title: Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health.
abstract: Bisphenol A (BPA) is an endocrine disrupting chemical (EDC) that has been implicated as a potential carcinogen and epigenotoxicant. We have previously reported dose-dependent incidence of hepatic tumors in 10-month-old isogenic mice perinatally exposed to BPA. Here, we evaluated DNA methylation at 3 candidate genes (Esr1, Il-6st, and Stat3) in liver tissue of BPA-exposed mice euthanized at 2 time points: post-natal day 22 (PND22; n = 147) or 10-months of age (n = 78, including n = 18 with hepatic tumors). Additionally, DNA methylation profiles were analyzed at human homologs of murine candidate genes in human fetal liver samples (n = 50) with known liver tissue BPA levels. Candidate genes were chosen based on reported expression changes in both rodent and human hepatocellular carcinoma (HCC). Regions for bisulfite sequencing were chosen by mining whole genome next generation sequencing methylation datasets of both mice and human liver samples with known perinatal BPA exposures. One of 3 candidate genes, Stat3, displayed dose-dependent DNA methylation changes in both 10-month mice with liver tumors as compared to those without liver tumors and 3-week sibling mice from the same exposure study, implicating Stat3 as a potential epigenetic biomarker of both early life BPA exposure and adult disease in mice. DNA methylation profiles within STAT3 varied with liver tissue BPA level in human fetal liver samples as well, suggesting STAT3 may be a translationally relevant candidate biomarker. These data implicate Stat3 as a potential early life biomarker of adult murine liver tumor risk following early BPA exposure with early evidence of relevance to human health.
authors.affiliation: a Department of Environmental Health Sciences ; University of Michigan ; Ann Arbor , Michigan , USA.
authors.forename: Caren
authors.initials: C
authors.lastname: Weinhouse
authors.affiliation: b Unit for Laboratory Animal Medicine; University of Michigan ; Ann Arbor , Michigan , USA.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Bergin
authors.affiliation: a Department of Environmental Health Sciences ; University of Michigan ; Ann Arbor , Michigan , USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Harris
authors.affiliation: a Department of Environmental Health Sciences ; University of Michigan ; Ann Arbor , Michigan , USA.|c Department of Nutritional Sciences ; University of Michigan ; Ann Arbor , Michigan , USA.
authors.forename: Dana C
authors.initials: DC
authors.lastname: Dolinoy
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity*; D019175:DNA Methylation / Q000187:drug effects*; D052244:Endocrine Disruptors / Q000633:toxicity*; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000633:toxicity*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D005819:Genetic Markers; D015850:Interleukin-6; D010636:Phenols; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: DNA methylation; Stat3; bisphenol A; developmental origins of health and disease; endocrine disruptors; epigenetics; hepatocellular carcinoma