oa Inactivation of the Putative Tumour Suppressor Gene DOK1 by Epigenetic Modifications in Human Cancers

Epigenetics investigates heritable changes in gene expression that occur without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation and histone modifications, can change genome function under exogenous influence. Results obtained from animal models indicate that in utero, or early-life environmental exposures, produce effects that can be inherited transgenerationally and are accompanied by epigenetic alterations. The search for human equivalents of the epigenetic mechanisms identified in animal models is in progress. I will present evidence from human environmental studies indicating that epigenetic alterations may mediate effects caused by exposure to environmental toxicants. In these investigations, we have shown that air pollution exposure is associated with altered methylation of human repetitive elements or genes. In recent preliminary studies, we have shown alterations of histone modifications in subjects exposed to metal-rich airborne particles. I will present original data demonstrating that altered DNA methylation in blood and other tissues is associated with environmentally induced disease, such as cardiovascular disease and asthma. On the basis of current evidence, I will propose possible models for the interplay between air pollution exposure and the human epigenome.