions from a residential wood log stove using different fuels and burning conditions, Atmos. Environ. 140 (2016) 1-9.

[50] G.M. Karavalakis, T. Robledo, A. Miguel. A review of polycyclic aromatic hydrocarbon and polycyclic aromatic hydrocarbon derivative emissions from off-road, light-duty, heavy-duty, and stationary sources. University of California, Riverside, and Bourns College of Engineering-Center for Environmental Research and Technology (CE-CERT); 2020.

[51] A.H. Hartikainen, M. Ihalainen, P. Yli-Pirilä, L. Hao, M. Kortelainen, S.M. Pieber, et al., Photochemical transformation and secondary aerosol formation potential of Euro6 gasoline and diesel passenger car exhaust emissions, J. Aerosol Sci 171 (2023), 106159.

[52] S.M. Platt, I. El Haddad, S.M. Pieber, A.A. Zardini, R. Suarez-Bertoa, M. Clairotte, et al., Gasoline cars produce more carbonaceous particulate matter than modern filter-equipped diesel cars, Sci. Rep. 7 (1) (2017) 4926.

[53] T. Skuland, V.S. Grytting, M. Låg, R.B. Jørgensen, B. Snilsberg, D. Leseman, et al., Road tunnel-derived coarse, fine and ultrafine particulate matter: physical and chemical characterization and pro-inflammatory responses in human bronchial epithelial cells, Part. Fibre Toxicol. 19 (1) (2022) 45.

[54] J.A. Holme, M. Låg, T. Skuland, M. Parenicová, M. Ciganek, K. Pencíková, et al., Characterization of elements, PAHs, AhR-activity and pro-inflammatory responses of road tunnel-derived particulate matter in human hepatocyte-like and bronchial epithelial cells, Toxicol. In Vitro 90 (2023), 105611.

[55] A. Feilberg, M.W.B. Poulsen, T. Nielsen, H. Skov, Occurrence and sources of particulate nitro-polycyclic aromatic hydrocarbons in ambient air in Denmark, Atmos. Environ. 35 (2001) 353-366.

[56] K. Pěncíková, M. Ciganek, J. Neča, P. Illés, Z. Dvorák, J. Vondráček, et al., Modulation of endocrine nuclear receptor activities by polyaromatic compounds present in fractionated extracts of diesel exhaust particles, Sci. Total Environ. 677 (2019) 626-636.

[57] Y.-Y. Lee, Y.-K. Hsieh, B.-W. Huang, J.K. Mutuku, G.-P. Chang-Chien, S. Huang, An overview: PAH and nitro-PAH emission from the stationary sources and their transformations in the atmosphere, Aerosol Air Qual. Res. 22 (7) (2022), 220164.

[58] P.T. Scheepers, M.H. Martens, D.D. Velders, M. Fijneman, M. van Kerkhoven, J. Noordhoek, et al., 1-Nitropyrene as a marker for the mutagenicity of diesel exhaust-derived particulate matter in workplace atmospheres, Environ. Mol. Mutagen. 25 (2) (1995) 134-147.

[59] L. Páková, J. Vondráček, L. Trilecová, M. Ciganek, K. Pěncíková, J. Neča, et al., The aryl hydrocarbon receptor-mediated and genotoxic effects of fractionated extract of standard reference diesel exhaust particle material in pulmonary, liver and prostate cells, Toxicol. In Vitro 29 (3) (2015) 438-448.

[60] M. Gualtieri, J. Øvrevik, J.A. Holme, M.G. Perrone, E. Bolzacchini, P.E. Schwarze, et al., Differences in cytotoxicity versus pro-inflammatory potency of different PM fractions in human epithelial lung cells, Toxicol. In Vitro 24 (1) (2010) 29-39.

[61] T. Hu, J. Zhang, X. Xing, C. Zhan, L. Zhang, H. Liu, et al., Seasonal variation and health risk assessment of atmospheric PM2.5-bound polycyclic aromatic hydrocarbons in a classic agglomeration industrial city, central China, Air Qual. Atmos. Health 11 (6) (2018) 683-694.

[62] Y. Ishihara, S.Y. Kado, K.J. Bein, Y. He, A.A. Pouraryan, A. Urban, et al., Aryl hydrocarbon receptor signaling synergizes with TLR/NF-κB-signaling for induction of IL-22 through canonical and non-canonical AhR pathways, Front Toxicol. 3 (2021), 787360.

[63] T.M. Young, G.P. Black, L. Wong, C.S. Bloszies, O. Fiehn, G. He, et al., Identifying toxicologically significant compounds in urban wildfire ash using In vitro bioassays and high-resolution mass spectrometry, Environ. Sci. Tech. 55 (6) (2021) 3657-3667.
[64] J.L. Goldfarb, E.M. Suuberg, Vapor pressures and thermodynamics of oxygen-containing polycyclic aromatic hydrocarbons measured using Knudsen effusion, Environ. Toxicol. Chem. 27 (6) (2008) 1244-1249.

[65] A.L. Kramer, K.J. Suski, D.M. Bell, A. Zelenyuk, S.L. Massey Simonich, Formation of polycyclic aromatic hydrocarbon oxidation products in α-pinene secondary organic aerosol particles formed through ozonolysis, Environ. Sci. Tech. 53 (12) (2019) 6669-6677.

[66] M. Machala, M. Ciganek, L. Bláha, K. Minksová, J. Vondráck, Aryl hydrocarbon receptor-mediated and estrogenic activities of oxygenated polycyclic aromatic hydrocarbons and azapeines originally identified in extracts of river sediments, Environ. Toxicol. Chem. 20 (12) (2001) 2736-2743.

[67] M. Larsson, J. Hagberg, J.P. Giesy, M. Engwall, Time-dependent relative potency factors for polycyclic aromatic hydrocarbons and their derivatives in the H4IIE-luc bioassay, Environ. Toxicol. Chem. 33 (4) (2014) 943-953.

[68] S. McCarrick, V. Cunha, O. Zapletal, J. Vondráček, K. Dreij, In vitro and in vivo genotoxicity of oxygenated polycyclic aromatic hydrocarbons, Environ. Pollut. 246 (2019) 678-687.

[69] G. Lammel, Z. Kitanovski, P. Kukučka, J. Novák, A.M. Arangio, G.P. Codling, et al., Oxygenated and nitrated polycyclic aromatic hydrocarbons in ambient air-levels, phase partitioning, mass size distributions, and inhalation bioaccessibility, Environ. Sci. Tech. 54 (5) (2020) 2615-2625.

[70] N. van Zandwijk, W.J. Mooi, S. Rodenhuis, Prognostic factors in NSCLC, Recent experiences. Lung Cancer. 12 (Suppl 1) (1995) S27-S33.

[71] J.H. Schiller, Current standards of care in small-cell and non-small-cell lung cancer, Oncology 61 (Suppl 1) (2001) 3-13.

[72] S. Ramalingam, K. Pawlish, S. Gadgeel, R. Demers, G.P. Kalemkerian, Lung cancer in young patients: analysis of a surveillance, epidemiology, and end results database, J. Clin. Oncol. 16 (2) (1998) 651-657.

[73] J.M. Hanna, M.W. Onaitis, Cell of origin of lung cancer, J Carcinog. 12 (2013) 6.

[74] A. Giangreco, K.R. Groot, S.M. Janes, Lung cancer and lung stem cells: strange bedfellows? Am. J. Respir. Crit. Care Med. 175 (6) (2007) 547-553.

[75] J.E. Larsen, J.D. Minna, Molecular biology of lung cancer: clinical implications, Clin. Chest Med. 32 (4) (2011) 703-740.

[76] M. Hollstein, D. Sidransky, B. Vogelstein, C.C. Harris, p53 mutations in human cancers, Science 253 (5015) (1991) 49-53.

[77] S. Toyooka, T. Tsuda, A.F. Gazdar, The TP53 gene, tobacco exposure, and lung cancer, Hum. Mutat. 21 (3) (2003) 229-239.

[78] G.P. Pfeifer, M.F. Denissenko, M. Olivier, N. Tretyakova, S.S. Hecht, P. Hainaut, Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers, Oncogene 21 (48) (2002) 7435-7451.

[79] I. Ferrer, J. Zugazagoitia, S. Herbertz, W. John, L. Paz-Ares, G. Schmid-Bindert, KRAS-Mutant non-small cell lung cancer: from biology to therapy, Lung Cancer 124 (2018) 53-64.

[80] G. Pinheiro, T. Pereira, C. Dias, C. Freitas, V. Hespanhol, J.L. Costa, et al., Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS, Sci. Rep. 10 (1) (2020) 3625.

[81] P.C. Mack, M.I. Klein, K.L. Ayers, X. Zhou, S. Guin, M. Fink, et al., Targeted next-generation sequencing reveals exceptionally high rates of molecular driver mutations in never-smokers with lung adenocarcinoma, Oncologist 27 (6) (2022) 476-486.

[82] S.E. Jorge, S.S. Kobayashi, D.B. Costa, Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data, Braz. J. Med. Biol. Res. 47 (11) (2014) 929-939.

[83] P.T. Harrison, S. Vyse, P.H. Huang, Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, Semin. Cancer Biol. 61 (2020) 167-179.

[84] M. Smalley, A. Ashworth, Stem cells and breast cancer: a field in transit, Nat. Rev. Cancer 3 (11) (2003) 832-844.

[85] T. Fukui, R. Shaykhiev, F. Agosto-Perez, J.G. Mezey, R.J. Downey, W.D. Travis, et al., Lung adenocarcinoma subtypes based on expression of human airway basal cell genes, Eur. Respir. J. 42 (5) (2013) 1332-1344.

[86] J. Sainz de Aja, A.F.M. Dost, C.F. Kim, Alveolar progenitor cells and the origin of lung cancer, J. Intern. Med. 289 (5) (2021) 629-635.

[87] C. Mingard, J.N.D. Battey, V. Takhaveev, K. Blatter, V. Hürlimann, N. Sierro, et al., Dissection of cancer mutualist signatures with individual components of cigarette smoking, Chem. Res. Toxicol. 36 (4) (2023) 714-723.

[88] W.S. Heng, R. Gosens, F.A.E. Kruyt, Lung cancer stem cells: origin, features, maintenance mechanisms and therapeutic targeting, Biochem. Pharmacol. 160 (2019) 121-133.

[89] H. Canever, P.S. Carollo, R. Fleurisson, P.P. Girard, N. Borghi, Molecular tension microscopy of e-cadherin during epithelial-mesenchymal transition, Methods Mol. Biol. 2179 (2021) 289-299.

[90] S. Xie, Z. Wu, Y. Qi, B. Wu, X. Zhu, The metastasizing mechanisms of lung cancer: Recent advances and therapeutic challenges, Biomed. Pharmacother. 138 (2021), 111450.

[91] J. Liu, D. Li, H. Luo, X. Zhu, Circular RNAs: The star molecules in cancer, Mol. Aspects Med. 70 (2019) 141-152.

[92] L. Riva, A.R. Pandiri, Y.R. Li, A. Droop, J. Hewinson, M.A. Quail, et al., The mutational signature profile of known and suspected human carcinogens in mice, Nat. Genet. 52 (11) (2020) 1189-1197.

[93] M. Sayan, B.T. Mossman, The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases, Part. Fibre Toxicol. 13 (1) (2016) 51.

[94] P.J. Borm, L. Tran, K. Donaldson, The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism, Crit. Rev. Toxicol. 41 (9) (2011) 756-770.

[95] C. Paris, P. Do, B. Mastroianni, A. Dixmier, P. Dumont, E. Pichon, et al., Association between lung cancer somatic mutations and occupational exposure in never-smokers, Eur. Respir. J. 50 (4) (2017).

[96] C.F.A. Vogel, Y. Ishihara, C.E. Campbell, S.Y. Kado, A. Nguyen-Chi, C. Sweeney, et al., A protective role of aryl hydrocarbon receptor repressor in inflammation and tumor growth, Cancers (Basel) 11 (5) (2019).

[97] A.M. Frankell, M. Dietzen, M. Al Bakir, E.L. Lim, T. Karasaki, S. Ward, et al., The evolution of lung cancer and impact of subclonal selection in TRACERx, Nature (2023).

[98] C.H. Kim, Y.C. Lee, R.J. Hung, S.R. McNallan, M.L. Cote, W.Y. Lim, et al., Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO), Int. J. Cancer 135 (8) (2014) 1918-1930.

[99] C. Ge, S. Peters, A. Olsson, L. Portengen, J. Schuz, J. Almansa, et al., Diesel engine exhaust exposure, smoking, and lung cancer subtype risks, a pooled exposure-response analysis of 14 case-control studies, Am. J. Respir. Crit. Care Med. 202 (3) (2020) 402-411.

[100] O.P. Kurmi, P.H. Arya, K.B. Lam, T. Sorahan, J.G. Ayres, Lung cancer risk and solid fuel smoke exposure: a systematic review and meta-analysis, Eur. Respir. J. 40 (5) (2012) 1228-1237.

[101] R.F. Xavier, D. Ramos, J.T. Ito, F.M. Rodrigues, G.N. Bertolini, M. Macchione, et al., Effects of cigarette smoking intensity on the mucociliary clearance of active smokers, Respiration 86 (6) (2013) 479-485.

[102] A.E. Tilley, M.S. Walters, R. Shaykhiev, R.G. Crystal, Cilia dysfunction in lung disease, Annu. Rev. Physiol. 77 (2015) 379-406.

[103] Iarc, Some aromatic amines, organic dyes, and related exposures, France International Agency for Research on Cancer, Lyon, 2010.

[104] D. Loomis, Y. Grosse, B. Lauby-Secretan, F. El Ghissassi, V. Bouvard, L. Benbrahim-Tallaa, et al., The carcinogenicity of outdoor air pollution, Lancet Oncol. 14 (13) (2013) 1262-1263.

[105] J. Topinka, S. Marvanová, J. Vondrácek, O. Sevastyanova, Z. Nováková, P. Krcmár, et al., DNA adducts formation and induction of apoptosis in rat liver epithelial 'stem-like' cells exposed to carcinogenic polycyclic aromatic hydrocarbons, Mutat. Res. 638 (1-2) (2008) 122-132.

[106] L. Svihálková-Sindlerová, M. Machala, K. Pencíková, S. Marvanová, J. Neca, J. Topinka, et al., Dibenzanthracenes and benzochrysenes elicit both genotoxic and nongenotoxic events in rat liver 'stem-like' cells, Toxicology 232 (1-2) (2007) 147-159.

[107] S. Marvanová, J. Vondrácek, K. Pencíková, L. Trilecová, P. Krcmár, J. Topinka, et al., Toxic effects of methylated benz[a]anthracenes in liver cells, Chem. Res. Toxicol. 21 (2) (2008) 503-512.

[108] M. Machala, L. Svihálková-Sindlerová, K. Pencíková, P. Krcmár, J. Topinka, A. Milcová, et al., Effects of methylated chrysenes on AhR-dependent and independent toxic events in rat liver epithelial cells, Toxicology 247 (2-3) (2008) 93-101.

[109] L. Trilecová, S. Krčková, S. Marvanová, K. Pěncíková, P. Krčmár, J. Neca, et al., Toxic effects of methylated benzo[a]pyrenes in rat liver stem-like cells, Chem. Res. Toxicol. 24 (6) (2011) 866-876.

[110] Z. Andryšík, J. Vondrácek, S. Marvanová, M. Ciganek, J. Neca, K. Pencíková, et al., Activation of the aryl hydrocarbon receptor is the major toxic mode of action of an organic extract of a reference urban dust particulate matter mixture: the role of polycyclic aromatic hydrocarbons, Mutat. Res. 714 (1-2) (2011) 53-62.

[111] A.I. Totlandsdal, F.R. Cassee, P. Schwarze, M. Refsnes, M. Låg, Diesel exhaust particles induce CYP1A1 and pro-inflammatory responses via differential pathways in human bronchial epithelial cells, Part. Fibre Toxicol. 7 (2010) 41.

[112] I. Fizešan, A. Chary, S. Cambier, E. Moschini, T. Serchi, I. Nelissen, et al., Responsiveness assessment of a 3D tetra-culture alveolar model exposed to diesel exhaust particulate matter, Toxicol. In Vitro 53 (2018) 67-79.

[113] C. Sweeney, G. Lazennec, C.F.A. Vogel, Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer, Front. Pharmacol. 13 (2022) 1095289.

[114] J.M. Su, P. Lin, H. Chang, Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer, Anticancer Res 33 (9) (2013) 3953-3961.

[115] M. Ye, Y. Zhang, H. Gao, Y. Xu, P. Jing, J. Wu, et al., Activation of the aryl hydrocarbon receptor leads to resistance to EGFR TKIs in non-small cell lung cancer by activating Src-mediated bypass signaling, Clin. Cancer Res. 24 (5) (2018) 1227-1239.

[116] H. Feng, B. Cao, X. Peng, Q. Wei, Cancer-associated fibroblasts strengthen cell proliferation and EGFR TKIs resistance through aryl hydrocarbon receptor dependent signals in non-small cell lung cancer, BMC Cancer 22 (1) (2022) 764.

[117] A. Nacarino-Palma, C.M. Rejano-Gordillo, F.J. González-Rico, A. Ordiales-Talavero, Á.C. Román, M. Cuadrado, et al., Loss of aryl hydrocarbon receptor favors K-Ras(G12D)-driven non-small cell lung cancer, Cancers (Basel) 13 (16) (2021).

[118] C.A. Demetriou, O. Raaschou-Nielsen, S. Loft, P. Møller, R. Vermeulen, D. Palli, et al., Biomarkers of ambient air pollution and lung cancer: a systematic review, Occup. Environ. Med. 69 (2) (2012) 619-627.

[119] D.M. DeMarini, Genotoxicity biomarkers associated with exposure to traffic and near-road atmospheres: a review, Mutagenesis 28 (5) (2013) 485-505.

[120] V. Bonvallot, A. Baeza-Squiban, A. Baulig, S. Brulant, S. Boland, F. Muzeau, et al., Organic compounds from diesel exhaust particles elicit a proinflammatory response in human airway epithelial cells and induce cytochrome p450 1A1 expression, Am. J. Respir. Cell Mol. Biol. 25 (4) (2001) 515-521.
[64] J.L. Goldfarb, E.M. Suuberg, Vapor pressures and thermodynamics of oxygen-containing polycyclic aromatic hydrocarbons measured using Knudsen effusion, *Environ. Toxicol. Chem.* 27 (6) (2008) 1244–1249.

[65] A.L. Kramer, K.J. Suski, D.M. Bell, A. Zelenyuk, S.L. Massey Simonich, Formation of polycyclic aromatic hydrocarbon oxidation products in α-pinene secondary organic aerosol particles formed through ozonolysis, *Environ. Sci. Tech.* 53 (12) (2019) 6669–6677.

[66] M. Machala, M. Ciganek, L. Bláha, K. Minksová, J. Vondráck, Aryl hydrocarbon receptor-mediated and estrogenic activities of oxygenated polycyclic aromatic hydrocarbons and azaaresnes originally identified in extracts of river sediments, *Environ. Toxicol. Chem.* 20 (12) (2001) 2736–2743.

[67] M. Larsson, J. Hagberg, J.P. Giesy, M. Engwall, Time-dependent relative potency factors for polycyclic aromatic hydrocarbons and their derivatives in the H4IIE-luc bioassay, *Environ. Toxicol. Chem.* 33 (4) (2014) 943–953.

[68] S. McCarrick, V. Cunha, O. Zapletal, J. Vondráček, K. Dreij, In vitro and in vivo genotoxicity of oxygenated polycyclic aromatic hydrocarbons, *Environ. Pollut.* 246 (2019) 678–687.

[69] G. Lammel, Z. Kitanovski, P. Kukučka, J. Novák, A.M. Arangio, G.P. Codling, et al., Oxygenated and nitrated polycyclic aromatic hydrocarbons in ambient air-levels, phase partitioning, mass size distributions, and inhalation bioaccessibility, *Environ. Sci. Tech.* 54 (5) (2020) 2615–2625.

[70] N. van Zandwijk, W.J. Mooi, S. Rodenhuis, Prognostic factors in NSCLC, Recent experiences, *Lung Cancer.* 12 (Suppl 1) (1995) S27–S33.

[71] J.H. Schiller, Current standards of care in small-cell and non-small-cell lung cancer, *Oncology* 61 (Suppl 1) (2001) 3–13.

[72] S. Ramalingam, K. Pawlish, S. Gadgeel, R. Demers, G.P. Kalemkerian, Lung cancer in young patients: analysis of a surveillance, epidemiology, and end results database, *J. Clin. Oncol.* 16 (2) (1998) 651–657.

[73] J.M. Hanna, M.W. Onaitis, Cell of origin of lung cancer, *J Carcinog.* 12 (2013) 6.

[74] A. Giangreco, K.R. Groot, S.M. Janes, Lung cancer and lung stem cells: strange bedfellows? *Am. J. Respir. Crit. Care Med.* 175 (6) (2007) 547–553.

[75] J.E. Larsen, J.D. Minna, Molecular biology of lung cancer: clinical implications, *Clin. Chest Med.* 32 (4) (2011) 703–740.

[76] M. Hollstein, D. Sidransky, B. Vogelstein, C.C. Harris, p53 mutations in human cancers, *Science* 253 (5015) (1991) 49–53.

[77] S. Toyooka, T. Tsuda, A.F. Gazdar, The TP53 gene, tobacco exposure, and lung cancer, *Hum. Mutat.* 21 (3) (2003) 229–239.

[78] G.P. Pfeifer, M.F. Denissenko, M. Olivier, N. Tretyakova, S.S. Hecht, P. Hainaut, Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers, *Oncogene* 21 (48) (2002) 7435–7451.

[79] I. Ferrer, J. Zugazagoitia, S. Herbertz, W. John, L. Paz-Ares, G. Schmid-Bindert, KRAS-Mutant non-small cell lung cancer: from biology to therapy, *Lung Cancer* 124 (2018) 53–64.

[80] G. Pinheiro, T. Pereira, C. Dias, C. Freitas, V. Hespanhol, J.L. Costa, et al., Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS, *Sci. Rep.* 10 (1) (2020) 3625.

[81] P.C. Mack, M.I. Klein, K.L. Ayers, X. Zhou, S. Guin, M. Fink, et al., Targeted next-generation sequencing reveals exceptionally high rates of molecular driver mutations in never-smokers with lung adenocarcinoma, *Oncologist* 27 (6) (2022) 476–486.

[82] S.E. Jorge, S.S. Kobayashi, D.B. Costa, Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data, *Braz. J. Med. Biol. Res.* 47 (11) (2014) 929–939.

[83] P.T. Harrison, S. Vyse, P.H. Huang, Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, *Semin. Cancer Biol.* 61 (2020) 167–179.

[84] M. Smalley, A. Ashworth, Stem cells and breast cancer: a field in transit, *Nat. Rev. Cancer* 3 (11) (2003) 832–844.

[85] T. Fukui, R. Shaykhiev, F. Agosto-Perez, J.G. Mezey, R.J. Downey, W.D. Travis, et al., Lung adenocarcinoma subtypes based on expression of human airway basal cell genes, *Eur. Respir. J.* 42 (5) (2013) 1332–1344.

[86] J. Sainz de Aja, A.F.M. Dost, C.F. Kim, Alveolar progenitor cells and the origin of lung cancer, *J. Intern. Med.* 289 (5) (2021) 629–635.

[87] C. Mingard, J.N.D. Battey, V. Takhaveev, K. Blatter, V. Hürlimann, N. Sierro, et al., Dissection of cancer mutualist signatures with individual components of cigarette smoking, *Chem. Res. Toxicol.* 36 (4) (2023) 714–723.

[88] W.S. Heng, R. Gosens, F.A.E. Kruyt, Lung cancer stem cells: origin, features, maintenance mechanisms and therapeutic targeting, *Biochem. Pharmacol.* 160 (2019) 121–133.

[89] H. Canever, P.S. Carollo, R. Fleurisson, P.P. Girard, N. Borghi, Molecular tension microscopy of e-cadherin during epithelial-mesenchymal transition, *Methods Mol. Biol.* 2179 (2021) 289–299.

[90] S. Xie, Z. Wu, Y. Qi, B. Wu, X. Zhu, The metastasizing mechanisms of lung cancer: Recent advances and therapeutic challenges, *Biomed. Pharmacother.* 138 (2021), 111450.

[91] J. Liu, D. Li, H. Luo, X. Zhu, Circular RNAs: The star molecules in cancer, *Mol. Aspects Med.* 70 (2019) 141–152.

[92] L. Riva, A.R. Pandiri, Y.R. Li, A. Droop, J. Hewinson, M.A. Quail, et al., The mutational signature profile of known and suspected human carcinogens in mice, *Nat. Genet.* 52 (11) (2020) 1189–1197.

[93] M. Sayan, B.T. Mossman, The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases, *Part. Fibre Toxicol.* 13 (1) (2016) 51.

[94] P.J. Borm, L. Tran, K. Donaldson, The carcinogenic action of crystalline silica: a review of the evidence supporting secondary inflammation-driven genotoxicity as a principal mechanism, *Crit. Rev. Toxicol.* 41 (9) (2011) 756–770.

[95] C. Paris, P. Do, B. Mastroianni, A. Dixmier, P. Dumont, E. Pichon, et al., Association between lung cancer somatic mutations and occupational exposure in never-smokers, *Eur. Respir. J.* 50 (4) (2017).

[96] C.F.A. Vogel, Y. Ishihara, C.E. Campbell, S.Y. Kado, A. Nguyen-Chi, C. Sweeney, et al., A protective role of aryl hydrocarbon receptor repressor in inflammation and tumor growth, *Cancers* (Basel) 11 (5) (2019).

[97] A.M. Frankell, M. Dietzen, M. Al Bakir, E.L. Lim, T. Karasaki, S. Ward, et al., The evolution of lung cancer and impact of subclonal selection in TRACERx, *Nature* (2023).

[98] C.H. Kim, Y.C. Lee, R.J. Hung, S.R. McNallan, M.L. Cote, W.Y. Lim, et al., Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO), *Int. J. Cancer* 135 (8) (2014) 1918–1930.

[99] C. Ge, S. Peters, A. Olsson, L. Portengen, J. Schuz, J. Almansa, et al., Diesel engine exhaust exposure, smoking, and lung cancer subtype risks, a pooled exposure-response analysis of 14 case-control studies, *Am. J. Respir. Crit. Care Med.* 202 (3) (2020) 402–411.

[100] O.P. Kurmi, P.H. Arya, K.B. Lam, T. Sorahan, J.G. Ayres, Lung cancer risk and solid fuel smoke exposure: a systematic review and meta-analysis, *Eur. Respir. J.* 40 (5) (2012) 1228–1237.

[101] R.F. Xavier, D. Ramos, J.T. Ito, F.M. Rodrigues, G.N. Bertolini, M. Macchione, et al., Effects of cigarette smoking intensity on the mucociliary clearance of active smokers, *Respiration* 86 (6) (2013) 479–485.

[102] A.E. Tilley, M.S. Walters, R. Shaykhiev, R.G. Crystal, Cilia dysfunction in lung disease, *Annu. Rev. Physiol.* 77 (2015) 379–406.

[103] Iarc, Some aromatic amines, organic dyes, and related exposures, *France International Agency for Research on Cancer, Lyon, 2010*.

[104] D. Loomis, Y. Grosse, B. Lauby-Secretan, F. El Ghissassi, V. Bouvard, L. Benbrahim-Tallaa, et al., The carcinogenicity of outdoor air pollution, *Lancet Oncol.* 14 (13) (2013) 1262–1263.

[105] P. Topinka, S. Marvanová, J. Vondrácek, O. Sevastyanova, Z. Nováková, P. Krcmár, et al., DNA adducts formation and induction of apoptosis in rat liver epithelial 'stem-like' cells exposed to carcinogenic polycyclic aromatic hydrocarbons, *Mutat. Res.* 638 (1–2) (2008) 122–132.

[106] L. Svihálková-Sindlerová, M. Machala, K. Pencíková, S. Marvanová, J. Neca, J. Topinka, et al., Dibenzanthracenes and benzochrysenes elicit both genotoxic and nongenotoxic events in rat liver 'stem-like' cells, *Toxicology* 232 (1–2) (2007) 147–159.

[107] S. Marvanová, J. Vondrácek, K. Pencíková, L. Trilecová, P. Krcmár, J. Topinka, et al., Toxic effects of methylated benz[a]anthracenes in liver cells, *Chem. Res. Toxicol.* 21 (2) (2008) 503–512.

[108] M. Machala, L. Svihálková-Sindlerová, K. Pencíková, P. Krcmár, J. Topinka, A. Milcová, et al., Effects of methylated chrysenes on AhR-dependent and independent toxic events in rat liver epithelial cells, *Toxicology* 247 (2–3) (2008) 93–101.

[109] L. Trilecová, S. Krčková, S. Marvanová, K. Pěncíková, P. Krčmár, J. Neca, et al., Toxic effects of methylated benzo[a]pyrenes in rat liver stem-like cells, *Chem. Res. Toxicol.* 24 (6) (2011) 866–876.

[110] Z. Andryšík, J. Vondrácek, S. Marvanová, M. Ciganek, J. Neca, K. Pencíková, et al., Activation of the aryl hydrocarbon receptor is the major toxic mode of action of an organic extract of a reference urban dust particulate matter mixture: the role of polycyclic aromatic hydrocarbons, *Mutat. Res.* 714 (1–2) (2011) 53–62.

[111] A.I. Totlandsdal, F.R. Cassee, P. Schwarze, M. Refsnes, M. Låg, Diesel exhaust particles induce CYP1A1 and pro-inflammatory responses via differential pathways in human bronchial epithelial cells, *Part. Fibre Toxicol.* 7 (2010) 41.

[112] I. Fizešan, A. Chary, S. Cambier, E. Moschini, T. Serchi, I. Nelissen, et al., Responsiveness assessment of a 3D tetra-culture alveolar model exposed to diesel exhaust particulate matter, *Toxicol. In Vitro* 53 (2018) 67–79.

[113] C. Sweeney, G. Lazennec, C.F.A. Vogel, Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer, *Front. Pharmacol.* 13 (2022) 1095289.

[114] J.M. Su, P. Lin, H. Chang, Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer, *Anticancer Res* 33 (9) (2013) 3953–3961.

[115] M. Ye, Y. Zhang, H. Gao, Y. Xu, P. Jing, J. Wu, et al., Activation of the aryl hydrocarbon receptor leads to resistance to EGFR TKIs in non-small cell lung cancer by activating Src-mediated bypass signaling, *Clin. Cancer Res.* 24 (5) (2018) 1227–1239.

[116] H. Feng, B. Cao, X. Peng, Q. Wei, Cancer-associated fibroblasts strengthen cell proliferation and EGFR TKIs resistance through aryl hydrocarbon receptor dependent signals in non-small cell lung cancer, *BMC Cancer* 22 (1) (2022) 764.

[117] A. Nacarino-Palma, C.M. Rejano-Gordillo, F.J. González-Rico, A. Ordiales-Talavero, Á.C. Román, M. Cuadrado, et al., Loss of aryl hydrocarbon receptor favors K-Ras(G12D)-driven non-small cell lung cancer, *Cancers* (Basel) 13 (16) (2021).

[118] C.A. Demetriou, O. Raaschou-Nielsen, S. Loft, P. Møller, R. Vermeulen, D. Palli, et al., Biomarkers of ambient air pollution and lung cancer: a systematic review, *Occup. Environ. Med.* 69 (2) (2012) 619–627.

[119] D.M. DeMarini, Genotoxicity biomarkers associated with exposure to traffic and near-road atmospheres: a review, *Mutagenesis* 28 (5) (2013) 485–505.

[120] V. Bonvallot, A. Baeza-Squiban, A. Baulig, S. Brulant, S. Boland, F. Muzeau, et al., Organic compounds from diesel exhaust particles elicit a proinflammatory response in human airway epithelial cells and induce cytochrome p450 1A1 expression, *Am. J. Respir. Cell Mol. Biol.* 25 (4) (2001) 515–521.
[121] J.A. Cavanagh, K. Trought, L. Brown, S. Duggan, Exploratory investigation of the chemical characteristics and relative toxicity of ambient air particulates from two New Zealand cities, Sci. Total Environ. 407 (18) (2009) 5007–5018.

[122] B. Moorthy, C. Chu, D.J. Carlin, Polycyclic aromatic hydrocarbons: from metabolism to lung cancer, Toxicol. Sci. 145 (1) (2015) 5–15.

[123] W. Xue, D. Warshawsky, Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review, Toxicol. Appl. Pharmacol. 206 (1) (2005) 73–93.

[124] F. Henkler, K. Stolpmann, A. Luch, Exposure to polycyclic aromatic hydrocarbons: bulky DNA adducts and cellular responses, Exp Suppl. 101 (2012) 107–131.

[125] T.M. Penning, Human aldo-keto reductases and the metabolic activation of polycyclic aromatic hydrocarbons, Chem. Res. Toxicol. 27 (11) (2014) 1901–1917.

[126] T. Oyama, K. Sugio, H. Uramoto, T. Kawamoto, N. Kagawa, S. Nadaf, et al., Cytochrome P450 expression (CYP) in non-small cell lung cancer, Front Biosci 12 (2007) 2299–2308.

[127] P. Zhan, Q. Wang, Q. Qian, S.Z. Wei, L.K. Yu, CYP1A1 MspI and exon7 gene polymorphisms and lung cancer risk: an updated meta-analysis and review, J. Exp. Clin. Cancer Res. 30 (1) (2011) 99.

[128] Z. Chen, Z. Li, X. Niu, X. Ye, Y. Yu, S. Lu, et al., The effect of CYP1A1 polymorphisms on the risk of lung cancer: a global meta-analysis based on 71 case-control studies, Mutagenesis 26 (3) (2011) 437–446.

[129] C. Liu, H. Cui, D. Gu, M. Zhang, Y. Fang, S. Chen, et al., Genetic polymorphisms and lung cancer risk: Evidence from meta-analyses and genome-wide association studies, Lung Cancer 113 (2017) 18–29.

[130] D.W. Nebert, Z. Shi, M. Gálvez-Peralta, S. Uno, N. Dragin, Oral benzo[a]pyrene: understanding pharmacokinetics, detoxication, and consequences-Cyp1 knockout mouse lines as a paradigm, Mol. Pharmacol. 84 (3) (2013) 304–313.

[131] J. Vondrářek, J. Pivnická, M. Machala, Polycyclic aromatic hydrocarbons and disruption of steroid signaling, Current Opinion in Toxicology. 11–12 (2018) 27–34.

[132] S.K. Kolluri, U.H. Jin, S. Safe, Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target, Arch. Toxicol. 91 (7) (2017) 2497–2513.

[133] A.J. Murk, J. Legler, M.S. Denison, J.P. Giesy, C. van de Guchte, A. Brouwer, Chemical-activated luciferase gene expression (CALUX): a novel in vitro bioassay for Ah receptor active compounds in sediments and pore water, Fundam. Appl. Toxicol. 33 (1) (1996) 149–160.

[134] M. Machala, J. Vondrářek, L. Bláha, M. Ciganek, J.V. Neca, Aryl hydrocarbon receptor-mediated activity of mutagenic polycyclic aromatic hydrocarbons determined using in vitro reporter gene assay, Mutat. Res. 497 (1–2) (2001) 49–62.

[135] M. Larsson, D. Orbe, M. Engwall, Exposure time-dependent effects on the relative potencies and additivity of PAHs in the Ah receptor-mediated H4IIE-luc bioassay, Environ. Toxicol. Chem. 31 (5) (2012) 1149–1157.

[136] B. Pieterse, E. Felzel, R. Winter, B. van der Burg, A. Brouwer, PAH-CALUX, an optimized bioassay for AhR-mediated hazard identification of polycyclic aromatic hydrocarbons (PAHs) as individual compounds and in complex mixtures, Environ. Sci. Tech. 47 (20) (2013) 11651–11659.

[137] J. Vondrářek, K. Pěncíková, J. Neca, M. Ciganek, A. Grycová, Z. Dvorák, et al., Assessment of the aryl hydrocarbon receptor-mediated activities of polycyclic aromatic hydrocarbons in a human cell-based reporter gene assay, Environ. Pollut. 220 (Pt A) (2017) 307–316.

[138] A. Novotna, P. Pavek, Z. Dvorak, Novel stably transfected gene reporter human hepatoma cell line for assessment of aryl hydrocarbon receptor transcriptional activity: construction and characterization, Environ. Sci. Tech. 45 (23) (2011) 10133–10139.

[139] J.T. Burgess, M. Rose, D. Boucher, J. Plowman, C. Molloy, M. Fisher, et al., The therapeutic potential of DNA damage repair pathways and genomic stability in lung cancer, Front. Oncol. 10 (2020) 1256.

[140] R. De Bont, N. van Larebeke, Endogenous DNA damage in humans: a review of quantitative data, Mutagenesis 19 (3) (2004) 169–185.

[141] J.P. Melis, H. van Steeg, M. Luijten, Oxidative DNA damage and nucleotide excision repair, Antioxid. Redox Signal. 18 (18) (2013) 2409–2419.

[142] A. Nikolaev, E.S. Yang, The impact of DNA repair pathways in cancer biology and therapy, Cancer (Basel) 9 (9) (2017).

[143] T. Lindahl, Instability and decay of the primary structure of DNA, Nature 362 (6422) (1993) 709–715.

[144] C. Greenman, P. Stephens, R. Smith, G.L. Dalgliesh, C. Hunter, G. Bignell, et al., Patterns of somatic mutation in human cancer genomes, Nature 446 (7132) (2007) 153–158.

[145] M.C. Tammemagi, J.R. McLaughlin, S.B. Bull, Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers, Cancer Epidemiol. Biomarkers Prev. 8 (7) (1999) 625–634.

[146] R. Nahta, F. Al-Mulla, R. Al-Temaimi, A. Amedei, R. Andrade-Vieira, S.N. Bay, et al., Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression, Carcinogenesis (2015;36 Suppl 1(Suppl 1),) S2–S.

[147] D.M. DeMarini, M.L. Shelton, D.A. Bell, Mutation spectra in Salmonella of complex mixtures: comparison of urban air to benzo[a]pyrene, Environ. Mol. Mutagen. 24 (4) (1994) 262–275.

[148] J.L. Durant, W.F. Busby Jr., A.L. Lafleur, B.W. Penman, C.L. Crespi, Human cell mutagenicity of oxygenated, nitrated and unsubstituted polycyclic aromatic hydrocarbons associated with urban aerosols, Mutat. Res. 371 (3–4) (1996) 123–157.

[149] J.L. Durant, A.L. Lafleur, W.F. Busby Jr., L.L. Donhoffner, B.W. Penman, C. L. Crespi, Mutagenicity of C24H14 PAH in human cells expressing CYP1A1, Mutat. Res. 446 (1) (1999) 1–14.

[150] I.C. Nisbet, P.K. LaGoy, Toxic equivalency factors (TEFs) for polycyclic aromatic hydrocarbons (PAHs), Regul. Toxicol. Pharm. 16 (3) (1992) 290–300.

[151] M.F. de Oliveira Galvão, I. Sadiktsis, T. Marques Pedro, K. Dreij, Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials, Environ. Int. 166 (2022), 107345.

[152] S.C. Chen, C.M. Liao, Health risk assessment on human exposed to environmental polycyclic aromatic hydrocarbons pollution sources, Sci. Total Environ. 366 (1) (2006) 112–123.

[153] R. Roy, R. Jan, G. Gunjal, R. Bhor, K. Pai, P.G. Satsangi, Particulate matter bound polycyclic aromatic hydrocarbons: Toxicity and health risk assessment of exposed inhabitants, Atmos. Environ. 210 (2019) 47–57.

[154] H.Y. Tong, F.W. Karasek, Quantitation of polycyclic aromatic hydrocarbons in diesel exhaust particulate matter by high-performance liquid chromatography fractionation and high-resolution gas chromatography, Anal. Chem. 56 (12) (1984) 2129–2134.

[155] S. Nesnow, J.A. Ross, G. Nelson, K. Wilson, B.C. Roop, A.J. Jeffers, et al., Cyclopenta[cd]pyrene-induced tumorigenicity, Ki-ras codon 12 mutations and DNA adducts in strain A/J mouse lung, Carcinogenesis 15 (4) (1994) 601–606.

[156] J. Vondrářek, K. Pěncíková, M. Ciganek, J. Pivnická, M. Karasová, M. Hýžďalová, et al., Environmental six-ring polycyclic aromatic hydrocarbons are potent inducers of the AhR-dependent signaling in human cells, Environ. Pollut. 266 (Pt 2) (2020), 115125.

[157] J.H. Park, S. Gelhaus, S. Vedantam, A.L. Oliva, A. Batra, I.A. Blair, et al., The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance, Chem. Res. Toxicol. 21 (5) (2008) 1039–1049.

[158] S.P. Hussain, P. Amstad, K. Raja, M. Sawyer, L. Hofseth, P.G. Shields, et al., Mutability of p53 hotspot codons to benzo[a]pyrene di epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung, Cancer Res. 61 (17) (2001) 6350–6355.

[159] L. Umannová, M. Machala, J. Topinka, J. Schmuczerová, P. Krčmář, J. Neča, et al., Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells, Toxicol. Lett. 206 (2) (2011) 121–129.

[160] L. Smerdová, J. Smerdová, M. Kabátková, J. Kohoutek, D. Blažek, M. Machala, et al., Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway, Carcinogenesis 35 (11) (2014) 2534–2543.

[161] S.N. Rodin, A.S. Rodin, Human lung cancer and p53: the interplay between mutagenesis and selection, PNAS 97 (22) (2000) 12244–12249.

[162] P. Keohavong, A. Melacrinos, R. Shukla, In vitro mutational spectrum of cyclopenta[cd]pyrene in the human HPRT gene, Carcinogenesis 16 (4) (1995) 855–860.

[163] D.M. DeMarini, Influence of DNA repair on mutation spectra in Salmonella, Mutat. Res. 450 (1–2) (2000) 5–17.

[164] L.B. Alexandrov, S. Nik-Zainal, D.C. Wedge, S.A. Aparicio, S. Behjati, A. V. Biankin, et al., Signatures of mutational processes in human cancer, Nature 500 (7463) (2013) 415–421.

[165] L.B. Alexandrov, J. Kim, N.J. Haradhvala, M.N. Huang, A.W. Tian Ng, Y. Wu, et al., The repertoire of mutational signatures in human cancer, Nature 578 (7793) (2020) 94–101.

[166] H. Nakagawa, M. Fujita, Whole genome sequencing analysis for cancer genomics and precision medicine, Cancer Sci. 109 (3) (2018) 513–522.

[167] J.E. Kucab, X. Zou, S. Morganella, M. Joel, A.S. Nanda, E. Nagy, et al., A compendium of mutational signatures of environmental agents. Cell. 2019;177 (4):821-36.e16.

[168] E. Seeberg, A.L. Steinum, M. Nordenskjöld, S. Söderhäll, B. Jernström, Strand- break formation in DNA modified by benzo[alpha]pyrene dioleoxide. Quantitative cleavage by Escherichia coli uvrABC endonuclease, Mutat. Res. 112 (3) (1983) 139–145.

[169] S.L. Hockley, V.M. Arlt, D. Brewer, R. Te Poele, P. Workman, I. Giddings, et al., AHR- and DNA-damage-mediated gene expression responses induced by benzo(a) pyrene in human cell lines, Chem. Res. Toxicol. 20 (12) (2007) 1797–1810.

[170] R.A. Clewell, C.M. Thompson, H.J. Clewell 3rd., Dose-dependence of chemical carcinogenicity: Biological mechanisms for thresholds and implications for risk assessment, Chem. Biol. Interact. 301 (2019) 112–127.

[171] A. Hartwig, M. Arand, B. Epe, S. Guth, G. Jahnke, A. Lampen, et al., Mode of action-based risk assessment of genotoxic carcinogens, Arch. Toxicol. 94 (6) (2020) 1787–1877.

[172] J.A. Holme, B. Trygg, E. Søderlund, Species differences in the metabolism of 2-acetylaminofluorene by hepatocytes in primary monolayer culture, Cancer Res. 46 (4 Pt 1) (1986) 1627–1632.

[173] U. Rannug, J.A. Holme, J.K. Hongslo, R. Srám, International commission for protection against environmental mutagens and carcinogens, an evaluation of the genetic toxicity of paracetamol, Mutat. Res. 327 (1–2) (1995) 179–200.

[174] J.L. Barnes, M. Zubair, K. John, M.C. Poirier, F.L. Martin, Carcinogens and DNA damage, Biochem. Soc. Trans. 46 (5) (2018) 1213–1224.

[175] H. Lu, M. Yang, Q. Zhou, Reprogramming transcription after DNA damage: recognition, response, repair, and restart, Trends Cell Biol. (2022).

[176] J. Øvrevik, M. Refsnes, M. Lag, B.C. Brinchmann, P.E. Schwarze, J.A. Holme, Triggering mechanisms and inflammatory effects of combustion exhaust particles
[121] J.A. Cavanagh, K. Trought, L. Brown, S. Duggan, Exploratory investigation of the chemical characteristics and relative toxicity of ambient air particulates from two New Zealand cities, Sci. Total Environ. 407 (18) (2009) 5007–5018.

[122] B. Moorthy, C. Chu, D.J. Carlin, Polycyclic aromatic hydrocarbons: from metabolism to lung cancer, Toxicol. Sci. 145 (1) (2015) 5–15.

[123] W. Xue, D. Warshawsky, Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review, Toxicol. Appl. Pharmacol. 206 (1) (2005) 73–93.

[124] F. Henkler, K. Stolpmann, A. Luch, Exposure to polycyclic aromatic hydrocarbons: bulky DNA adducts and cellular responses, Exp Suppl. 101 (2012) 107–131.

[125] T.M. Penning, Human aldo-keto reductases and the metabolic activation of polycyclic aromatic hydrocarbons, Chem. Res. Toxicol. 27 (11) (2014) 1901–1917.

[126] T. Oyama, K. Sugio, H. Uramoto, T. Kawamoto, N. Kagawa, S. Nadaf, et al., Cytochrome P450 expression (CYP) in non-small cell lung cancer, Front Biosci 12 (2007) 2299–2308.

[127] P. Zhan, Q. Wang, Q. Qian, S.Z. Wei, L.K. Yu, CYP1A1 MspI and exon7 gene polymorphisms and lung cancer risk: an updated meta-analysis and review, J. Exp. Clin. Cancer Res. 30 (1) (2011) 99.

[128] Z. Chen, Z. Li, X. Niu, X. Ye, Y. Yu, S. Lu, et al., The effect of CYP1A1 polymorphisms on the risk of lung cancer: a global meta-analysis based on 71 case-control studies, Mutagenesis 26 (3) (2011) 437–446.

[129] C. Liu, H. Cui, D. Gu, M. Zhang, Y. Fang, S. Chen, et al., Genetic polymorphisms and lung cancer risk: Evidence from meta-analyses and genome-wide association studies, Lung Cancer 113 (2017) 18–29.

[130] D.W. Nebert, Z. Shi, M. Gálvez-Peralta, S. Uno, N. Dragin, Oral benzo[a]pyrene: understanding pharmacokinetics, detoxication, and consequences-Cyp1 knockout mouse lines as a paradigm, Mol. Pharmacol. 84 (3) (2013) 304–313.

[131] J. Vondrářek, J. Pivnická, M. Machala, Polycyclic aromatic hydrocarbons and disruption of steroid signaling, Current Opinion in Toxicology. 11–12 (2018) 27–34.

[132] S.K. Kolluri, U.H. Jin, S. Safe, Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target, Arch. Toxicol. 91 (7) (2017) 2497–2513.

[133] A.J. Murk, J. Legler, M.S. Denison, J.P. Giesy, C. van de Guchte, A. Brouwer, Chemical-activated luciferase gene expression (CALUX): a novel in vitro bioassay for Ah receptor active compounds in sediments and pore water, Fundam. Appl. Toxicol. 33 (1) (1996) 149–160.

[134] M. Machala, J. Vondrářek, L. Bláha, M. Ciganek, J.V. Neca, Aryl hydrocarbon receptor-mediated activity of mutagenic polycyclic aromatic hydrocarbons determined using in vitro reporter gene assay, Mutat. Res. 497 (1–2) (2001) 49–62.

[135] M. Larsson, D. Orbe, M. Engwall, Exposure time-dependent effects on the relative potencies and additivity of PAHs in the Ah receptor-mediated H4IIE-luc bioassay, Environ. Toxicol. Chem. 31 (5) (2012) 1149–1157.

[136] B. Pieterse, E. Felzel, R. Winter, B. van der Burg, A. Brouwer, PAH-CALUX, an optimized bioassay for AhR-mediated hazard identification of polycyclic aromatic hydrocarbons (PAHs) as individual compounds and in complex mixtures, Environ. Sci. Tech. 47 (20) (2013) 11651–11659.

[137] J. Vondrářek, K. Pěncíková, J. Neca, M. Ciganek, A. Grycová, Z. Dvorák, et al., Assessment of the aryl hydrocarbon receptor-mediated activities of polycyclic aromatic hydrocarbons in a human cell-based reporter gene assay, Environ. Pollut. 220 (Pt A) (2017) 307–316.

[138] A. Novotna, P. Pavek, Z. Dvorak, Novel stably transfected gene reporter human hepatoma cell line for assessment of aryl hydrocarbon receptor transcriptional activity: construction and characterization, Environ. Sci. Tech. 45 (23) (2011) 10133–10139.

[139] J.T. Burgess, M. Rose, D. Boucher, J. Plowman, C. Molloy, M. Fisher, et al., The therapeutic potential of DNA damage repair pathways and genomic stability in lung cancer, Front. Oncol. 10 (2020) 1256.

[140] R. De Bont, N. van Larebeke, Endogenous DNA damage in humans: a review of quantitative data, Mutagenesis 19 (3) (2004) 169–185.

[141] J.P. Melis, H. van Steeg, M. Luijten, Oxidative DNA damage and nucleotide excision repair, Antioxid. Redox Signal. 18 (18) (2013) 2409–2419.

[142] A. Nikolaev, E.S. Yang, The impact of DNA repair pathways in cancer biology and therapy, Cancer (Basel) 9 (9) (2017).

[143] T. Lindahl, Instability and decay of the primary structure of DNA, Nature 362 (6422) (1993) 709–715.

[144] C. Greenman, P. Stephens, R. Smith, G.L. Dalgliesh, C. Hunter, G. Bignell, et al., Patterns of somatic mutation in human cancer genomes, Nature 446 (7132) (2007) 153–158.

[145] M.C. Tammemagi, J.R. McLaughlin, S.B. Bull, Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers, Cancer Epidemiol. Biomarkers Prev. 8 (7) (1999) 625–634.

[146] R. Nahta, F. Al-Mulla, R. Al-Temaimi, A. Amedei, R. Andrade-Vieira, S.N. Bay, et al., Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression, Carcinogenesis (2015;36 Suppl 1(Suppl 1),) S2–S.

[147] D.M. DeMarini, M.L. Shelton, D.A. Bell, Mutation spectra in Salmonella of complex mixtures: comparison of urban air to benzo[a]pyrene, Environ. Mol. Mutagen. 24 (4) (1994) 262–275.

[148] J.L. Durant, W.F. Busby Jr., A.L. Lafleur, B.W. Penman, C.L. Crespi, Human cell mutagenicity of oxygenated, nitrated and unsubstituted polycyclic aromatic hydrocarbons associated with urban aerosols, Mutat. Res. 371 (3–4) (1996) 123–157.

[149] J.L. Durant, A.L. Lafleur, W.F. Busby Jr., L.L. Donhoffner, B.W. Penman, C. L. Crespi, Mutagenicity of C24H14 PAH in human cells expressing CYP1A1, Mutat. Res. 446 (1) (1999) 1–14.

[150] I.C. Nisbet, P.K. LaGoy, Toxic equivalency factors (TEFs) for polycyclic aromatic hydrocarbons (PAHs), Regul. Toxicol. Pharm. 16 (3) (1992) 290–300.

[151] M.F. de Oliveira Galvão, I. Sadiktsis, T. Marques Pedro, K. Dreij, Determination of whole mixture-based potency factors for cancer risk assessment of complex environmental mixtures by in vitro testing of standard reference materials, Environ. Int. 166 (2022), 107345.

[152] S.C. Chen, C.M. Liao, Health risk assessment on human exposed to environmental polycyclic aromatic hydrocarbons pollution sources, Sci. Total Environ. 366 (1) (2006) 112–123.

[153] R. Roy, R. Jan, G. Gunjal, R. Bhor, K. Pai, P.G. Satsangi, Particulate matter bound polycyclic aromatic hydrocarbons: Toxicity and health risk assessment of exposed inhabitants, Atmos. Environ. 210 (2019) 47–57.

[154] H.Y. Tong, F.W. Karasek, Quantitation of polycyclic aromatic hydrocarbons in diesel exhaust particulate matter by high-performance liquid chromatography fractionation and high-resolution gas chromatography, Anal. Chem. 56 (12) (1984) 2129–2134.

[155] S. Nesnow, J.A. Ross, G. Nelson, K. Wilson, B.C. Roop, A.J. Jeffers, et al., Cyclopenta[cd]pyrene-induced tumorigenicity, Ki-ras codon 12 mutations and DNA adducts in strain A/J mouse lung, Carcinogenesis 15 (4) (1994) 601–606.

[156] J. Vondrářek, K. Pěncíková, M. Ciganek, J. Pivnická, M. Karasová, M. Hýžďalová, et al., Environmental six-ring polycyclic aromatic hydrocarbons are potent inducers of the AhR-dependent signaling in human cells, Environ. Pollut. 266 (Pt 2) (2020), 115125.

[157] J.H. Park, S. Gelhaus, S. Vedantam, A.L. Oliva, A. Batra, I.A. Blair, et al., The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance, Chem. Res. Toxicol. 21 (5) (2008) 1039–1049.

[158] S.P. Hussain, P. Amstad, K. Raja, M. Sawyer, L. Hofseth, P.G. Shields, et al., Mutability of p53 hotspot codons to benzo[a]pyrene di epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung, Cancer Res. 61 (17) (2001) 6350–6355.

[159] L. Umannová, M. Machala, J. Topinka, J. Schmuczerová, P. Krčmář, J. Neča, et al., Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells, Toxicol. Lett. 206 (2) (2011) 121–129.

[160] L. Smerdová, J. Smerdová, M. Kabátková, J. Kohoutek, D. Blažek, M. Machala, et al., Upregulation of CYP1B1 expression by inflammatory cytokines is mediated by the p38 MAP kinase signal transduction pathway, Carcinogenesis 35 (11) (2014) 2534–2543.

[161] S.N. Rodin, A.S. Rodin, Human lung cancer and p53: the interplay between mutagenesis and selection, PNAS 97 (22) (2000) 12244–12249.

[162] P. Keohavong, A. Melacrinos, R. Shukla, In vitro mutational spectrum of cyclopenta[cd]pyrene in the human HPRT gene, Carcinogenesis 16 (4) (1995) 855–860.

[163] D.M. DeMarini, Influence of DNA repair on mutation spectra in Salmonella, Mutat. Res. 450 (1–2) (2000) 5–17.

[164] L.B. Alexandrov, S. Nik-Zainal, D.C. Wedge, S.A. Aparicio, S. Behjati, A. V. Biankin, et al., Signatures of mutational processes in human cancer, Nature 500 (7463) (2013) 415–421.

[165] L.B. Alexandrov, J. Kim, N.J. Haradhvala, M.N. Huang, A.W. Tian Ng, Y. Wu, et al., The repertoire of mutational signatures in human cancer, Nature 578 (7793) (2020) 94–101.

[166] H. Nakagawa, M. Fujita, Whole genome sequencing analysis for cancer genomics and precision medicine, Cancer Sci. 109 (3) (2018) 513–522.

[167] J.E. Kucab, X. Zou, S. Morganella, M. Joel, A.S. Nanda, E. Nagy, et al., A compendium of mutational signatures of environmental agents. Cell. 2019;177 (4):821-36.e16.

[168] E. Seeberg, A.L. Steinum, M. Nordenskjöld, S. Söderhäll, B. Jernström, Strand- break formation in DNA modified by benzo[alpha]pyrene dioleoxide. Quantitative cleavage by Escherichia coli uvrABC endonuclease, Mutat. Res. 112 (3) (1983) 139–145.

[169] S.L. Hockley, V.M. Arlt, D. Brewer, R. Te Poele, P. Workman, I. Giddings, et al., AHR- and DNA-damage-mediated gene expression responses induced by benzo(a) pyrene in human cell lines, Chem. Res. Toxicol. 20 (12) (2007) 1797–1810.

[170] R.A. Clewell, C.M. Thompson, H.J. Clewell 3rd., Dose-dependence of chemical carcinogenicity: Biological mechanisms for thresholds and implications for risk assessment, Chem. Biol. Interact. 301 (2019) 112–127.

[171] A. Hartwig, M. Arand, B. Epe, S. Guth, G. Jahnke, A. Lampen, et al., Mode of action-based risk assessment of genotoxic carcinogens, Arch. Toxicol. 94 (6) (2020) 1787–1877.

[172] J.A. Holme, B. Trygg, E. Søderlund, Species differences in the metabolism of 2-acetylaminofluorene by hepatocytes in primary monolayer culture, Cancer Res. 46 (4 Pt 1) (1986) 1627–1632.

[173] U. Rannug, J.A. Holme, J.K. Hongslo, R. Srám, International commission for protection against environmental mutagens and carcinogens, an evaluation of the genetic toxicity of paracetamol, Mutat. Res. 327 (1–2) (1995) 179–200.

[174] J.L. Barnes, M. Zubair, K. John, M.C. Poirier, F.L. Martin, Carcinogens and DNA damage, Biochem. Soc. Trans. 46 (5) (2018) 1213–1224.

[175] H. Lu, M. Yang, Q. Zhou, Reprogramming transcription after DNA damage: recognition, response, repair, and restart, Trends Cell Biol. (2022).

[176] J. Øvrevik, M. Refsnes, M. Lag, B.C. Brinchmann, P.E. Schwarze, J.A. Holme, Triggering mechanisms and inflammatory effects of combustion exhaust particles
with implication for carcinogenesis, Basic Clin. Paharmacol. Toxicol. 121 (Suppl 3) (2017) 55-62.

[177] A. Solhaug, M. Refsnes, M. Låg, P.E. Schwarze, T. Husøy, J.A. Holme, Polycyclic aromatic hydrocarbons induce both apoptotic and anti-apoptotic signals in Hepa1c1c7 cells, Carcinogenesis 25 (5) (2004) 809-819.

[178] N.E. Landvik, M. Gorria, V.M. Arlt, N. Asare, A. Solhaug, D. Lagadic-Gossmann, et al., Effects of nitrated-polycyclic aromatic hydrocarbons and diesel exhaust particle extracts on cell signalling related to apoptosis: possible implications for their mutagenic and carcinogenic effects, Toxicology 231 (2-3) (2007) 159-174.

[179] M. Liamin, E. Boutet-Robinet, E.L. Jamin, M. Fernier, L. Khoury, B. Kopp, et al., Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes, Biochem. Pharmacol. 137 (2017) 113-124.

[180] W. Zhou, D. Tian, J. He, Y. Wang, L. Zhang, L. Cui, et al., Repeated PM2.5 exposure inhibits BEAS-2B cell P53 expression through ROS-Akt-DNMT3B pathway-mediated promoter hypermethylation, Oncotarget 7 (15) (2016) 20691-20703.

[181] Q.A. Khan, K.H. Vousden, A. Dipple, Cellular response to DNA damage from a potent carcinogen involves stabilization of p53 without induction of p21(waf1/cip1), Carcinogenesis 18 (12) (1997) 2313-2318.

[182] A. Dipple, Q.A. Khan, J.E. Page, I. Pontén, J. Szeliga, DNA reactions, mutagenic action and stealth properties of polycyclic aromatic hydrocarbon carcinogens (review), Int. J. Oncol. 14 (1) (1999) 103-111.

[183] M. Malmlöf, G. Pääjärvi, J. Högberg, U. Stenius, Mdm2 as a sensitive and mechanistically informative marker for genotoxicity induced by benzo[a]pyrene and dibenzo[a, I]pyrene, Toxicol. Sci. 102 (2) (2008) 232-240.

[184] J.L. Marlowe, Y. Fan, X. Chang, L. Peng, E.S. Knudsen, Y. Xia, et al., The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis, Mol. Biol. Cell 19 (8) (2008) 3263-3271.

[185] R. Barouki, X. Coumoul, P.M. Fernandez-Salguero, The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein, FEBS Lett. 581 (19) (2007) 3608-3615.

[186] S.L. Tannheimer, S.L. Barton, S.P. Ethier, S.W. Burchiel, Carcinogenic polycyclic aromatic hydrocarbons increase intracellular Ca2+ and cell proliferation in primary human mammary epithelial cells, Carcinogenesis 18 (6) (1997) 1177-1182.

[187] S.L. Tannheimer, S.P. Ethier, K.K. Caldwell, S.W. Burchiel, Benzo[a]pyrene- and TCDD-induced alterations in tyrosine phosphorylation and insulin-like growth factor signaling pathways in the MCF-10A human mammary epithelial cell line, Carcinogenesis 19 (7) (1998) 1291-1297.

[188] M. Plísková, J. Vondráček, B. Vojtesek, A. Kozubík, M. Machala, Deregulation of cell proliferation by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells reflects both genotoxic and nongenotoxic events, Toxicol. Sci. 83 (2) (2005) 246-256.

[189] Z. Andryšik, J. Vondráček, M. Machala, P. Krcmár, L. Svihálková-Sindlerová, A. Kranz, et al., The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells, Mutat. Res. 615 (1-2) (2007) 87-97.

[190] F. Matsumura, The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects, Biochem. Pharmacol. 77 (4) (2009) 608-626.

[191] M.S. Denison, A.A. Soshilov, G. He, D.E. DeGroot, B. Zhao, Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor, Toxicol. Sci. 124 (1) (2011) 1-22.

[192] N.C. Sondermann, S. Faßbender, F. Hartung, A.M. Hätälä, K.M. Rolfs, C.F. A. Vogel, et al., Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway, Biochem. Pharmacol. 208 (2023), 115371.

[193] E. Guyot, A. Chevallier, R. Barouki, X. Coumoul, The AhR twist: ligand-dependent AhR signaling and pharmac-toxicological implications, Drug Discov. Today 18 (9-10) (2013) 479-486.

[194] K. Taniguchi, M. Karin, NF-κB, inflammation, immunity and cancer: coming of age, Nat. Rev. Immunol. 18 (5) (2018) 309-324.

[195] Y. Tian, A.B. Rabson, M.A. Gallo, Ah receptor and NF-kappaB interactions: mechanisms and physiological implications, Chem. Biol. Interact. 141 (1-2) (2002) 97-115.

[196] C.F. Vogel, E. Sciuullo, W. Li, P. Wong, G. Lazennec, F. Matsumura, RelB, a new partner of aryl hydrocarbon receptor-mediated transcription, Mol. Endocrinol. 21 (12) (2007) 2941-2955.

[197] C.F. Vogel, F. Matsumura, A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family, Biochem. Pharmacol. 77 (4) (2009) 734-745.

[198] P.H. Chen, H. Chang, J.T. Chang, P. Lin, Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer, Oncogene 31 (20) (2012) 2555-2565.

[199] S. Kobayashi, H. Okamoto, T. Iwamoto, Y. Toyama, T. Tomatsu, H. Yamanaka, et al., A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis, Rheumatology (Oxford) 47 (9) (2008) 1317-1322.

[200] N. Podechard, V. Lecureur, E. Le Ferrec, I. Guenon, L. Sparfel, D. Gilot, et al., Interleukin-8 induction by the environmental contaminant benzo(a)pyrene is aryl hydrocarbon receptor-dependent and leads to lung inflammation, Toxicol. Lett. 177 (2) (2008) 130-137.

[201] D.W. Kim, L. Gazourian, S.A. Quadri, R. Romieu-Mourez, D.H. Sherr, G. E. Sonenshein, The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells, Oncogene 19 (48) (2000) 5498-5506.

[202] T.H. Thatcher, S.B. Maggirwar, C.J. Baglole, H.F. Lakatos, T.A. Gasiewicz, R. P. Phipps, et al., Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB, Am. J. Pathol. 170 (3) (2007) 855-864.

[203] C.A. Beamer, B.P. Seaver, D.M. Shepherd, Aryl hydrocarbon receptor (AhR) regulates silica-induced inflammation but not fibrosis, Toxicol. Sci. 126 (2) (2012) 554-568.

[204] G. Vázquez-Gómez, M. Karasová, Z. Tylichová, M. Kabátková, A. Hampl, J. Matthews, et al., Aryl hydrocarbon receptor (AhR) limits the inflammatory responses in human lung adenocarcinoma A549 cells via interference with NF-κB signaling, Cells. 11 (4) (2022).

[205] J. Øvrevik, M. Låg, V. Lecureur, D. Gilot, D. Lagadic-Gossmann, M. Refsnes, et al., AhR and Arnt differentially regulate NF-κB signaling and chemokine responses in human bronchial epithelial cells, Cell Commun. Signal 12 (2014) 48.

[206] E. Oesterling, M. Toborek, B. Hennig, Benzo[a]pyrene induces intercellular adhesion molecule-1 through a caveolae and aryl hydrocarbon receptor mediated pathway, Toxicol. Appl. Pharmacol. 232 (2) (2008) 309-316.

[207] J. Rey-Barroso, A. Alvarez-Barrientos, E. Rico-Leo, M. Contador-Troca, J. M. Carvajal-Gonzalez, A. Echarri, et al., The Dioxin receptor modulates Caveolin-1 mobilization during directional migration: role of cholesterol, Cell Commun. Signal 12 (2014) 57.

[208] A.L. Plant, R.D. Knapp, L.C. Smith, Mechanism and rate of permeation of cells by polycyclic aromatic hydrocarbons, J. Biol. Chem. 262 (6) (1987) 2514-2519.

[209] R. Barhoumi, Y. Mouneimne, K.S. Ramos, S.H. Safe, T.D. Phillips, V.E. Centonze, et al., Analysis of benzo[a]pyrene partitioning and cellular homeostasis in a rat liver cell line, Toxicol. Sci. 53 (2) (2000) 264-270.

[210] N.A. Abumrad, A.G. Cabodevilla, D. Samovski, T. Pietka, D. Basu, I.J. Goldberg, Endothelial cell receptors in tissue lipid uptake and metabolism, Circ. Res. 128 (3) (2021) 433-450.

[211] S. Luo, M. Yang, H. Zhao, Y. Han, N. Jiang, J. Yang, et al., Caveolin-1 regulates cellular metabolism: A potential therapeutic target in kidney disease, Front. Pharmacol. 12 (2021), 768100.

[212] A. Penn, G. Murphy, S. Barker, W. Henk, L. Penn, Combustion-derived ultrafine particles transport organic toxicants to target respiratory cells, Environ. Health Perspect. 113 (8) (2005) 956-963.

[213] B.C. Brinchmann, E. Le Ferrec, N. Podechard, D. Lagadic-Gossmann, K.F. Shoji, A. Penna, et al., Lipophilic chemicals from diesel exhaust particles trigger calcium response in human endothelial cells via aryl hydrocarbon receptor non-genomic signalling, Int. J. Mol. Sci. 19 (5) (2018).

[214] B.C. Brinchmann, E. Le Ferrec, W.H. Bisson, N. Podechard, H.S. Huiftdelt, I. Gallais, et al., Evidence of selective activation of aryl hydrocarbon receptor nongenomic calcium signaling by pyrene, Biochem. Pharmacol. 158 (2018) 1-12.

[215] R.K. Robinson, M.A. Birrell, J.J. Adcock, M.A. Wortley, E.D. Dubuis, S. Chen, et al. Mechanistic link between diesel exhaust particles and respiratory reflexes. J Allergy Clin Immunol. 2018;141(3):1074-84.e9.

[216] M.T. Tran, Overview of Ca(2+) signaling in lung cancer progression and metastatic lung cancer with bone metastasis, Explor Target Antitumor Ther. 2 (3) (2021) 249-265.

[217] T. Zhong, W. Zhang, H. Guo, X. Pan, X. Chen, Q. He, et al., The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies, Acta Pharm. Sin. B 12 (4) (2022) 1761-1780.

[218] β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives, J. Cancer Res. Clin. Oncol. 143 (2) (2017) 275-291.

[219] M.B. Nilsson, X. Le, J.V. Heymach, β-adrenergic signaling in lung cancer: a potential role for beta-blockers, J. Neuroimmune Pharmacol. 15 (1) (2020) 27-36.

[220] H.M. Schuller, P.K. Tithof, M. Williams, H. Plummer 3rd., The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptor-mediated release of arachidonic acid, Cancer Res. 59 (18) (1999) 4510-4515.

[221] M.D.F. Askari, M.-S. Tsao, H.M. Schuller, The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors, J. Cancer Res. Clin. Oncol. 131 (10) (2005) 639-648.

[222] A. Mayati, N. Levoin, H. Paris, M. N'Diaye, A. Courtois, P. Uriac, et al., Induction of intracellular calcium concentration by environmental benzo(a)pyrene involves a β2-adrenergic receptor/adenylyl cyclase/Epac-1/inositol 1,4,5-triphosphate pathway in endothelial cells, J. Biol. Chem. 287 (6) (2012) 4041-4052.

[223] R. Rosell, A.F. Cardona, O. Arrieta, A. Aguilar, M. Ito, C. Pedraz, et al., Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities, Br. J. Cancer 125 (12) (2021) 1602-1611.

[224] Z. Lei, W. Yang, Y. Zuo, Beta-blocker and survival in patients with lung cancer: A meta-analysis, PLoS One 16 (2) (2021) e0245773.

[225] B.V. Madhukar, D.W. Brewster, F. Matsumura, Effects of in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor binding of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster, PNAS 81 (23) (1984) 7407-7411.

[226] C. Köhle, H. Gschaidmeier, D. Lauth, S. Topell, H. Zitzer, K.W. Bock, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells, Arch. Toxicol. 73 (3) (1999) 152-158.

[227] H. Cheon, Y.S. Woo, J.Y. Lee, H.S. Kim, H.J. Kim, S. Cho, et al., Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-alpha production in
with implication for carcinogenesis, Basic Clin. Paharmacol. Toxicol. 121 (Suppl 3) (2017) 55-62.

[177] A. Solhaug, M. Refsnes, M. Låg, P.E. Schwarze, T. Husøy, J.A. Holme, Polycyclic aromatic hydrocarbons induce both apoptotic and anti-apoptotic signals in Hepa1c1c7 cells, Carcinogenesis 25 (5) (2004) 809-819.

[178] N.E. Landvik, M. Gorria, V.M. Arlt, N. Asare, A. Solhaug, D. Lagadic-Gossmann, et al., Effects of nitrated-polycyclic aromatic hydrocarbons and diesel exhaust particle extracts on cell signalling related to apoptosis: possible implications for their mutagenic and carcinogenic effects, Toxicology 231 (2-3) (2007) 159-174.

[179] M. Liamin, E. Boutet-Robinet, E.L. Jamin, M. Fernier, L. Khoury, B. Kopp, et al., Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes, Biochem. Pharmacol. 137 (2017) 113-124.

[180] W. Zhou, D. Tian, J. He, Y. Wang, L. Zhang, L. Cui, et al., Repeated PM2.5 exposure inhibits BEAS-2B cell P53 expression through ROS-Akt-DNMT3B pathway-mediated promoter hypermethylation, Oncotarget 7 (15) (2016) 20691-20703.

[181] Q.A. Khan, K.H. Vousden, A. Dipple, Cellular response to DNA damage from a potent carcinogen involves stabilization of p53 without induction of p21(waf1/cip1), Carcinogenesis 18 (12) (1997) 2313-2318.

[182] A. Dipple, Q.A. Khan, J.E. Page, I. Pontén, J. Szeliga, DNA reactions, mutagenic action and stealth properties of polycyclic aromatic hydrocarbon carcinogens (review), Int. J. Oncol. 14 (1) (1999) 103-111.

[183] M. Malmlöf, G. Pääjärvi, J. Högberg, U. Stenius, Mdm2 as a sensitive and mechanistically informative marker for genotoxicity induced by benzo[a]pyrene and dibenzo[a, I]pyrene, Toxicol. Sci. 102 (2) (2008) 232-240.

[184] J.L. Marlowe, Y. Fan, X. Chang, L. Peng, E.S. Knudsen, Y. Xia, et al., The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis, Mol. Biol. Cell 19 (8) (2008) 3263-3271.

[185] R. Barouki, X. Coumoul, P.M. Fernandez-Salguero, The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein, FEBS Lett. 581 (19) (2007) 3608-3615.

[186] S.L. Tannheimer, S.L. Barton, S.P. Ethier, S.W. Burchiel, Carcinogenic polycyclic aromatic hydrocarbons increase intracellular Ca2+ and cell proliferation in primary human mammary epithelial cells, Carcinogenesis 18 (6) (1997) 1177-1182.

[187] S.L. Tannheimer, S.P. Ethier, K.K. Caldwell, S.W. Burchiel, Benzo[a]pyrene- and TCDD-induced alterations in tyrosine phosphorylation and insulin-like growth factor signaling pathways in the MCF-10A human mammary epithelial cell line, Carcinogenesis 19 (7) (1998) 1291-1297.

[188] M. Plísková, J. Vondráček, B. Vojtesek, A. Kozubík, M. Machala, Deregulation of cell proliferation by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells reflects both genotoxic and nongenotoxic events, Toxicol. Sci. 83 (2) (2005) 246-256.

[189] Z. Andryšik, J. Vondráček, M. Machala, P. Krcmár, L. Svihálková-Sindlerová, A. Kranz, et al., The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells, Mutat. Res. 615 (1-2) (2007) 87-97.

[190] F. Matsumura, The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects, Biochem. Pharmacol. 77 (4) (2009) 608-626.

[191] M.S. Denison, A.A. Soshilov, G. He, D.E. DeGroot, B. Zhao, Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor, Toxicol. Sci. 124 (1) (2011) 1-22.

[192] N.C. Sondermann, S. Faßbender, F. Hartung, A.M. Hätälä, K.M. Rolfs, C.F. A. Vogel, et al., Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway, Biochem. Pharmacol. 208 (2023), 115371.

[193] E. Guyot, A. Chevallier, R. Barouki, X. Coumoul, The AhR twist: ligand-dependent AhR signaling and pharmac-toxicological implications, Drug Discov. Today 18 (9-10) (2013) 479-486.

[194] K. Taniguchi, M. Karin, NF-κB, inflammation, immunity and cancer: coming of age, Nat. Rev. Immunol. 18 (5) (2018) 309-324.

[195] Y. Tian, A.B. Rabson, M.A. Gallo, Ah receptor and NF-kappaB interactions: mechanisms and physiological implications, Chem. Biol. Interact. 141 (1-2) (2002) 97-115.

[196] C.F. Vogel, E. Sciuillo, W. Li, P. Wong, G. Lazennec, F. Matsumura, RelB, a new partner of aryl hydrocarbon receptor-mediated transcription, Mol. Endocrinol. 21 (12) (2007) 2941-2955.

[197] C.F. Vogel, F. Matsumura, A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family, Biochem. Pharmacol. 77 (4) (2009) 734-745.

[198] P.H. Chen, H. Chang, J.T. Chang, P. Lin, Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer, Oncogene 31 (20) (2012) 2555-2565.

[199] S. Kobayashi, H. Okamoto, T. Iwamoto, Y. Toyama, T. Tomatsu, H. Yamanaka, et al., A role for the aryl hydrocarbon receptor and the dioxin TCDD in rheumatoid arthritis, Rheumatology (Oxford) 47 (9) (2008) 1317-1322.

[200] N. Podechard, V. Lecureur, E. Le Ferrec, I. Guenon, L. Sparfel, D. Gilot, et al., Interleukin-8 induction by the environmental contaminant benzo(a)pyrene is aryl hydrocarbon receptor-dependent and leads to lung inflammation, Toxicol. Lett. 177 (2) (2008) 130-137.

[201] D.W. Kim, L. Gazourian, S.A. Quadri, R. Romieu-Mourez, D.H. Sherr, G. E. Sonenshein, The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells, Oncogene 19 (48) (2000) 5498-5506.

[202] T.H. Thatcher, S.B. Maggirwar, C.J. Baglole, H.F. Lakatos, T.A. Gasiewicz, R. P. Phipps, et al., Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB, Am. J. Pathol. 170 (3) (2007) 855-864.

[203] C.A. Beamer, B.P. Seaver, D.M. Shepherd, Aryl hydrocarbon receptor (AhR) regulates silica-induced inflammation but not fibrosis, Toxicol. Sci. 126 (2) (2012) 554-568.

[204] G. Vázquez-Gómez, M. Karasová, Z. Tylichová, M. Kabátková, A. Hampl, J. Matthews, et al., Aryl hydrocarbon receptor (AhR) limits the inflammatory responses in human lung adenocarcinoma A549 cells via interference with NF-κB signaling, Cells. 11 (4) (2022).

[205] J. Øvrevik, M. Låg, V. Lecureur, D. Gilot, D. Lagadic-Gossmann, M. Refsnes, et al., AhR and Arnt differentially regulate NF-κB signaling and chemokine responses in human bronchial epithelial cells, Cell Commun. Signal 12 (2014) 48.

[206] E. Oesterling, M. Toborek, B. Hennig, Benzo[a]pyrene induces intercellular adhesion molecule-1 through a caveolae and aryl hydrocarbon receptor mediated pathway, Toxicol. Appl. Pharmacol. 232 (2) (2008) 309-316.

[207] J. Rey-Barroso, A. Alvarez-Barrientos, E. Rico-Leo, M. Contador-Troca, J. M. Carvajal-Gonzalez, A. Echarri, et al., The Dioxin receptor modulates Caveolin-1 mobilization during directional migration: role of cholesterol, Cell Commun. Signal 12 (2014) 57.

[208] A.L. Plant, R.D. Knapp, L.C. Smith, Mechanism and rate of permeation of cells by polycyclic aromatic hydrocarbons, J. Biol. Chem. 262 (6) (1987) 2514-2519.

[209] R. Barhoumi, Y. Mouneimne, K.S. Ramos, S.H. Safe, T.D. Phillips, V.E. Centonze, et al., Analysis of benzo[a]pyrene partitioning and cellular homeostasis in a rat liver cell line, Toxicol. Sci. 53 (2) (2000) 264-270.

[210] N.A. Abumrad, A.G. Cabodevilla, D. Samovski, T. Pietka, D. Basu, I.J. Goldberg, Endothelial cell receptors in tissue lipid uptake and metabolism, Circ. Res. 128 (3) (2021) 433-450.

[211] S. Luo, M. Yang, H. Zhao, Y. Han, N. Jiang, J. Yang, et al., Caveolin-1 regulates cellular metabolism: A potential therapeutic target in kidney disease, Front. Pharmacol. 12 (2021), 768100.

[212] A. Penn, G. Murphy, S. Barker, W. Henk, L. Penn, Combustion-derived ultrafine particles transport organic toxicants to target respiratory cells, Environ. Health Perspect. 113 (8) (2005) 956-963.

[213] B.C. Brinchmann, E. Le Ferrec, N. Podechard, D. Lagadic-Gossmann, K.F. Shoji, A. Penna, et al., Lipophilic chemicals from diesel exhaust particles trigger calcium response in human endothelial cells via aryl hydrocarbon receptor non-genomic signalling, Int. J. Mol. Sci. 19 (5) (2018).

[214] B.C. Brinchmann, E. Le Ferrec, W.H. Bisson, N. Podechard, H.S. Huiftdelt, I. Gallais, et al., Evidence of selective activation of aryl hydrocarbon receptor nongenomic calcium signaling by pyrene, Biochem. Pharmacol. 158 (2018) 1-12.

[215] R.K. Robinson, M.A. Birrell, J.J. Adcock, M.A. Wortley, E.D. Dubuis, S. Chen, et al. Mechanistic link between diesel exhaust particles and respiratory reflexes. J Allergy Clin Immunol. 2018;141(3):1074-84.e9.

[216] M.T. Tran, Overview of Ca(2+) signaling in lung cancer progression and metastatic lung cancer with bone metastasis, Explor Target Antitumor Ther. 2 (3) (2021) 249-265.

[217] T. Zhong, W. Zhang, H. Guo, X. Pan, X. Chen, Q. He, et al., The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies, Acta Pharm. Sin. B 12 (4) (2022) 1761-1780.

[218] β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives, J. Cancer Res. Clin. Oncol. 143 (2) (2017) 275-291.

[219] M.B. Nilsson, X. Le, J.V. Heymach, β-adrenergic signaling in lung cancer: a potential role for beta-blockers, J. Neuroimmune Pharmacol. 15 (1) (2020) 27-36.

[220] H.M. Schuller, P.K. Tithof, M. Williams, H. Plummer 3rd., The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a beta-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via beta-adrenergic receptor-mediated release of arachidonic acid, Cancer Res. 59 (18) (1999) 4510-4515.

[221] M.D.F. Askari, M.-S. Tsao, H.M. Schuller, The tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through β-adrenergic transactivation of EGF receptors, J. Cancer Res. Clin. Oncol. 131 (10) (2005) 639-648.

[222] A. Mayati, N. Levoin, H. Paris, M. N'Diaye, A. Courtois, P. Uriac, et al., Induction of intracellular calcium concentration by environmental benzo(a)pyrene involves a β2-adrenergic receptor/adenylyl cyclase/Epac-1/inositol 1,4,5-trisphosphate pathway in endothelial cells, J. Biol. Chem. 287 (6) (2012) 4041-4052.

[223] R. Rosell, A.F. Cardona, O. Arrieta, A. Aguilar, M. Ito, C. Pedraz, et al., Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities, Br. J. Cancer 125 (12) (2021) 1602-1611.

[224] Z. Lei, W. Yang, Y. Zuo, Beta-blocker and survival in patients with lung cancer: A meta-analysis, PLoS One 16 (2) (2021) e0245773.

[225] B.V. Madhukar, D.W. Brewster, F. Matsumura, Effects of in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor binding of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster, PNAS 81 (23) (1984) 7407-7411.

[226] C. Köhle, H. Gschaidmeier, D. Lauth, S. Topell, H. Zitzer, K.W. Bock, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated membrane translocation of c-Src protein kinase in liver WB-F344 cells, Arch. Toxicol. 73 (3) (1999) 152-158.

[227] H. Cheon, Y.S. Woo, J.Y. Lee, H.S. Kim, H.J. Kim, S. Cho, et al., Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-alpha production in
[228] J. Övrevik, M. Refsnes, A.I. Totlandsdal, J.A. Holme, P.E. Schwarze, M. Låg, TACE/TGF-α/EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components, Eur. Respir. J. 38 (5) (2011) 1189-1199.

[229] C. Vogel, A.M. Boerboom, C. Baechle, C. El-Bahay, R. Kahl, G.H. Degen, et al., Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway, Carcinogenesis 21 (12) (2000) 2267-2274.

[230] C.F. Vogel, W. Li, E. Sciullo, J. Newman, B. Hammock, J.R. Reader, et al., Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression, Am. J. Pathol. 171 (5) (2007) 1538-1548.

[231] A.B. Sandler, S.M. Dubinet, COX-2 inhibition and lung cancer, Semin. Oncol. 31 (2 Suppl 7) (2004) 45-52.

[232] D. Wölfle, S. Marotzki, D. Dartsch, W. Schäfer, H. Marquardt, Induction of cyclooxygenase expression and enhancement of malignant cell transformation by 2,3,7,8-tetrachlorodibenzo-p-dioxin, Carcinogenesis 21 (1) (2000) 15-21.

[233] C. Vogeley, N.C. Sondermann, S. Woeste, A.A. Momin, V. Gilardino, F. Hartung, et al., Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response, Environ. Int. 158 (2022), 106989.

[234] G. Xie, Z. Peng, J.P. Raufman, Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation, Am. J. Physiol. Gastrointest. Liver Physiol. 302 (9) (2012) G1006-G1015.

[235] Y. Cui, T. Zhu, X. Song, J. Liu, S. Liu, R. Zhao, Downregulation of caveolin-1 increased EGFR-TKIs sensitivity in lung adenocarcinoma cell line with EGFR mutation, Biochem. Biophys. Res. Commun. 495 (1) (2018) 733-739.

[236] E.J. Lim, Z. Májková, S. Xu, L. Bachas, X. Arzuaga, E. Smart, et al., Coplanar polychlorinated biphenyl-induced CYP1A1 is regulated through caveolae signaling in vascular endothelial cells, Chem. Biol. Interact. 176 (2-3) (2008) 71-78.

[237] Y.B. Shi, J. Li, X.N. Lai, R. Jiang, R.C. Zhao, L.X. Xiong, Multifaceted roles of caveolin-1 in lung cancer: A new investigation focused on tumor occurrence, development and therapy, Cancers (Basel) 12 (2) (2020).

[238] C. Thiebaut, V. Vlaeminck-Guillem, O. Trédan, C. Poulard, M. Le Romancer, Non-genomic signaling of steroid receptors in cancer, Mol. Cell. Endocrinol. 538 (2021), 111453.

[239] F. Mauvais-Jarvis, C.A. Lange, E.R. Levin, Membrane-initiated estrogen, androgen, and progesterone receptor signaling in health and disease, Endocr. Rev. 43 (4) (2022) 720-742.

[240] J. Mazières, I. Rouquette, B. Lepage, J. Milia, L. Brouchet, N. Guibert, et al., Specificities of lung adenocarcinoma in women who have never smoked, J. Thorac. Oncol. 8 (7) (2013) 923-929.

[241] D.M. Tappenden, S.G. Lynn, R.B. Crawford, K. Lee, A. Vengellur, N.E. Kaminski, et al., The aryl hydrocarbon receptor interacts with ATP5alpha1, a subunit of the ATP synthase complex, and modulates mitochondrial function, Toxicol. Appl. Pharmacol. 254 (3) (2011) 299-310.

[242] H.J. Hwang, P. Dornbos, M. Steidemann, T.K. Dunivin, M. Rizzo, J.J. LaPres, Mitochondrial-targeted aryl hydrocarbon receptor and the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin on cellular respiration and the mitochondrial proteome, Toxicol. Appl. Pharmacol. 304 (2016) 121-132.

[243] K. Hardonniere, E. Saunier, A. Lemarie, M. Fernier, I. Gallais, C. Helies-Toussaint, et al., The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival, Sci. Rep. 6 (2016) 30776.

[244] K. Hardonniere, L. Huc, O. Sergent, J.A. Holme, D. Lagadic-Gossmann, Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism, Semin. Cancer Biol. 43 (2017) 49-65.

[245] X. Li, M. Liu, H. Liu, J. Chen, Tumor metabolic reprogramming in lung cancer progression, Oncol. Lett. 24 (2) (2022) 287.

[246] K. Vanhove, G.J. Graulus, L. Mesotten, M. Thomeer, E. Derveaux, J.P. Noben, et al., The metabolic landscape of lung cancer: New insights in a disturbed glucose metabolism, Front. Oncol. 9 (2019) 1215.

[247] Q. Chen, Y. Wang, L. Yang, L. Sun, Y. Wen, Y. Huang, et al., PM2.5 promotes NSCLC carcinogenesis through translation and transcriptionally activating DLAT-mediated glycolysis reprogramming, J. Exp. Clin. Cancer Res. 41(1):229 (2022).

[248] M.M. Pierdomini, Diesel exhaust particle exposure in vitro impacts T lymphocyte phenotype and function, Part. Fibre Toxicol. 11 (74) (2014) 1-14.

[249] I.B. Ferecatu, Polycyclic aromatic hydrocarbon components contribute to the mitochondria-antiapoptotic effect of fine particulate matter on human bronchial epithelial cells via the aryl hydrocarbon receptor, Part. Fibre Toxicol. 7 (18) (2010) 1-14.

[250] A.P. Andersen, J.M. Moreira, S.F. Pedersen, Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment, Philos. Trans. R. Soc. Lond. B Biol. Sci. 369 (1638) (2014) 20130098.

[251] D. Lagadic-Gossmann, K. Hardonniere, B. Mograbi, O. Sergent, L. Huc, Disturbances in H(+) dynamics during environmental carcinogenesis, Biochimie 163 (2019) 171-183.

[252] W.T. Cottle, C.H. Wallert, K.K. Anderson, M.F. Tran, C.L. Bakker, M.A. Wallert, et al. Calcineurin homologous protein isoform 2 supports tumor survival via the sodium hydrogen exchanger isoform 1 in non-small cell lung cancer. Tumour Biol. 2020;42(7):1010428320937863.

[253] L. Huc, L. Sparfel, M. Rissel, M.-T. Dimanche-Boitrel, A. Guillouzo, O. Fardel, et al., Identification of Na+/H+ exchange as a new target for toxic polycyclic aromatic hydrocarbons in liver cells, FASEB J. 18 (2) (2004) 1-26.

[254] L. Sánchez-Cenizo, L. Formentini, M. Aldea, A.D. Ortega, P. García-Huerta, M. Sánchez-Aragó, et al., Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+–ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype, J. Biol. Chem. 285 (33) (2010) 25308-25313.

[255] D. Paul, A.N. Sinha, A. Ray, M. Lal, S. Nayak, A. Sharma, et al., A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoeditied in glioblastoma multiforme, Sci. Rep. 7 (1) (2017) 2466.

[256] K. Hardonnière, D. Lagadic-Gossmann, ATPase inhibitory factor 1 (IF1): a novel player in pollutant-related diseases? Current Opinion in Toxicology. 8 (2018) 42-47.

[257] X. Han, H. Liu, Z. Zhang, W. Yang, C. Wu, X. Liu, et al., Epitranscriptomic 5-methylcytosine profile in PM(2.5)-induced mouse pulmonary fibrosis, Genomics Proteomics Bioinformatics 18 (1) (2020) 41-51.

[258] M. Mesnil, S. Crespin, J.L. Avanzo, M.L. Zaidan-Dagli, Defective gap junctional intercellular communication in the carcinogenic process, BBA 1719 (1-2) (2005) 125-145.

[259] R.J. Ruch, S. Porter, L.D. Koffler, L.D. Dwyer-Nield, A.M. Malkinson, Defective gap junctional intercellular communication in lung cancer: loss of an important mediator of tissue homeostasis and phenotypic regulation, Exp. Lung Res. 27 (3) (2001) 231-243.

[260] J.L. Avanzo, M. Mesnil, F.J. Hernandez-Blazquez, I.I. Mackowiak, C.M. Mori, T. C. da Silva, et al., Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43, Carcinogenesis 25 (10) (2004) 1973-1982.

[261] T.J. King, P.D. Lampe, The gap junction protein connexin32 is a mouse lung tumor suppressor, Cancer Res. 64 (20) (2004) 7191-7196.

[262] M. Zhou, M. Zheng, X. Zhou, S. Tian, X. Yang, Y. Ning, et al., The roles of connexins and gap junctions in the progression of cancer, Cell Commun. Signal 21 (1) (2023) 8.

[263] R.J. Ruch, J.E. Klaunig, Effects of tumor promoters, genotoxic carcinogens and hepatocytotoxins on mouse hepatocyte intercellular communication, Cell Biol. Toxicol. 2 (4) (1986) 469-483.

[264] H. Yamasaki, Role of disrupted gap junctional intercellular communication in detection and characterization of carcinogens, Mutat. Res. 365 (1-3) (1996) 91-105.

[265] H.S. Rosenkranz, N. Pollack, A.R. Cunningham, Exploring the relationship between the inhibition of gap junctional intercellular communication and other biological phenomena, Carcinogenesis 21 (5) (2000) 1007-1011.

[266] L. Bláha, P. Kapplová, J. Vondráček, B. Upham, M. Machala, Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons, Toxicol. Sci. 65 (1) (2002) 43-51.

[267] B.L. Upham, L. Bláha, P. Babica, J.S. Park, I. Sovadinaova, C. Pudrith, et al., Tumor promoting properties of a cigarette smoke prevalent polycyclic aromatic hydrocarbon as indicated by the inhibition of gap junctional intercellular communication via phosphatidylcholine-specific phospholipase C, Cancer Sci. 99 (4) (2008) 696-705.

[268] J. Vondráček, L. Svihálková-Sindlerová, K. Pencíková, S. Marvanová, P. Krcmár, M. Ciganek, et al., Concentrations of methylated naphthalenes, anthracenes, and phenanthrenes occurring in Czech river sediments and their effects on toxic events associated with carcinogenesis in rat liver cell lines, Environ. Toxicol. Chem. 26 (11) (2007) 2308-2316.

[269] E. Rivedal, O. Myhre, T. Sanner, I. Eide, Supplemental role of the Ames mutation assay and gap junction intercellular communication in studies of possible carcinogenic compounds from diesel exhaust particles, Arch. Toxicol. 77 (9) (2003) 533-542.

[270] A.A. Rutten, W.M. Jongen, L.H. de Haan, E.G. Hendriksen, J.H. Koeman, Effect of retinol and cigarette-smoke condensate on dye-coupled intercellular communication between hamster tracheal epithelial cells, Carcinogenesis 9 (2) (1988) 315-320.

[271] E. Roemer, H.P. Lammerich, L.L. Conroy, D. Weisensee, Characterization of a gap-junctional intercellular communication (GJIC) assay using cigarette smoke, Toxicol. Lett. 219 (3) (2013) 248-253.

[272] M. Koval, Sharing signals: connecting lung epithelial cells with gap junction channels, Am. J. Physiol. Lung Cell. Mol. Physiol. 283 (5) (2002) L875-L893.

[273] R.S. Osgood, B.L. Upham, T. Hill 3rd, K.L. Helms, K. Velmurugan, P. Babica, et al., Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure, PLoS One 8 (6) (2014) e65150.

[274] A.K. Bauer, K. Velmurugan, S. Plöttner, K.J. Siegrist, D. Romo, P. Welge, et al., Environmentally prevalent polycyclic aromatic hydrocarbons can elicit co-carcinogenic properties in an in vitro murine lung epithelial cell model, Arch. Toxicol. 92 (3) (2018) 1311-1322.

[275] O. Brózman, J. Novák, A.K. Bauer, P. Babica, Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line, Environ. Toxicol. Pharmacol. 79 (2020), 103422.

[276] M. Kabátková, J. Svobodová, K. Pencíková, D.S. Mohatad, L. Smerdová, A. Kozubík, et al., Interactive effects of inflammatory cytokine and abundant low-molecular-weight PAHs on inhibition of gap junctional intercellular communication, disruption of cell proliferation control, and the AhR-dependent transcription, Toxicol. Lett. 232 (1) (2015) 113-121.
[228] J. Övrevik, M. Refsnes, A.I. Totlandsdal, J.A. Holme, P.E. Schwarze, M. Låg, TACE/TGF-α/EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components, Eur. Respir. J. 38 (5) (2011) 1189-1199.

[229] C. Vogel, A.M. Boerboom, C. Baechle, C. El-Bahay, R. Kahl, G.H. Degen, et al., Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway, Carcinogenesis 21 (12) (2000) 2267-2274.

[230] C.F. Vogel, W. Li, E. Sciullo, J. Newman, B. Hammock, J.R. Reader, et al., Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression, Am. J. Pathol. 171 (5) (2007) 1538-1548.

[231] A.B. Sandler, S.M. Dubinet, COX-2 inhibition and lung cancer, Semin. Oncol. 31 (2 Suppl 7) (2004) 45-52.

[232] D. Wölfle, S. Marotzki, D. Dartsch, W. Schäfer, H. Marquardt, Induction of cyclooxygenase expression and enhancement of malignant cell transformation by 2,3,7,8-tetrachlorodibenzo-p-dioxin, Carcinogenesis 21 (1) (2000) 15-21.

[233] C. Vogeley, N.C. Sondermann, S. Woeste, A.A. Momin, V. Gilardino, F. Hartung, et al., Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response, Environ. Int. 158 (2022), 106989.

[234] G. Xie, Z. Peng, J.P. Raufman, Src-mediated aryl hydrocarbon and epidermal growth factor receptor cross talk stimulates colon cancer cell proliferation, Am. J. Physiol. Gastrointest. Liver Physiol. 302 (9) (2012) G1006-G1015.

[235] Y. Cui, T. Zhu, X. Song, J. Liu, S. Liu, R. Zhao, Downregulation of caveolin-1 increased EGFR-TKIs sensitivity in lung adenocarcinoma cell line with EGFR mutation, Biochem. Biophys. Res. Commun. 495 (1) (2018) 733-739.

[236] E.J. Lim, Z. Májková, S. Xu, L. Bachas, X. Arzuaga, E. Smart, et al., Coplanar polychlorinated biphenyl-induced CYP1A1 is regulated through caveolae signaling in vascular endothelial cells, Chem. Biol. Interact. 176 (2-3) (2008) 71-78.

[237] Y.B. Shi, J. Li, X.N. Lai, R. Jiang, R.C. Zhao, L.X. Xiong, Multifaceted roles of caveolin-1 in lung cancer: A new investigation focused on tumor occurrence, development and therapy, Cancers (Basel) 12 (2) (2020).

[238] C. Thiebaut, V. Vlaeminck-Guillem, O. Trédan, C. Poulard, M. Le Romancer, Non-genomic signaling of steroid receptors in cancer, Mol. Cell. Endocrinol. 538 (2021), 111453.

[239] F. Mauvais-Jarvis, C.A. Lange, E.R. Levin, Membrane-initiated estrogen, androgen, and progesterone receptor signaling in health and disease, Endocr. Rev. 43 (4) (2022) 720-742.

[240] J. Mazières, I. Rouquette, B. Lepage, J. Milia, L. Brouchet, N. Guibert, et al., Specificities of lung adenocarcinoma in women who have never smoked, J. Thorac. Oncol. 8 (7) (2013) 923-929.

[241] D.M. Tappenden, S.G. Lynn, R.B. Crawford, K. Lee, A. Vengellur, N.E. Kaminski, et al., The aryl hydrocarbon receptor interacts with ATP5alpha1, a subunit of the ATP synthase complex, and modulates mitochondrial function, Toxicol. Appl. Pharmacol. 254 (3) (2011) 299-310.

[242] H.J. Hwang, P. Dornbos, M. Steidemann, T.K. Dunivin, M. Rizzo, J.J. LaPres, Mitochondrial-targeted aryl hydrocarbon receptor and the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin on cellular respiration and the mitochondrial proteome, Toxicol. Appl. Pharmacol. 304 (2016) 121-132.

[243] K. Hardonniere, E. Saunier, A. Lemarie, M. Fernier, I. Gallais, C. Helies-Toussaint, et al., The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival, Sci. Rep. 6 (2016) 30776.

[244] K. Hardonniere, L. Huc, O. Sergent, J.A. Holme, D. Lagadic-Gossmann, Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism, Semin. Cancer Biol. 43 (2017) 49-65.

[245] X. Li, M. Liu, H. Liu, J. Chen, Tumor metabolic reprogramming in lung cancer progression, Oncol. Lett. 24 (2) (2022) 287.

[246] K. Vanhove, G.J. Graulus, L. Mesotten, M. Thomeer, E. Derveaux, J.P. Noben, et al., The metabolic landscape of lung cancer: New insights in a disturbed glucose metabolism, Front. Oncol. 9 (2019) 1215.

[247] Q. Chen, Y. Wang, L. Yang, L. Sun, Y. Wen, Y. Huang, et al., PM2.5 promotes NSCLC carcinogenesis through translation and transcriptionally activating DLAT-mediated glycolysis reprogramming, J. Exp. Clin. Cancer Res. 41(1):229 (2022).

[248] M.M. Pierdomini, Diesel exhaust particle exposure in vitro impacts T lymphocyte phenotype and function, Part. Fibre Toxicol. 11 (74) (2014) 1-14.

[249] I.B. Ferecatu, Polycyclic aromatic hydrocarbon components contribute to the mitochondria-antiapoptotic effect of fine particulate matter on human bronchial epithelial cells via the aryl hydrocarbon receptor, Part. Fibre Toxicol. 7 (18) (2010) 1-14.

[250] A.P. Andersen, J.M. Moreira, S.F. Pedersen, Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment, Philos. Trans. R. Soc. Lond. B Biol. Sci. 369 (1638) (2014) 20130098.

[251] D. Lagadic-Gossmann, K. Hardonniere, B. Mograbi, O. Sergent, L. Huc, Disturbances in H(+) dynamics during environmental carcinogenesis, Biochimie 163 (2019) 171-183.

[252] W.T. Cottle, C.H. Wallert, K.K. Anderson, M.F. Tran, C.L. Bakker, M.A. Wallert, et al. Calcineurin homologous protein isoform 2 supports tumor survival via the sodium hydrogen exchanger isoform 1 in non-small cell lung cancer. Tumour Biol. 2020;42(7):1010428320937863.

[253] L. Huc, L. Sparfel, M. Rissel, M.-T. Dimanche-Boitrel, A. Guillouzo, O. Fardel, et al., Identification of Na+/H+ exchange as a new target for toxic polycyclic aromatic hydrocarbons in liver cells, FASEB J. 18 (2) (2004) 1-26.

[254] L. Sánchez-Cenizo, L. Formentini, M. Aldea, A.D. Ortega, P. García-Huerta, M. Sánchez-Aragó, et al., Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype, J. Biol. Chem. 285 (33) (2010) 25308-25313.

[255] D. Paul, A.N. Sinha, A. Ray, M. Lal, S. Nayak, A. Sharma, et al., A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoeditied in glioblastoma multiforme, Sci. Rep. 7 (1) (2017) 2466.

[256] K. Hardonnière, D. Lagadic-Gossmann, ATPase inhibitory factor 1 (IF1): a novel player in pollutant-related diseases? Current Opinion in Toxicology. 8 (2018) 42-47.

[257] X. Han, H. Liu, Z. Zhang, W. Yang, C. Wu, X. Liu, et al., Epitranscriptomic 5-methylcytosine profile in PM(2.5)-induced mouse pulmonary fibrosis, Genomics Proteomics Bioinformatics 18 (1) (2020) 41-51.

[258] M. Mesnil, S. Crespin, J.L. Avanzo, M.L. Zaidan-Dagli, Defective gap junctional intercellular communication in the carcinogenic process, BBA 1719 (1-2) (2005) 125-145.

[259] R.J. Ruch, S. Porter, L.D. Koffler, L.D. Dwyer-Nield, A.M. Malkinson, Defective gap junctional intercellular communication in lung cancer: loss of an important mediator of tissue homeostasis and phenotypic regulation, Exp. Lung Res. 27 (3) (2001) 231-243.

[260] J.L. Avanzo, M. Mesnil, F.J. Hernandez-Blazquez, I.I. Mackowiak, C.M. Mori, T. C. da Silva, et al., Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43, Carcinogenesis 25 (10) (2004) 1973-1982.

[261] T.J. King, P.D. Lampe, The gap junction protein connexin32 is a mouse lung tumor suppressor, Cancer Res. 64 (20) (2004) 7191-7196.

[262] M. Zhou, M. Zheng, X. Zhou, S. Tian, X. Yang, Y. Ning, et al., The roles of connexins and gap junctions in the progression of cancer, Cell Commun. Signal 21 (1) (2023) 8.

[263] R.J. Ruch, J.E. Klaunig, Effects of tumor promoters, genotoxic carcinogens and hepatocytotoxins on mouse hepatocyte intercellular communication, Cell Biol. Toxicol. 2 (4) (1986) 469-483.

[264] H. Yamasaki, Role of disrupted gap junctional intercellular communication in detection and characterization of carcinogens, Mutat. Res. 365 (1-3) (1996) 91-105.

[265] H.S. Rosenkranz, N. Pollack, A.R. Cunningham, Exploring the relationship between the inhibition of gap junctional intercellular communication and other biological phenomena, Carcinogenesis 21 (5) (2000) 1007-1011.

[266] L. Bláha, P. Kapplová, J. Vondráček, B. Upham, M. Machala, Inhibition of gap-junctional intercellular communication by environmentally occurring polycyclic aromatic hydrocarbons, Toxicol. Sci. 65 (1) (2002) 43-51.

[267] B.L. Upham, L. Bláha, P. Babica, J.S. Park, I. Sovadinaova, C. Pudrith, et al., Tumor promoting properties of a cigarette smoke prevalent polycyclic aromatic hydrocarbon as indicated by the inhibition of gap junctional intercellular communication via phosphatidylcholine-specific phospholipase C, Cancer Sci. 99 (4) (2008) 696-705.

[268] J. Vondráček, L. Svihálková-Sindlerová, K. Pencíková, S. Marvanová, P. Krcmár, M. Ciganek, et al., Concentrations of methylated naphthalenes, anthracenes, and phenanthrenes occurring in Czech river sediments and their effects on toxic events associated with carcinogenesis in rat liver cell lines, Environ. Toxicol. Chem. 26 (11) (2007) 2308-2316.

[269] E. Rivedal, O. Myhre, T. Sanner, I. Eide, Supplemental role of the Ames mutation assay and gap junction intercellular communication in studies of possible carcinogenic compounds from diesel exhaust particles, Arch. Toxicol. 77 (9) (2003) 533-542.

[270] A.A. Rutten, W.M. Jongen, L.H. de Haan, E.G. Hendriksen, J.H. Koeman, Effect of retinol and cigarette-smoke condensate on dye-coupled intercellular communication between hamster tracheal epithelial cells, Carcinogenesis 9 (2) (1988) 315-320.

[271] E. Roemer, H.P. Lammerich, L.L. Conroy, D. Weisensee, Characterization of a gap-junctional intercellular communication (GJIC) assay using cigarette smoke, Toxicol. Lett. 219 (3) (2013) 248-253.

[272] M. Koval, Sharing signals: connecting lung epithelial cells with gap junction channels, Am. J. Physiol. Lung Cell. Mol. Physiol. 283 (5) (2002) L875-L893.

[273] R.S. Osgood, B.L. Upham, T. Hill 3rd, K.L. Helms, K. Velmurugan, P. Babica, et al., Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure, PLoS One 8 (6) (2014) e65150.

[274] A.K. Bauer, K. Velmurugan, S. Plöttner, K.J. Siegrist, D. Romo, P. Welge, et al., Environmentally prevalent polycyclic aromatic hydrocarbons can elicit carcinogenic properties in an in vitro murine lung epithelial cell model, Arch. Toxicol. 92 (3) (2018) 1311-1322.

[275] O. Brózman, J. Novák, A.K. Bauer, P. Babica, Airborne PAHs inhibit gap junctional intercellular communication and activate MAPKs in human bronchial epithelial cell line, Environ. Toxicol. Pharmacol. 79 (2020), 103422.

[276] M. Kabátková, J. Svobodová, K. Pencíková, D.S. Mohatad, L. Smerdová, A. Kozubík, et al., Interactive effects of inflammatory cytokine and abundant low-molecular-weight PAHs on inhibition of gap junctional intercellular communication, disruption of cell proliferation control, and the AhR-dependent transcription, Toxicol. Lett. 232 (1) (2015) 113-121.
[277] D. Romo, K. Velmurugan, B.L. Upham, L.D. Dwyer-Nield, A.K. Bauer, Dysregulation of gap junction function and cytokine production in response to non-genotoxic polycyclic aromatic hydrocarbons in an in vitro lung cell model, *Cancers* (Basel) 11 (4) (2019).

[278] C. Dietrich, B. Kaina, The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth, *Carcinogenesis* 31 (8) (2010) 1319–1328.

[279] T. Kung, K.A. Murphy, L.A. White, The aryl hydrocarbon receptor (AhR) pathway as a regulatory pathway for cell adhesion and matrix metabolism, *Biochem. Pharmacol.* 77 (4) (2009) 536–546.

[280] S. Shimba, K. Komiyama, I. Moro, M. Tezuka, Overexpression of the aryl hydrocarbon receptor (AhR) accelerates the cell proliferation of A549 cells, *J. Biochem.* 132 (5) (2002) 795–802.

[281] M. Hýzfalová, J. Procházková, S. Strapáčová, L. Svržková, O. Vacek, R. Fedr, et al., A prolonged exposure of human lung carcinoma epithelial cells to benzo[a] pyrene induces p21-dependent epithelial-to-mesenchymal transition (EMT)-like phenotype, *Chemosphere* 263 (2021), 128126.

[282] K. Misaki, T. Takamura-Enya, H. Ogawa, K. Takamori, M. Yanagida, Tumour-promoting activity of polycyclic aromatic hydrocarbons and their oxygenated or nitrated derivatives, *Mutagenesis* 31 (2) (2016) 205–213.

[283] K. Chramostová, J. Vondráček, L. Sindlerová, B. Vojtesek, A. Kozubík, M. Machala, Polycyclic aromatic hydrocarbons modulate cell proliferation in rat hepatic epithelial stem-like WB-F344 cells, *Toxicol. Appl. Pharmacol.* 196 (1) (2004) 136–148.

[284] Z. Andryšk, J. Procházková, M. Kabátková, L. Umannová, P. Simečková, J. Kohoutek, et al., Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication, *Arch. Toxicol.* 87 (3) (2013) 491–503.

[285] J. Procházková, M. Kabátková, V. Bryja, L. Umannová, O. Bernatík, A. Kozubík, et al., The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors, *Toxicol. Sci.* 122 (2) (2011) 349–360.

[286] J. Svobodová, J. Procházková, M. Kabátková, M. Krkoska, L. Šmerdová, H. Libálová, et al., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disrupts control of cell proliferation and apoptosis in a human model of adult liver progenitors, *Toxicol. Sci.* 172 (2) (2019) 368–384.

[287] K. Brune, J. Frank, A. Schwingshackl, J. Finigan, V.K. Sidhaye, Pulmonary epithelial barrier function: some new players and mechanisms, *Am. J. Physiol. Lung Cell. Mol. Physiol.* 308 (8) (2015) L731–L745.

[288] O.H. Wittekindt, Tight junctions in pulmonary epithelia during lung inflammation, *Pflugers Arch.* 469 (1) (2017) 135–147.

[289] D. Kyuno, A. Takasawa, S. Kikuchi, I. Takemasa, M. Osanai, T. Kojima, Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells, *Biochim. Biophys. Acta Biomembr.* 1863 (3) (2021), 183503.

[290] J. Liu, X. Chen, M. Dou, H. He, M. Ju, S. Ji, et al., Particulate matter disrupts airway epithelial barrier via oxidative stress to promote Pseudomonas aeruginosa infection, *J. Thorac. Dis.* 11 (6) (2019) 2617–2627.

[291] S.S. Kim, C.H. Kim, J.W. Kim, H.C. Kung, T.W. Park, Y.S. Shin, et al., Airborne particulate matter increases MUC5AC expression by downregulating Claudin-1 expression in human airway cells, *BMB Rep.* 50 (10) (2017) 516–521.

[292] T. Smyth, J. Veazey, S. Eliseeva, D. Chalupa, A. Elder, S.N. Georas, Diesel exhaust particle exposure reduces expression of the epithelial tight junction protein Tricellulin, *Part. Fibre Toxicol.* 17 (1) (2020) 52.

[293] M.R. Zeglinski, C.T. Turner, R. Zeng, C. Schwartz, S. Santacruz, M.A. Pawluk, et al., Soluble wood smoke extract promotes barrier dysfunction in alveolar epithelial cells through a MAPK signaling pathway, *Sci. Rep.* 9 (1) (2019) 10027.

[294] D.H. Ho, W.W. Burggren, Blood-brain barrier function, cell viability, and gene expression of tight junction-associated proteins in the mouse are disrupted by crude oil, benzo[a]pyrene, and the dispersant COREXIT, *Comp. Biochem. Physiol. C: Toxicol. Pharmacol.* 223 (2019) 96–105.

[295] C. Tomkiewicz, L. Herry, L.C. Bui, C. Métayer, M. Bourdeloux, R. Barouki, et al., The aryl hydrocarbon receptor regulates focal adhesion sites through a non-genomic FAK/Src pathway, *Oncogene* 32 (14) (2013) 1811–1820.

[296] P. Wee, Z. Wang, Epidermal growth factor receptor cell proliferation signaling pathways, *Cancers* (Basel) 9 (5) (2017).

[297] P. Lin, H. Chang, W.T. Tsai, M.H. Wu, Y.S. Liao, J.T. Chen, et al., Overexpression of aryl hydrocarbon receptor in human lung carcinomas, *Toxicol. Pathol.* 31 (1) (2003) 22–30.

[298] R. Gouasmi, C. Ferraro-Peyret, S. Nancey, I. Coste, T. Renno, C. Chaveroux, et al., The kynurenine pathway and cancer: Why keep it simple when you can make it complicated, *Cancers* (Basel) 14 (11) (2022).

[299] Y. Liu, X. Liang, W. Dong, Y. Fang, J. Lv, T. Zhang, *A tumor-repopulating cells induce PD-1 expression in CD8(+)* T cells by transferring kynurenine and AhR activation. *Cancer Cell.* 2018;33(3):480-94.e7.

[300] Y. Han, D. Liu, L. Li, PD-1/PD-L1 pathway: current researches in cancer, *Am. J. Cancer Res.* 10 (3) (2020) 727–742.

[301] G.Z. Wang, L. Zhang, X.C. Zhao, S.H. Gao, L.W. Qu, H. Yu, et al., The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy, *Nat. Commun.* 10 (1) (2019) 1125.

[302] T.H. Wang, K.Y. Huang, C.C. Chen, Y.H. Chang, H.Y. Chen, C. Hsueh, et al., PM2.5 promotes lung cancer progression through activation of the AhR-TMPRSS2-IL18 pathway, *EMBO Mol. Med.* 15 (6) (2023) e17014.

[303] S. Nothdurft, C. Thumser-Henner, F. Breitenbücher, R.A. Okimoto, M. Dorsch, C. A. Opitz, et al., Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis, *Oncogenesis.* 9 (11) (2020) 102.

[304] M.A. Sartor, M. Schnekenburger, J.L. Marlowe, J.F. Reichard, Y. Wang, Y. Fan, et al., Genomewide analysis of aryl hydrocarbon receptor binding targets reveals an

extensive array of gene clusters that control morphogenetic and developmental programs, *Environ. Health Perspect.* 117 (7) (2009) 1139–1146.

[305] G. van Niel, G. D'Angelo, G. Raposo, Shedding light on the cell biology of extracellular vesicles, *Nat. Rev. Mol. Cell Biol.* 19 (4) (2018) 213–228.

[306] F. Urabe, N. Kosaka, K. Ito, T. Kimura, S. Egawa, T. Ochiya, Extracellular vesicles as biomarkers and therapeutic targets for cancer, *Am. J. Physiol. Cell Phys.* 318 (1) (2020) C29–C39.

[307] Z. Al Amir Dache, A. Otandault, R. Tanos, B. Pastor, R. Meddeb, C. Sanchez, et al., Blood contains circulating cell-free respiratory competent mitochondria, *FASEB J.* 34 (3) (2020) 3616–3630.

[308] A. Mohan, S. Agarwal, M. Claus, N.S. Britt, N.K. Dhillon, Extracellular vesicles: novel communicators in lung diseases, *Respir. Res.* 21 (1) (2020) 175.

[309] R.Y. Mahida, S. Matsumoto, M.A. Matthay, Extracellular vesicles in ARDS: New insights into pathogenesis with novel clinical applications, in: *J.~L. Vincent (Ed.), Annual Update in Intensive Care and Emergency Medicine 2020*, Springer International Publishing, Cham, 2020, pp. 53–65.

[310] S. Soni, M.R. Wilson, K.P. O'Dea, M. Yoshida, U. Katbeh, S.J. Woods, et al., Alveolar macrophage-derived microvesicles mediate acute lung injury, *Thorax* 71 (11) (2016) 1020–1029.

[311] H. Lee, D. Zhang, Z. Zhu, C.S. Dela Cruz, Y. Jin, Epithelial cell-derived microvesicles activate macrophages and promote inflammation via microvesicle-containing microRNAs, *Sci. Rep.* 6 (1) (2016) 35250.

[312] Y. Liu, Y. Gu, Y. Han, Q. Zhang, Z. Jiang, X. Zhang, et al., Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils, *Cancer Cell* 30 (2) (2016) 243–256.

[313] D. de Miguel-Perez, A. Russo, O. Arrieta, M. Ak, F. Barron, M. Gunasekaran, et al., Extracellular vesicle PD-L1 dynamics predict durable response to immune-checkpoint inhibitors and survival in patients with non-small cell lung cancer, *J. Exp. Clin. Cancer Res.* 41 (1) (2022) 186.

[314] C.K. Carberry, J.E. Rager, The impact of environmental contaminants on extracellular vesicles and their key molecular regulators: A literature and database-driven review, *Environ. Mol. Mutagen.* 64 (1) (2023) 50–66.

[315] C.M. Eckhardt, A.A. Baccarelli, H. Wu, Environmental Exposures and Extracellular Vesicles: Indicators of Systemic Effects and Human Disease, *Current Environmental Health Reports.* 9 (3) (2022) 465–476.

[316] M. Le Goff, D. Lagadic-Gossmann, R. Latour, N. Podechard, N. Grova, F. Gauffre, et al., PAHs increase the production of extracellular vesicles both in vitro in endothelial cells and in vivo in urines from rats, *Environ. Pollut.* 255 (Pt 1) (2019), 113171.

[317] N. van Meteren, D. Lagadic-Gossmann, M. Chevanne, I. Gallais, D. Gobart, A. Burel, et al., Polycyclic aromatic hydrocarbons can trigger hepatocyte release of extracellular vesicles by various mechanisms of action depending on their affinity for the aryl hydrocarbon receptor, *Toxicol. Sci.* 171 (2) (2019) 443–462.

[318] Z. Chen, H. Wu, W. Fan, J. Zhang, Y. Yao, W. Su, et al., Naringenin suppresses BEAS-2B-derived extracellular vesicular cargoes disorder caused by cigarette smoke extract thereby inhibiting M1 macrophage polarization, *Front. Immunol.* 13 (2022).

[319] M. Ghildiyal, P.D. Zamore, Small silencing RNAs: an expanding universe, *Nat. Rev. Genet.* 10 (2) (2009) 94–108.

[320] H. Osada, T. Takahashi, let-7 and miR-17-92: Small-sized major players in lung cancer development, *Cancer Sci.* 102 (1) (2011) 9–17.

[321] P.Y. Lin, S.L. Yu, P.C. Yang, MicroRNA in lung cancer, *Br. J. Cancer* 103 (8) (2010) 1144–1148.

[322] M.S. Kumar, J. Lu, K.L. Mercer, T.R. Golub, T. Jacks, Impaired microRNA processing enhances cellular transformation and tumorigenesis, *Nat. Genet.* 39 (5) (2007) 673–677.

[323] M.A. Iqbal, S. Arora, G. Prakasam, G.A. Calin, M.A. Syed, MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance, *Mol. Aspects Med.* 70 (2019) 3–20.

[324] M. Cheng, B. Wang, M. Yang, J. Ma, Z. Ye, L. Xie, et al., microRNAs expression in relation to particulate matter exposure: A systematic review, *Environ. Pollut.* 260 (2020), 113961.

[325] L. Dai, F. Chen, Y. Zheng, D. Zhang, B. Qian, H. Ji, et al., miR-21 regulates growth and EMT in lung cancer cells via PTEN/Akt/GSK3β signaling, *FBL, 24* (8) (2019) 1426–1439.

[326] L.R. Barkley, C. Santocanale, MicroRNA-29a regulates the benzo[a]pyrene dihydrodiol epoxide-induced DNA damage response through Cdc7 kinase in lung cancer cells, *Oncogenesis.* 2(7):e57-e (2013).

[327] S.-L. Yu, H.-Y. Chen, G.-C. Chang, C.-Y. Chen, H.-W. Chen, S. Singh, et al., MicroRNA signature predicts survival and relapse in lung cancer, *Cancer Cell* 13 (1) (2008) 48–57.

[328] Y. Fujita, K. Kuwano, T. Ochiya, F. Takeshita, The impact of extracellular vesicle-encapsulated circulating microRNAs in lung cancer research, *Biomed. Res. Int.* 2014 (2014), 486413.

[329] A. Izzotti, R. Balansky, G. Ganchev, M. Iltcheva, M. Longobardi, A. Pulliero, et al., Blood and lung microRNAs as biomarkers of pulmonary tumorigenesis in cigarette smoke-exposed mice, *Oncotarget* 7 (51) (2016) 84758–84774.

[330] V. Bollati, B. Marinelli, P. Apostoli, M. Bonzini, F. Nordio, M. Hoxha, et al., Exposure to metal-Rch particulate matter modifies the expression of candidate microRNAs in peripheral blood leukocytes, *Environ. Health Perspect.* 118 (6) (2010) 763–768.

[331] I. Ryning, V.M. Arlt, K. Vrbova, J. Neca, P. Rossner Jr., J. Klema, et al., Bulky DNA adducts, microRNA profiles, and lipid biomarkers in Norwegian tunnel finishing workers occupationally exposed to diesel exhaust, *Occup. Environ. Med.* 76 (1) (2019) 10–16.