Biological embedding, the air we breathe, and carcinogenesis
Authors: Anders C Erickson, Hind Sbihi
Journal: The Lancet Planetary Health (2018)

Early life environments predispose children to later health outcomes; this process, known as biological embedding, is central to the developmental origins of health and disease (DOHaD) concept. Indeed, the responsiveness, plasticity, and memory characteristics of epigenetics make it one of the most attractive models to explain biological embedding. Epigenetics refers to modifications of DNA and DNA packaging that modify the accessibility of DNA for gene expression without changing the sequence of the DNA itself. Therefore, epigenetics is one way by which external factors, such as environmental exposures, might contribute to the development of disease via persistent—but possibly not permanently—altered gene expression. DNA methylation, arguably the most highly studied epigenetic mark, has been correlated with early life environmental exposures. For example, the relationship between maternal exposure to cigarette smoke and cancer outcomes in their offspring has received considerable attention.1Joubert BR Felix JF Yousefi P et al.DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis.Am J Hum Genet. 2016; 98: 680-696Summary Full Text Full Text PDF PubMed Scopus (523) Google Scholar Similarly, air pollution, specifically fine particulate matter (PM2·5) is also classified as a group 1 carcinogen,2Straif K Cohen A Samet J Outdoor air pollution a leading environmental cause of cancer deaths. International Agency for Research on Cancer, Lyon2013Google Scholar and mounting evidence has linked maternal PM2·5 exposure during pregnancy with childhood cancers.3Lavigne É Bélair M-A Do MT et al.Maternal exposure to ambient air pollution and risk of early childhood cancers: a population-based study in Ontario, Canada.Environ Int. 2017; 100: 139-147Crossref PubMed Scopus (74) Google Scholar Thus, it is timely to examine DNA methylation changes in the placenta, the biological specimen of choice for investigations into the interplay between the air we breathe and fetal development.4Green BB Marsit CJ Select prenatal environmental exposures and subsequent alterations of gene-specific and repetitive element DNA methylation in fetal tissues.Curr Environ Heal reports. 2015; 2: 126-136Crossref PubMed Scopus (35) Google Scholar In The Lancet Planetary Health, Kristof Neven and colleagues5Neven KY Saenen ND Tarantini L et al.Placental promoter methylation of DNA repair genes and prenatal exposure to particulate air pollution: an ENVIRONAGE cohort study.Lancet Planet Health. 2018; 2: e174-e183Summary Full Text Full Text PDF PubMed Scopus (56) Google Scholar address some of the central questions regarding prenatal exposures to PM2·5 and the DOHaD concept of carcinogenesis. The investigators showed that prenatal exposure to low levels of particulate air pollution was associated with an increased placental mutation rate measured in Alu (as an estimate of global mutation), as well as DNA methylation of key DNA repair and tumour suppressor genes, suggesting a potential mechanism for increased cancer risk across the life course. Epigenetics in general, and DNA methylation in particular, hold great promise for the discovery of molecular mechanisms by which the environment interacts with the genome. However, much remains to be discovered: most studies of the interactions between the genome, gene expression, and the epigenome do not carefully ascertain all of the environmental exposures and specific health outcomes required to define the contribution of the epigenome to health and disease.6Jones MJ Fejes AP Kobor MS DNA methylation, genotype and gene expression: who is driving and who is along for the ride?.Genome Biol. 2013; 14: 126Crossref PubMed Scopus (43) Google Scholar Neven and colleagues have started to address these priority knowledge gaps through a precise exposure assessment. Their highly resolved spatiotemporal air pollution model had strong predictive power to estimate each participant's daily personal exposure to air pollution. With such granularity enabled by the model, the authors were able to examine the exposure estimates for pregnant mothers by trimester, which allowed for the identification of potential critical time windows for transplacental carcinogenesis: mutation rate was affected by late pregnancy exposures whereas hypermethylation of tumour suppressor genes and hypomethylation of DNA repair genes were affected by mid to late pregnancy. Personal exposure levels were also assigned throughout the entire pregnancy period and the associations were stronger in this analysis than those in the trimester-specific analyses. Models were controlled for an extensive list of potential risk factors that could confound the air pollution-outcomes associations, as well as thorough sensitivity analyses, lending further confidence to the findings. Although the exposure assessment is definitely a strength of their investigation, PM2·5 remains a non-specific air pollution mixture that results from various sources, thus making it difficult to target with preventive measures. Notably, Neven and colleagues showed that black carbon, a more specific marker of traffic-related air pollution, had similar associations to PM2·5. Although this finding strengthens the evidence to support local or regional transportation policy measures to reduce vehicle emissions,7Rich DQ Accountability studies of air pollution and health effects: lessons learned and recommendations for future natural experiment opportunities.Environ Int. 2017; 100: 62-78Crossref PubMed Scopus (57) Google Scholar future work should investigate measures of toxicity (eg, oxidative potential) in particulate air pollution8Weichenthal S Crouse DL Pinault L et al.Oxidative burden of fine particulate air pollution and risk of cause-specific mortality in the Canadian Census Health and Environment Cohort (CanCHEC).Environ Res. 2016; 146: 92-99Crossref PubMed Scopus (71) Google Scholar to enable a targeted and evidence-based exposure mitigation approach. There remains a need to define how early life exposures can become biologically embedded and drive the development of specific cancers. Future research should examine mechanistic pathways and questions about specific sites of DNA methylation associated with exposures: if key environmental exposures create independent or overlapping epigenomic patterns, research can then start to pinpoint an optimal healthy environment that can mitigate or reverse epigenetic changes. The identification of prenatal epigenetic biomarkers associated with carcinogenesis offers the possibility to circumvent the challenging task of linking PM2·5 exposure with long latency cancer outcomes. Perhaps one of the most important assumptions that was implied in this study was that transplancetal changes translate into fetal tissues changes. This assumption notwithstanding, the stability of DNA methylation and its potential for tumorigenesis still needs to be established. Indeed, in the relatively recent field of environmental epigenetics, an important caveat is the highly variable nature of DNA methylation mechanisms, especially in early life. This study has the merit of being able to open the way for further work on the kinetics of DNA methylation by leveraging the longitudinal nature of the ENVIRONAGE birth cohort. We declare no competing interests. Placental promoter methylation of DNA repair genes and prenatal exposure to particulate air pollution: an ENVIRONAGE cohort studyTransplacental in-utero exposure to particulate matter is associated with an increased overall placental mutation rate (as measured with Alu), which occurred in concert with epigenetic alterations in key DNA repair and tumour suppressor genes. Our results suggest that exposure to air pollution can induce changes to fetal and neonatal DNA repair capacity. Future studies will be essential to elucidate whether these changes persist and have a role in carcinogenic insults later in life. Full-Text PDF Open Access