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.
Highlights
Environmental epigenetics, or the study of the impact of environmental exposures on patterns of epigenetic regulation, seeks to identify future public health interventions that may reverse deleterious effects of the social, nutritional, and chemical environment to facilitate the prevention of exposure-linked disease
We have previously reported a dose-dependent increase in hepatic tumors in 10-month mice that were perinatally exposed to one of 3 doses of the endocrine disrupting chemical (EDC) bisphenol A (BPA).[3]
We demonstrate the utility of a novel method for detection of candidate epigenetic biomarkers of both exposure and disease
Summary
Environmental epigenetics, or the study of the impact of environmental exposures on patterns of epigenetic regulation, seeks to identify future public health interventions that may reverse deleterious effects of the social, nutritional, and chemical environment to facilitate the prevention of exposure-linked disease. Environmental exposures that occur during early life development, in particular, have been shown to induce altered epigenetic programs that affect adult health outcomes.[1,2]. The classical sexual dimorphism of a higher tumor rate in males as compared to females was not present.[3] Developmental BPA exposure has been linked to proliferative tissue changes in rat mammary glands[4] and to frank prostate cancer in mice with human prostate stem cell xenografts supplemented with sex steroid hormones to mimic human male aging.[5] these studies have identified epigenetic profiles linked to BPA dose and tissue alterations, supporting the hypothesis that epigenetic changes may mediate the relationship between early life BPA exposure and adult health outcomes, including cancer.[4,6]
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