LONG-TERM OBJECTIVES AND SPECIFIC AIMS: Our scientific hypothesis is that arsenic is a fetal epimutagen, maternal lipotropic nutrition a fetal anti-epimutagen, and that the balance of the two will determine fetal gene silencing and adult-onset cancer incidence. This hypothesis is supported by the following observations. First, fetal exposure to arsenic is a complete carcinogen in mice: a brief exposure in utero results in multiple adult-onset cancers. In this model, arsenic has been proposed to act by depleting methyl donors, resulting in epigenetic aberrations that contribute to carcinogenesis. Second, in rodent models of methyl deficiency-induced hepatocellular carcinoma, altered global and gene-specific DMA methylation was a consistent finding, suggesting that it was causative. Third, arsenic administration causes global and gene-specific hypomethylation of liver DNA in mice that is correlated with differential expression of affected genes. Fourth, fetal exposure to the dietary lipotropes betaine, choline, folate and vitamin B12, through maternal supplementation, alters DNA methylation in utero. We propose to: 1. identify and quantitate stable changes in gene expression caused by fetal exposure to arsenic and maternal dietary methyl supplementation, 2. correlate differential expression of genes with defects in DNA methylation, and 3. evaluate tumor incidence resulting from fetal arsenic exposure in the presence and absence of maternal methyl supplementation. If successful, our proposal will test the theory that arsenic is an epimutagen, test the theory that nutrients are anti-epimutagens, identify genes that are susceptible to arsenic and diet, and provide a general screening technique for use in quantifying fetal epigenetic risks.
exposure to arsenic in drinking water is a known human carcinogen, yet its mechanism of action is not well understood. Poor nutrition is also a key risk factor for cancer in humans, also by poorly defined mechanisms. Recent animal studies suggest that brief exposure to arsenic, and altered dietary supply of nutrients such as folate and B12 in the womb, may influence cancer incidence years later, in adults. The proposed research will investigate the potential links between exposure to environmental toxicants and dietary nutrition in utero that may contribute significantly to human cancer. ? ? ?
