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. 2016 Jul;57(6):435-46.
doi: 10.1002/em.22024. Epub 2016 Jun 23.

Epigenome-wide DNA Methylation Analysis Implicates Neuronal and Inflammatory Signaling Pathways in Adult Murine Hepatic Tumorigenesis Following Perinatal Exposure to Bisphenol A

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Free PMC article

Epigenome-wide DNA Methylation Analysis Implicates Neuronal and Inflammatory Signaling Pathways in Adult Murine Hepatic Tumorigenesis Following Perinatal Exposure to Bisphenol A

Caren Weinhouse et al. Environ Mol Mutagen. .
Free PMC article

Abstract

Developmental exposure to the endocrine-active compound bisphenol A (BPA) has been linked to epigenotoxic and potential carcinogenic effects in rodent liver, prostate, and mammary glands. A dose-dependent increase in hepatic tumors in 10-month mice perinatally exposed to one of three doses of BPA (50 ng, 50 µg, or 50 mg BPA/kg chow) was previously reported. These tumors represent early-onset disease and lack classical sexual dimorphism in incidence. Here, adult epigenome-wide liver DNA methylation profiles to identify gene promoters associated with perinatal BPA exposure and disease in 10-month mice with and without liver tumors were investigated. Mice with hepatic tumors showed 12,822 (1.8%) probes with differential methylation as compared with non-tumor animals, of which 8,656 (67.5%) were hypomethylated. A significant enrichment of differential methylation in Gene Ontology (GO) terms and biological processes related to morphogenesis and development, and epigenomic alteration were observed. Pathway enrichment revealed a predominance of hypermethylated neuronal signaling pathways linked to energy regulation and metabolic function, supporting metabolic consequences in the liver via BPA-induced disruption of neuronal signaling pathways. Hypothesis-driven pathway analysis revealed mouse and human genes linked to BPA exposure related to intracellular Jak/STAT and MAPK signaling pathways. Taken together, these findings are indicators of the relevance of the hepatic tumor phenotype seen in BPA-exposed mice to human health. This work demonstrated that epigenome-wide discovery experiments in animal models were effective tools for identification and understanding of paralagous epimutations salient to human disease. Environ. Mol. Mutagen. 57:435-446, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: bisphenol A (BPA); developmental origins of health and disease (DOHaD); endocrine disruptors; environmental epigenetics; epigenetics; hepatocellular carcinoma.

Figures

Figure 1
Figure 1. Overlapping mouse and human genes altered by BPA exposure in the Jak-Stat signaling pathway
Unique mouse microarray gene IDs involved in Jak/Stat signaling that overlap with human JAK/STAT gene IDs with known interactions with BPA in The Comparative Toxicogenomics Database are shown in red.
Figure 2
Figure 2. Overlapping mouse and human genes altered by BPA exposure in the Mapk signaling pathway
Unique mouse microarray gene IDs involved in Mapk signaling that overlap with human MAPK gene IDs with known interactions with BPA in The Comparative Toxicogenomics Database are shown in red.

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