Citation:

Carswell, G., L. Wehmas, S. Hester, B. Vallanat, J. Chamberlin, C. Wood, B. Chorley, AND B. Bennett. DNA Methylation Alterations Associated with Latent Carcinogenic Activity of Dichloroacetic Acid in Mice. DNA and RNA Methylation - Keystone Symposia, Vancouver, British Columbia, CANADA, January 21 - 26, 2018.

Impact/Purpose:

This work contributes to understanding the link between early-life chemical exposure and latent carcinogenicity. In particular, the study examines the possible role of epigenetic regulation in cancer development and adverse health outcomes after short-term exposure. Epigenetic changes are widely viewed as promising biomarkers in predicting adverse health outcomes in human populations after environmental exposures.

Description:

Early-life environmental factors can influence later-life susceptibility to cancer. Epigenetic changes serve as promising biomarkers for these latent effects. Previously, we reported that short-term postnatal exposure to dichloroacetic acid (DCA), a byproduct of drinking water chlorination, increased liver tumor incidence in mice 84 weeks after prior exposure. Persistent alterations in liver cell proliferation, apoptosis, necrosis, or DNA sequence variants were not observed over time, ruling out classical cytotoxic, mitogenic, and genotoxic modes of action for carcinogenesis. We hypothesized that the latent carcinogenic activity of prior DCA exposure may be mediated by epigenetic mechanisms. DNA methylation and gene expression were measured by next generation sequencing in livers collected from 78 week-old mice exposed continuously to DCA at 3.5g/l in drinking water (direct group), short-term 10-week exposure to 3.5g/l DCA followed by 68 weeks of water (stop group), or drinking water only (control group). Robust alterations in gene expression were observed in the direct group when compared to controls (1774 differentially expressed genes (DEGs)). DEGs were linked to biological pathways of fatty acid metabolism, acute phase response, and NRF2-mediated oxidative stress. Similarly, 4172 differentially methylated regions (DMRs) were identified in the direct group compared to control. The majority of these DMRs were hypomethylated (79%). In addition, 54% of the DMRs mapped within gene regions, which included 176 DEGs. At 78 weeks, significant mRNA changes in the stop group (35 DEGs) showed little overlap with genes in the direct group (7). A total of 662 DMRs were measured in the stop group; 87 overlapped with the direct group DMRs and 52 of those mapped to gene regulatory regions. These data suggest that DCA exposure alters methylation profiles; however, the biological impact and the contribution of DMRs to latent carcinogenesis is not known. This abstract does not represent EPA policy.

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