Dose-Dependent Incidence of Hepatic Tumors in Adult Mice following Perinatal Exposure to Bisphenol A

Abstract

Background: Bisphenol A (BPA) is a high production volume chemical with hormone-like properties that has been implicated as a potential carcinogen. Early-life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between BPA exposure and cancer development.Objective: We explored the effects of BPA exposure during gestation and lactation on adult incidence of hepatic tumors in mice.Methods: Isogenic mice were perinatally exposed to BPA through maternal diets containing one of four environmentally relevant doses of BPA (0, 50 ng, 50 μg, or 50 mg per kilogram of diet), and we followed approximately one male and one female per litter until they were 10 months of age. Animals were tested for known risk factors for hepatocellular carcinoma, including bacterial and viral infections.Results: We found dose-dependent incidence of hepatic tumors in 10-month-old BPA-exposed mice. Of the offspring examined, 23% presented with hepatic tumors or preneoplastic lesions. We observed a statistically significant dose–response relationship, with an odds ratio for neoplastic and preneoplastic lesions of 7.23 (95% CI: 3.23, 16.17) for mice exposed to 50 mg BPA/kg diet compared with unexposed controls. Observed early disease onset, absence of bacterial or viral infection, and lack of characteristic sexual dimorphism in tumor incidence support a nonclassical etiology.Conclusions: To our knowledge, this is the first report of a statistically significant association between BPA exposure and frank tumors in any organ. Our results link early-life exposure to BPA with the development of hepatic tumors in rodents, and have potential implications for human health and disease.Citation: Weinhouse C, Anderson OS, Bergin IL, Vandenbergh DJ, Gyekis JP, Dingman MA, Yang J, Dolinoy DC. 2014. Dose-dependent incidence of hepatic tumors in adult mice following perinatal exposure to bisphenol A. Environ Health Perspect 122:485–491; http://dx.doi.org/10.1289/ehp.1307449

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

“…BPA was associated with hypomethylation in human fetal livers, indicating that Esr1 methylation may be altered by BPA exposure but is not linked to the previously observed liver tumor phenotype. 3 DNA methylation at human homolog ESR1 decreased with low level BPA exposure and increased with higher exposure, supporting a potentially non-linear epigenetic response to BPA. These results support Esr1 as a potential target of BPA-induced DNA methylation change, but do not implicate this candidate gene as a candidate biomarker of both exposure and disease in this study.…”

“…3 Offspring of virgin wild type (a/a) females and heterozygous (A vy /a) males were exposed during gestation and lactation to one of 3 doses of BPA (50 ng, 50 mg, or 50 mg BPA/kg maternal diet) or to a phytoestrogen-free control diet, as previously described. 3 Briefly, 6-week-old virgin wild type a/a female mice were randomly assigned to a phytoestrogen-free AIN-93G diet [TD.95092, with 7% corn oil instead of 7% soybean oil; Harlan Teklad, Madison, WI (composition available at http://www.harlan.com)] supplemented with one of 4 levels of BPA (0, 50 ng, 50 mg, or 50 mg /kg diet). The BPA was provided by the National Toxicology Program (NTP, Research Triangle Park, NC).…”

“…1,2 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 Notably, a significant increase in liver tumors was evident at 10-months of age, which represents early onset disease in mice. Furthermore, the classical sexual dimorphism of a higher tumor rate in males as compared to females was not present.…”

“…Furthermore, the classical sexual dimorphism of a higher tumor rate in males as compared to females was not present. 3 Developmental BPA exposure has also 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 Additionally, 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.…”

Low‐Dose Bisphenol A Exposure: A Seemingly Instigating Carcinogenic Effect on Breast Cancer

“…Thus, these preliminary studies suggest that low‐dose BPA has the potential to pose health hazards. Recent studies have also aimed to evaluate the role of BPA in carcinogenesis,7, 22, 23 and have indicated that exposure to BPA may account, at least partially, for the increased incidence of multiple cancers, including breast cancer,24, 25, 26, 27 ovarian cancer,28, 29 uterine cancer,30 prostate cancer,31, 32 testicular cancer,33 and liver cancer 34. The carcinogenic effects of BPA are summarized in Table 1 .…”