Estrogens in the wrong place at the wrong time: Fetal BPA exposure and mammary cancer

Abstract

Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the genital tract and predisposed individuals to develop clear cell carcinoma of the vagina as well as breast cancer later in life. Gestational exposure of rodents to a related compound, the xenoestrogen bisphenol-A (BPA) increases the propensity to develop mammary cancer during adulthood, long after cessation of exposure. Exposure to BPA during gestation induces morphological alterations in both the stroma and the epithelium of the fetal mammary gland at 18 days of age. We postulate that the primary target of BPA is the fetal stroma, the only mammary tissue expressing estrogen receptors during fetal life. BPA would then alter the reciprocal stroma-epithelial interactions that mediate mammogenesis. In addition to this direct effect on the mammary gland, BPA is postulated to affect the hypothalamus and thus in turn affect the regulation of mammotropic hormones at puberty and beyond.

Keywords: Endocrine disruptors; Environmental exposure; Fetal mammary gland; Mammary gland development; Prenatal exposure; Xenoestrogens.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1

Hierarchical Clustering analyses of the transcriptomal profiles show the effects of perinatal exposure to BPA, ethinyl estradiol (EE2) and vehicle on peri-ductal stroma (left panel) and epithelium (right panel) of WT and null ERα mice. Status of mouse genotype is indicated on the left (Green: WT (+/+), Black: ER knock-out (−/−)) and treatment is indicated on the right of the heat maps. Unique gene clusters observed are shown on the top of the heat maps. Originally published in Wadia et al PLOS ONE 2013 (20).

Figure 2

Whole mounts of neonatal mammary glands of control and BPA dosed non-human primates. (A) Control; (B) BPA dosed. Scale bar is equivalent to 500 µm. Originally published in Tharp et al., Proc. Natl. Acad. Sci USA 2012 (19).

Figure 3

Increased lateral branching observed in adult mammary glands of mice exposed in utero to BPA. (A) Number of side branches per 500 µm of ductal length in mammary glands of 4 month-old mice treated perinatally with vehicle, 25 ng BPA/kg bw/day and 250 ng BPA/kg bw/day (* p<0.05). Error bars indicate SEM. (B) Whole mounts of adult mammary glands of vehicle (left panel) and 25 ng BPA/kg bw/day (right panel) treated animals. Scale bar represents 1 mm. Originally published in Munoz de Toro et al, Endocrinology (69) Copyright 2005, The Endocrine Society.

Figure 4

Quantification of ductal and alveolar structures shows an increase in the relative area of (A) ducts, (B) terminal ducts and, (C) alveolar buds in mammary glands of 6 months-old mice exposed in utero to 25 or 250 ng/kg of BPA relative to control. (*p<0.05) relative to control. Originally published in Markey et al. Biol. Reprod. 2001 (70).

Figure 5

Ratio of DNA synthesis between the stroma and the epithelium. Bar graph represents the ratio of the percentage of epithelial cells that incorporated BrdU to the percentage of stromal cells that incorporated BrdU in the mammary glands of 6 months-old mice exposed in utero to 25 or 250 ng/kg of BPA or control. Originally published in Markey et al. Biol. Reprod. 2001 (70).

Figure 6

Whole mount mammary glands of male mice at two different ages. These animals were exposed in utero to BPA. The black box indicates samples where the epithelium was small. All samples from the same age were taken at the same magnification. Scale bar represents 1 mm in all panels. Reprinted from Vandenberg et al, Reproductive Toxicology 2013 (71) with permission from Elsevier.

Figure 7

BPA-induced changes in DNA methylation observed at PND 4, PND 21 and PND 50 in the mammary glands of perinatally exposed Wistar-Furth rats. The red graphs to the left of each chromosome indicate relative numbers of the transcriptional initiation sites found within a 1 megabase window, which corresponds to the density of promoters. Originally published in Dhimolea et al PLOS ONE 2014 (74).

Figure 8

BPA exposure alters mammary gland development and increases the risk of mammary carcinogenesis: BPA binds to the fetal mammary gland mesenchymal ERs, and in turn affects the composition of the ECM increasing tissue rigidity. Increased rigidity delays lumen formation. BPA also induces precocious adipocyte differentiation, which in turn accelerates duct elongation and branching. These changes lead to an increased sensitivity to mammotropic hormones in adulthood. BPA also binds to ER in the hypothalamus, where it alters the control of ovarian cyclicity and the control of the secretion of mammotropic hormones. The solid arrows link effects of in utero exposure to BPA in rodents and non-human primates. Dashed arrows indicate hypothesized links between effects during fetal mammary gland development and mammary carcinogenesis.