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Examination of age-related epigenetic changes following early-life exposure to dichloroacetic acid
Citation:
Carswell, G., B. Chorley, S. Hester, A. Deangelo, AND C. Wood. Examination of age-related epigenetic changes following early-life exposure to dichloroacetic acid. To be Presented at Keystone Symposium, Keystone, CO, March 29 - April 03, 2015.
Impact/Purpose:
To be presented at the Keystone Colorado Meeting: March 29-April 3, 2015
Description:
Recent studies have shown that transient early-life exposure to dichloroacetic acid (DCA), a pyruvate analog and metabolic reprogramming agent, increases liver cancer incidence in older mice. This carcinogenic effect is not associated with direct mutagenicity, persistent cytotoxicity, or cellular proliferation. To help identify an epigenetic basis for this carryover effect, messenger RNA/miRNA expression and DNA methylation were measured in liver samples at multiple time points following postnatal exposure to 3.5 g/L of DCA for 10, 26, 52, or 78 weeks in male B6C3F1 mice. DCA stop-exposures <78 weeks were followed by control treatment. Major changes in mRNA expression profiles were transient and reverted back to control levels after DCA stop-exposure. Mice exposed to DCA for 10 weeks early in life had significantly lower expression of a small cluster of miRNAs (chrX: mir465-mir743) compared to control mice at 78 weeks (ANOVA, p-value<0.05; average fold decrease 5.7). Published evidence has suggested these miRNAs are linked to cellular differentiation processes, but little is known about the regulation of this cluster. High resolution melt curve analysis (HRM) showed significantly higher global DNA methylation in the older control group mice (+10% at 26 vs. 78 weeks). Direct DCA exposure tended to suppress this age-dependent increase but this DCA effect did not exhibit long-term carryover. Using HRM or restriction enzyme assays, we also examined the nearest flanking CpG regions to the chrX miRNA cluster, as well as promoter regions in a selected panel of genes associated with mouse liver cancer. No significant methylation changes were detected, suggesting that DNA methylation was not a primary determinant of expression for this miRNA cluster. These findings show that age-dependent changes in DNA methylation status and miRNA may be altered by both persistent and early-life exposures. This abstract does not necessarily reflect the policy of the US EPA.