BPA oral prenatal exposure increases mammary cancer susceptibility in offspring
Background Bisphenol-A (BPA) is a ubiquitous environmental chemical with reported endocrine-disrupting properties.
Objective Our goal in this study was to determine whether prenatal exposure to BPA predisposes the adult rat mammary gland to carcinogenesis.
Methods Pregnant 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.
Results Prenatal 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.
Conclusions Our 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.
Le 19 novembre 2010 se tenait au Sénat un colloque sur le Distilbène, ce médicament prescrit jusqu’en 1977 aux femmes ayant des problèmes de fécondité et qui a provoqué des cancers et malformations génitales chez leurs descendants. UniverScienceTV recevait le gynécologue Michel Tournaire, ancien chef de service de la maternité de l’hôpital Saint-Vincent-de-Paul à Paris.
In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer
Diethylstilbestrol (DES) and Bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p < 0.05) as well as increased EZH2 protein expression. Mice exposed to DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p < 0.05). EZH2 protein was elevated in mammary tissue of mice exposed to DES or BPA. Histone H3 trimethylation was increased in MCF-7 cells treated with BPA or DES. Similarly, mice exposed to BPA or DES in utero showed increased mammary histone H3 trimethylation. Developmental programming of EZH2 is a novel mechanism by which in utero exposure to endocrine disruptors leads to epigenetic regulation of the mammary gland.
We have demonstrated a novel mechanism by which endocrine-disrupting chemicals regulate developmental programming in the breast. Exposure to DES or BPA in utero alters mammary tissue expression of EZH2, a histone methyltransferase with known associations to tumorigenesis. EZH2 function, measured by examination of histone H3 (tri methyl K27), also increases as a result of exposure to DES or BPA. Increased expression of EZH2 within the breast, even in morphologically normal appearing tissue, may prove to be a marker of increased breast cancer risk. The increase in EZH2 expression and function shown here in mice after in utero exposure to these chemicals is a potential mechanism for the increased risk of breast cancer as a result of exposure to these EDCs. This study also generates important safety concerns about exposures to environmental endocrine disruptors such as BPA and suggests a potential need to monitor women exposed to these chemicals for the development of breast lesions as adults.
Sources and full study
In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer, NCBI PMID: 21761357, Horm Cancer. 1(3):146-55. doi: 10.1007/s12672-010-0015-9, 2010 Jun.
Full text PMCID: PMC3140020, NIHMSID: NIHMS309412, doi: 10.1007/s12672-010-0015-9, Jul 20, 2011.
We asked women participating in a large, multi-centre study of prenatal DES exposure to report birth defects occurring among 4029 sons and 3808 daughters (i.e., the third generation). A subcohort of 793 third generation daughters was also queried for birth defects. We used logistic regression models to generate odds ratio and 95% confidence intervals for the association between prenatal DES exposure in the mother and birth defects in the offspring. Based on the mothers’ reports, overall birth defects were elevated in the sons (OR = 1.53; 95% CI = 1.04, 2.23) and in the daughters (OR = 2.35; 95% CI = 1.44, 3.82). Most estimates of association were imprecise, but daughters appeared to have an excess of heart conditions (OR = 4.56; 95% CI = 1.27, 16.34).
Our data suggest a possible association between the mother’s prenatal DES exposure and birth defects in their offspring, particularly in daughters. We cannot, however, rule-out the possible influence of reporting bias. In particular, the exposed daughters’ elevated risk of cardiac defects may be as a result of the underreporting of these conditions by unexposed mothers.
The DES Combined Cohort Follow-Up Study
The DES Third Generation Cohort Study
Agreement between mothers’ and daughters’ reports
Statistical analysis of birth defects
Mothers’ reports of birth defects in their offspring
Birth defects self-reported by third generation women
Birth defects in the sons and daughters of women who were exposed in utero to diethylstilbestrol (DES), NCBI, PMID: 20002218, 2010 Apr;33(2):377-84. doi: 10.1111/j.1365-2605.2009.01010.x. Epub 2009 Nov 30. Full text PMC2874639.