Occupational exposure to polycyclic aromatic hydrocarbons and early biomarkers related to cardiovascular disease and cancer

Polycyclic aromatic hydrocarbons (PAH) are omnipresent environmental pollutants composed of fused benzene rings and mainly produced by incomplete combustion of organic material. PAH exposure has been associated with increased risk of cancer and probably cardiovascular disease (CVD). In one way or another, everyone is exposed to PAH, but the dose and the period of exposure vary between individuals. Workers who remove soot from chimneys (chimney sweeps) are likely exposed to higher levels of PAH compared with the general population. However, whether the current PAH exposure among chimney sweeps leads to disease is not known. The overall aim of this thesis was to evaluate PAH exposure among currently working chimney sweeps as well as explore early biomarkers related to cardiovascular disease (CVD) and cancer. For this purpose, we recruited 151 chimney sweeps and 152 unexposed control individuals, all males from southern Sweden, from whom we collected questionnaires and biological samples. In one of the studies, we additionally used data and biological samples from 19 creosote-exposed workers, i.e. workers who impregnate wood panels with black oily material rich in PAH known as creosote. We found that PAH exposure (measured as PAH metabolites in urine) was up to 7 times higher among chimney sweeps compared with unexposed control workers, and the levels of PAH metabolites were positively associated with diastolic blood pressure. Moreover, we found higher serum concentrations of the classical risk markers for CVD (homocysteine and cholesterol) in chimney sweeps, compared with controls. Further, we found 25 putative CVD-related serum proteins differentially expressed between nonsmoking chimney sweeps and controls, among which follistatin (FS), heat shock protein beta-1 (HSP 27), and pro-interleukin-16 (IL-16) showed positive dose-response relationships with PAH metabolites. Pathway analysis demonstrated that these 25 proteins were mainly involved in inflammatory response and immune function. We also demonstrated hypomethylation (lower methylation) of the genes F2RL3 and AHRR, risk markers for lung cancer, among chimney sweeps and creosote-exposed workers, compared with controls. Notably, creosote-exposed workers had the highest PAH exposure and the lowest DNA methylation, compared with both chimney sweeps and controls, which suggests a dose-response relationship. In addition, we found 17 putative cancer-related serum proteins differentially expressed between nonsmoking chimney sweeps and controls, among which kallikrein-13 (KLK13) showed positive dose-response relationships with the metabolites of carcinogenic PAH (BaP and BaA). Pathway analysis showed that most of the differentially expressed proteins were involved in cell movement, cell migration, and cell invasion. Overall, findings from this thesis indicate that (i) currently working chimney sweeps are markedly exposed to PAH, (ii) chimney sweeps showed molecular changes related to CVD and cancer, and (iii) some of these molecular changes seem to be, at least partly, induced by PAH exposure. These results stress that protective measures are warranted to reduce PAH exposure among chimney sweeps as well as other occupational groups at risk of PAH exposure. In addition, further research exploring mechanisms of PAH-induced CVD and cancer is encouraged in order to develop strategies of early detection of disease among individuals known to be exposed to PAH. LIST OF SCIENTIFIC PAPERS I. Alhamdow, A. , Lindh, C. , Albin, M. , Gustavsson, P., Tinnerberg, H. , Broberg, K. , 2017. Early markers of cardiovascular disease are associated with occupational exposure to polycyclic aromatic hydrocarbons. Scientific Reports, 7(1):9426 II. Alhamdow, A. , Lindh, C. , Albin, M. , Gustavsson, P., Tinnerberg, H. , Broberg, K. Cardiovascular disease-related serum proteins in workers occupationally exposed to polycyclic aromatic hydrocarbons. (Submitted manuscript) III. Alhamdow, A. , Lindh, C. , Hagberg, J., Graff, P., Westberg, H. , Krais, A.M., Albin, M. , Gustavsson, P., Tinnerberg, H. , Broberg, K. , 2018. DNA-methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons. Carcinogenesis, 39(7):869-878 IV. Alhamdow, A. , Tinnerberg, H. , Lindh, C. , Albin, M. , Broberg, K. , 2019. Cancer-related proteins in serum are altered in workers occupationally exposed to polycyclic aromatic hydrocarbons: a cross-sectional study. Carcinogenesis, [Epub 2019 Feb 8] V. I.