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Genetic and epigenetic alterations associated with latent liver carcinogenesis due to early-life dichloroacetic acid exposure in mice
Citation:
Chorley, B. Genetic and epigenetic alterations associated with latent liver carcinogenesis due to early-life dichloroacetic acid exposure in mice. Society of Toxicology, San Diego, CA, March 27 - 31, 2022. https://doi.org/10.23645/epacomptox.19412348
Impact/Purpose:
The presented research describes a case-study of epigenetic alterations due to early-life chemical exposure that link to later-in-life adverse outcomes - in this case the water disinfectant byproduct, dichloroacetic acid exposure in mouse leading to liver cancer outcomes. The importance of this work is to demonstrate the utility of measuring epigenetic biomarkers that may influence later in life susceptibilities. Assessing such mechanisms is important to establish quantitative measure of susceptibility cause by environmental pollutants.
Description:
Early-life environmental factors can influence later-life susceptibility to cancer. Previously, we reported that exposure to dichloroacetic acid (DCA), a byproduct of water chlorination, increased liver cancer incidence in mice 84 weeks after prior exposure. However, we did not observe classical cytotoxic, mitogenic, and genotoxic modes of action for carcinogenesis. We hypothesized that the latent carcinogenic activity of prior DCA exposure is mediated by persistent effects, which may be indicated by epigenetic footprints. Gene expression were measured by S1500+ gene set (TempO-seq) in mouse liver samples collected from a stop-promotion study in which DCA at 3.5g/l in drinking water continuously (direct group) or shorter periods followed by water only (stop groups) up to 78 weeks of age. Genome-scaled DNA methylation was assessed at 78 weeks in the control, direct, and stop groups. Our results indicated that many significantly altered genes are reduced as a function of time since exposure occurs. However, gene pathway-level analyses revealed that certain pathways persisted, were more enriched, or even directionally flipped from direct group exposures. This latter group of pathways, which include GP6 signaling, stellate cell activation, and fibrotic processes, may indicate unique biological effects in the stop groups compared to constant DCA exposure - thereby distinguishing the differential tumorigenic processes caused by latent and persistent exposure. Additionally, DNA methylation patterns measured at 78-weeks were linked to genes of these pathways and may serve as biomarkers of pathway perturbation involved in DCA mode-of-action. This study highlights the use of a multi-omic approach to identify the mechanisms of early-life environmental chemical exposure on later life adverse outcomes. This abstract does not represent EPA policy.
URLs/Downloads:
DOI: Genetic and epigenetic alterations associated with latent liver carcinogenesis due to early-life dichloroacetic acid exposure in mice
220330_SOT PRESENTATION_BNC_V4 TO STICS.PDF (PDF, NA pp, 2216.484 KB, about PDF)