Evaluation of Prenatal Exposure to Bisphenol Analogues on Development and Long-Term Health of the Mammary Gland in Female Mice

Abstract

Background:Continued efforts to phase out bisphenol A (BPA) from consumer products have been met with the challenges of finding safer alternatives.Objectives:This study aimed to determine whether early-life exposure to BPA and its related analogues, bisphenol AF (BPAF) and bisphenol S (BPS), could affect female pubertal mammary gland development and long-term mammary health in mice.Methods:Timed pregnant CD-1 mice were exposed to vehicle, BPA (0.5, 5, 50mg/kg), BPAF (0.05, 0.5, 5mg/kg), or BPS (0.05, 0.5, 5mg/kg) via oral gavage between gestation days 10–17. Mammary glands were collected from resulting female offspring at postnatal day (PND) 20, 28, 35, and 56, and at 3, 8, and 14 months for whole mount, histopathological evaluation, and quantitative real-time polymerase chain reaction (qPCR); serum steroid concentrations were also measured at these time points.Results:In the bisphenol-exposed mice, accelerated mammary gland development was evident during early puberty and persisted into adulthood. By late adulthood, mammary glands from bisphenol-exposed female offspring exhibited adverse morphology in comparison with controls; most prominent were undifferentiated duct ends, significantly more lobuloalveolar hyperplasia and perivascular inflammation, and various tumors, including adenocarcinomas. Effects were especially prominent in the BPAF 5mg/kg and BPS 0.5mg/kg groups. Serum steroid concentrations and mammary mRNA levels of Esr1, Pgr, Ar, and Gper1 were similar to controls.Conclusions:These data demonstrate that prenatal exposure of mice to BPAF or BPS induced precocious development of the mammary gland, and that siblings were significantly more susceptible to spontaneous preneoplastic epithelial lesions and inflammation, with an incidence greater than that observed in vehicle- and BPA-exposed animals. https://doi.org/10.1289/EHP3189

A Combined Morphometric and Statistical Approach to Assess Nonmonotonicity in the Developing Mammary Gland of Rats in the CLARITY-BPA Study

“…As in the mouse model, some effects of BPA are not similar to those of estrogens, for example, inhibition of ductal growth at puberty (Markey et al 2001;Muñoz-de-Toro et al 2005), enhanced ductal growth during fetal life (Vandenberg et al 2007;Speroni et al 2017), others are clearly estrogen-like, such as the increased score at PND90P reported here and the accelerated expression of lateral branching in the mouse (Muñoz- de-Toro et al 2005). There are also other effects seemingly unrelated to estrogenicity; changes in the stromal fraction of the gland and inflammatory cell responses that have been noted in response to developmental BPA exposures (Tucker et al 2018;Wadia et al 2013).…”

A combined morphometric and statistical approach to assess non-monotonicity in the developing mammary gland of rats in the CLARITY-BPA study

“…Like in the mouse model, some effects of BPA are not similar to those of estrogens, for example, inhibition of ductal growth at puberty (Markey et al 2001;Munoz de Toro et al 2005), enhanced ductal growth during fetal life Speroni et al 2017), others are clearly estrogen-like, such as the increased score at PND90P reported here and the accelerated expression of lateral branching in the mouse (Munoz de Toro et al 2005). There are also other effects seemingly unrelated to estrogenicity; changes in the stromal fraction of the gland and inflammatory cell responses which have been noted (Tucker et al 2018;Wadia et al 2013) in response to developmental BPA exposures.…”

“…Alterations in ductal elongation at puberty and lateral branching and budding during adulthood were attributed to altered responses to mammotropic hormones Ayyanan et al 2011). Recent studies confirmed that developmental exposures to other BPA related substances (BPS and BPAF) in mice also induce precocious development of the mammary epithelium, and increased epithelial lesions and mammary tumors in adulthood (Tucker et al 2018). However, these results were obtained in the mouse, which is not considered as good a model for mammary cancer as the rat.…”

Data describing effects of perinatal exposure to bisphenol S on a peripubertal estrogen challenge in intact female CD-1 mice

“…The mid dose (200 μg BPS/kg/day) was selected based on prior studies showing that this dose disrupted maternal behaviors, the lactating mother, and development of the mammary gland [2] , [4] , [5] . The highest dose (2000 μg BPS/kg/day) was selected based on results from a recent study at the National Toxicology Program which revealed significant effects of BPS on the female mammary gland at a similar dose (5000 μg/kg/day) [6] . Doses were adjusted daily for body weight.…”