title: Epigenome-wide DNA methylation analysis implicates neuronal and inflammatory signaling pathways in adult murine hepatic tumorigenesis following perinatal exposure to bisphenol A.
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.
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Caren
authors.initials: C
authors.lastname: Weinhouse
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Christopher
authors.initials: C
authors.lastname: Faulk
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.|Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Anderson
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Karilyn E
authors.initials: KE
authors.lastname: Sant
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.|Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Craig
authors.initials: C
authors.lastname: Harris
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan.|Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Dolinoy
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D004247:DNA / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D063990:Gene Ontology; D055106:Genome-Wide Association Study; D007774:Lactation; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D010636:Phenols / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000235:genetics*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002274:Carcinogens, Environmental; D004247:DNA; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: bisphenol A (BPA); developmental origins of health and disease (DOHaD); endocrine disruptors; environmental epigenetics; epigenetics; hepatocellular carcinoma