Environmental Carcinogenesis and Transgenerational Transmission of Carcinogenic Risk: From Genetics to Epigenetics

The dominant pathogenic model, somatic mutation theory (SMT), considers carcinogenesis as a ‘genetic accident’ due to the accumulation of ‘stochastic’ DNA mutations. This model was proposed and accepted by the scientific community when cancer mainly affected the elderly, but it does not explain the epidemiological observation of the continuous increase in cancer incidence among children and young adults. Somatic mutation theory has been proposed for a revision based on the emerging experimental evidence, as it does not fully address some issues that have proven to be crucial for carcinogenesis, namely: the inflammatory context of cancer; the key role played by the stroma, microenvironment, endothelial cells, activated macrophages, and surrounding tissues; and the distorted developmental course followed by the neoplastic tissue. Furthermore, SMT is often not able to consider either the existence of specific mutations resulting in a well-defined cancer type, or a clear relationship between mutations and tumor progression. Moreover, it does not explain the mechanism of action of the non-mutagenic and environmental carcinogens. In the last decade, cancer research has highlighted the prominent role of an altered regulation of gene expression, suggesting that cancer should be considered as a result of a polyclonal epigenetic disruption of stem/progenitor cells, mediated by tumour-inducing genes. The maternal and fetal exposure to a wide range of chemicals and environmental contaminants is raising the attention of the scientific community. Indeed, the most powerful procarcinogenic mechanisms of endocrine disruptors and other pollutants is linked to their potential to interfere epigenetically with the embryo-fetal programming of tissues and organs, altering the regulation of the genes involved in the cell cycle, cell proliferation, apoptosis, and other key signaling pathways. The embryo-fetal exposure to environmental, stressful, and proinflammatory triggers (first hit), seems to act as a ‘disease primer’, making fetal cells and tissues more susceptible to the subsequent environmental exposures (second hit), triggering the carcinogenic pathways. Furthermore, even at the molecular level, in carcinogenesis, ‘epigenetics precedes genetics’ as global DNA hypomethylation, and the hypermethylation of tumor suppressor genes are common both in cancerous and in precancerous cells, and generally precede mutations. These epigenetic models may better explain the increase of cancer and chronic/degenerative diseases in the last decades and could be useful to adopt appropriate primary prevention measures, essentially based on the reduction of maternal-fetal and child exposure to several procarcinogenic agents and factors dispersed in the environment and in the food-chains, as recently suggested by the World Health Organization.