On the Chemical Causation of Methyl Deficiency and its Attendant Pathologies

1 FDA's National Center for Toxicological Research (NCTR), Jefferson, Arkansas 72079, 2 Investigacion Biomedica en Cancer, IB-INCan, Box 70-228, Mexico City 04510, Mexico (LAH) Abstract: It is now fairly well established that physiological methyl group deficiency and abnormal DNA methylation are involved in the etiology of several pathological processes. The proceedings of a recent meeting on this subject held at the NIH campus in Bethesda, MD, the "Trans-HHS Workshop: Diet, DNA Methylation Processes and Health", have recently been described (Journal of Nutrition, 132 (8S):2329S-2484S, 2002). The pathologies considered at the workshop included: cancer, atheroscle­ rosis, birth defects, aging, diabetes and pancreatic toxicity, and hepatotoxicity. Two major causes of the diseases related to methyl group insufficiency were considered at this conference: dietary defi­ ciency and genetic polymorphism. A third prospective cause, chemicals, was not treated in depth. The purpose of this article is to explore the evidence that exogenous chemicals, like dietary imbal­ ances and genetic defects, may produce the abnormal methylation processes linked to the etiology of disease. The pathologies con sidered are cancer, pancreatic toxicity and diabetes, atherosclerosis, birth defects, and neurotoxicity. Four categories of toxic chemicals are considered: the antimetab­ olites of the methyl donors, the anticonvulsants, polyhalogenated compounds, and metals. The re­ sults indicate that a number of such agents appear to exert their pathological effects, at least in part, through abnormal methylation processes.