Epigenetic Regulation in Environmental Chemical Carcinogenesis and its Applicability in Human Health Risk Assessment.
Although several studies have shown that chemically mediated epigenetic changes are an etiological factor in several human disease conditions, the utility of epigenetic data, such as DNA methylation, in the current human health risk assessment paradigm is unclear. The objective of this study is to investigate the relationship between the points of departure (PODs) for cancer incidence and DNA methylation changes in laboratory animals exposed to the following environmental toxicants: bromodichloromethane, dibromochloromethane, chloroform, hydrazine, trichloroethylene, benzidine, trichloroacetic acid, and di(2-ethylhexyl) phthalate (DEHP; a known reproductive toxicant). The results demonstrate that the PODs for cancer incidence and altered DNA methylation are similar. Furthermore, based on the available data, the POD for DNA methylation appeared more sensitive compared to that for cancer incidence following the administration of DEHP to rats during different life stages. The high degree of correlation between PODs for cancer incidence and DNA methylation (for both total DNA and individual genes) suggests that DNA methylation end points could potentially be used as a screening tool in predicting the potential toxicity/carcinogenicity and in prioritizing large numbers of chemicals with sparse toxicity databases. The life stage during which treatment occurs is also an important consideration when assessing the potential application of epigenetic end points as a screening tool.
Oak Ridge Institute for Science and Education Participant at the U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH, USA.
Senthilkumar P
SP
Kuppusamy
U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment. Cincinnati, OH, USA.
J Phillip
JP
Kaiser
U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment. Cincinnati, OH, USA wesselkamper.scott@epa.gov.
Scott C
SC
Wesselkamper
D000818:Animals; D001560:Benzidines / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D019175:DNA Methylation; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D044127:Epigenesis, Genetic; D006801:Humans; D006834:Hydrazines / Q000633:toxicity; D006846:Hydrocarbons, Halogenated / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics; D018570:Risk Assessment
D001560:Benzidines; D002273:Carcinogens; D006834:Hydrazines; D006846:Hydrocarbons, Halogenated; C029424:hydrazine; C029876:benzidine; D004051:Diethylhexyl Phthalate
DNA methylation; cancer; epigenetics; human health risk assessment