In Utero Exposure to Bisphenol A Shifts the Window of Susceptibility for Mammary Carcinogenesis in the Rat

Abstract

BackgroundBisphenol A (BPA) is a ubiquitous environmental chemical with reported endocrine-disrupting properties.ObjectiveOur goal in this study was to determine whether prenatal exposure to BPA predisposes the adult rat mammary gland to carcinogenesis.MethodsPregnant rats were treated orally with 0, 25, or 250 μg BPA/kg body weight (BW) from gestation day (GD) 10 to GD21. For tumorigenesis experiments, prenatally exposed female offspring received a single gavage of 7,12-dimethylbenz(a)anthracene (DMBA; 30 mg/kg BW) on postnatal day (PND) 50, or PND100.ResultsPrenatal exposure of the dam to 250 μg BPA/kg BW combined with a single exposure of female offspring to DMBA on PND100, but not on PND50, significantly increased tumor incidence while decreasing tumor latency compared with the control group. Prenatal exposure of the dam to 250 μg BPA/kg BW, in the absence of DMBA to the female offspring, increased cell proliferation and elicited differential effects at the protein level at PND100 compared with PND50. Differentially regulated proteins in the mammary gland included estrogen receptor-α, progesterone receptor-A, Bcl-2, steroid receptor coactivators, epidermal growth factor receptor, phospho-insulin-like growth factor 1 receptor, and phospho-Raf.ConclusionsOur study demonstrates that oral prenatal exposure to BPA increases mammary cancer susceptibility in offspring and shifts the window of susceptibility for DMBA-induced tumorigenesis in the rat mammary gland from PND50 to PND100. These changes are accompanied by differential effects of prenatal BPA exposure on the expression of key proteins involved in cell proliferation.

Bisphenol A alters the development of the rhesus monkey mammary gland

“…Furthermore, rats exposed to BPA in utero developed precancerous and cancerous lesions (32). Also, perinatal exposure increased rodents' sensitivity to chemical carcinogens (33)(34)(35)(36). Although a small human study found no association between To whom correspondence should be addressed.…”

Scientific Opinion on Bisphenol A: evaluation of a study investigating its neurodevelopmental toxicity, review of recent scientific literature on its toxicity and advice on the Danish risk assessment of Bisphenol A

“…GD 10-21) did not appear to induce overt toxicity nor to affect sex hormone regulation (17-β oestradiol and progesterone), but altered the expression of key proteins (vimentin, SPARC, 14-3-3) steering cell proliferation and survival. In a subsequent publication, Betancourt et al (2010b;see section 5.2.1.2) supported these findings by showing that -consistent with increased proliferation of epithelial cells of the mammary gland in the high dose group -the levels of EGFR, phosphorylated IGF-1R, phosphorylated c-Raf,, phosphorylated ERKs 1/2, phosphorylated ErbB2 and phosphorylated Akt were increased. Studies using s.c. application of BPA also indicated that prenatal BPA exposure results in an increased cell proliferation/apoptosis ratio in normal tissue as well as preneoplastic lesions of rat mammary gland (Durando et al, 2007;Murray et al, 2007;Vandenberg et al, 2007;.…”

“…Studies using s.c. application of BPA also indicated that prenatal BPA exposure results in an increased cell proliferation/apoptosis ratio in normal tissue as well as preneoplastic lesions of rat mammary gland (Durando et al, 2007;Murray et al, 2007;Vandenberg et al, 2007;. Altogether the data by Betancourt et al (2010b) suggest that either lactational or in utero exposure to BPA may increase the susceptibility of the rat mammary gland to cancer induction by DMBA. This may be linked to an enhanced cell proliferation/apoptosis ratio, known to increase the probability of the formation of precancerous cells upon a genotoxic challenge (tumour initiation) and in subsequent stages of carcinogenesis, to accelerate the manifestation of frank neoplasia (tumour promotion and progression).…”

“…Using the same model of dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis but in utero BPA exposure, Betancourt et al (2010) also reported an enhancement of susceptibility for mammary gland carcinogenesis. In consideration of the shortcomings in the design of both studies, in particular the uncertainty regarding the lactational as well as in utero exposure of the offspring to BPA, and of the limitations in reporting the Panel concluded that these results can not be used to set a new TDI for BPA.…”

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“…In the study reported by Stump et al (2009) The study by is the first oral study on a possible BPA-induced enhancement of sensitivity of the mammary gland to carcinogen-induced breast tumour formation in rat offspring following lactational BPA exposure of pups. Using the same model of dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis but in utero BPA exposure, Betancourt et al (2010b) also reported an enhancement of susceptibility for mammary gland carcinogenesis. In consideration of the shortcomings in the design of both studies, in particular the uncertainty regarding the lactational as well as in utero exposure of the offspring to BPA, and of the limitations in reporting the Panel concluded that these results cannot be taken into consideration for derivation of a TDI.…”