There is an increasing suggestion in the academic literature that exposure to environmental contaminants may play an aetiological role in a range of disease-predisposing conditions, including obesity. Although high-density calorie diet and lack of physical activity might be the primary causes of obesity, endocrine disruptors acting as obesogens could initiate or exacerbate this morbidity [61
]. In addition to endocrine disruptors, there is a growing body of evidence that heavy metals, including nickel, lead, cadmium, arsenic and others, asbestos, and alcohol intake all act to variously modify the potential for epigenetic alterations [63
]. Air pollution constituents, especially particulate matter (PM), appear to alter the profile of miRNAs [18
]. PM is known to alter epigenetic markers (e.g., DNA methylation and histone modifications), which may contribute to air-pollution-mediated health consequences including an elevated risk for cardiovascular diseases or events; identifying individual epigenetic loci associated with dysregulated gene expression following exposure could generate novel intervention strategies mitigating the development of such adverse outcomes [64
]. Ionizing radiation and nanomaterials are also thought to induce epigenetic alterations. In addition, perfluorinated compounds are of significant concern as they bioaccumulate with suggestions that in utero
human exposure is associated with global hypomethylation of the genome; recently, perfluorooctanoic acid-mediated toxicity was associated with aberrant methylation of glutathione-S
-transferase Pi [65
], a carcinogen-detoxifying enzyme.
Chemical pollutants, dietary components, temperature changes, and other external stresses can indeed have long-lasting effects on development, metabolism, and health, sometimes even in generations subsequent to the exposed individual [66
]. A growing body of epidemiological evidence demonstrates associations between parental usage (especially occupational) of pesticides, particularly insecticides, giving rise to acute lymphocytic leukaemia and brain tumours in offspring [67
]. Accumulating evidence suggests that environmental and occupational exposures to natural substances, as well as man-made chemical and physical agents, play an aetiological role in human cancer; carcinogenesis may be induced by either genotoxic or nongenotoxic carcinogens (e.g., arsenic, 1,3-butadiene) that also cause prominent epigenetic changes [68
]. Cadmium is a toxic, nonessential transition metal and contributes a health risk to humans, including strong associations between its exposure and various cancers or cardiovascular diseases. This agent has been shown to induce various epigenetic changes in plant and mammalian cells in vitro
and in vivo
, and this is likely the primary mechanism via
which it mediates its toxicity [69
The importance of early-life changes towards future susceptibility to chronic age-related diseases is gaining increasing recognition. Of major concern in this regard are observations that common environmental contaminants such a bisphenol A and phthalates can variously be hypomethylating and alter miRNA expression levels or DNMT activities [70
]; the fact that such agents appear to induce low-dose effects postmaternal exposure in the genital tract of female offspring of mice [71
] suggests a phenotype change associated with an epigenetic alteration that has later-life consequences. In fact, in the area of environmental epigenetics, such agents as well as other endocrine disruptors including organochlorines, are likely to play a pivotal role [72
]. This could be an important link with cancers arising from hormone-responsive tissues, including the breast and prostate. Disruptors of hormonal status via epimutagenic processes are yet to be understood in terms of their long-term health consequences.
The interplay between genotoxicity and epigenetic alterations remains to be elucidated; for instance, acetylation of histones occurs during the process of DNA damage induction [73
]. As direct-acting DNA-damaging agents are traditionally known as genotoxins, agents that induce aberrant epigenetic alterations may be known as epimutagens. In general, cancer is typified by global genomic hypomethylation and site-specific hypermethylation [74
], especially at TSGs: the former being associated with an overactive genome and proliferation, and the latter with inactivation of genes such as TP53 that might sit at the crossroads between induction of aberrant proliferation and apoptosis. Time of exposure during life, dose, gender, and organ specificity all need to be considered in the development of epigenetic endpoints as biomarkers for exposure to epimutagenic toxicants [75
]. How at different stages of life in a particular target organ there is induction of irreversible changes to the genetic material (i.e., DNA mutations) against a backdrop of putatively reversible changes to the epigenetic landscape (i.e., changes in the DNA methylation and chromatin modification state) remains to be understood [76
]. Does the latter modify accessibility of the genome in a fashion that predisposes it to genotoxic insult? This may underpin the interplay between genotoxic and epigenetic mechanisms in the aetiology of cancer.