Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors - PubMed (original) (raw)

Review

Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors

Ana M Soto et al. J Mammary Gland Biol Neoplasia. 2013 Jun.

Abstract

We are now witnessing a resurgence of theories of development and carcinogenesis in which the environment is again being accepted as a major player in phenotype determination. Perturbations in the fetal environment predispose an individual to disease that only becomes apparent in adulthood. For example, gestational exposure to diethylstilbestrol resulted in clear cell carcinoma of the vagina and breast cancer. In this review the effects of the endocrine disruptor bisphenol-A (BPA) on mammary development and tumorigenesis in rodents is used as a paradigmatic example of how altered prenatal mammary development may lead to breast cancer in humans who are also widely exposed to it through plastic goods, food and drink packaging, and thermal paper receipts. Changes in the stroma and its extracellular matrix led to altered ductal morphogenesis. Additionally, gestational and lactational exposure to BPA increased the sensitivity of rats and mice to mammotropic hormones during puberty and beyond, thus suggesting a plausible explanation for the increased incidence of breast cancer.

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Figures

Figure 1. Effects of exposure to 250ng BPA/kg/day from E8 to E18 on mice

Trichrome stained 5 μm section of control (A, E) and BPA-exposed (B, F) E18 mammary glands (EP denotes epithelium). Collagen stains deep blue; note the reduction of collagen deposition in the mesenchyme distal to the epithelium. Immuno-histochemical localization of TnC in controls (C) and BPA-exposed (D) mammary glands. Red alkaline phosphatase staining of TnC is observed in the stroma surrounding the epithelial ducts. The density of collagen in the entire stromal compartment is significantly decreased in BPA-exposed females compared with controls, p=0.010 (G). However, the density of collagen within 10μm of the epithelial ducts is significantly increased in BPA females, p=0.042 (H). All scale bars represent 100 μm. (I) Quantification showed that the number of adipocytes was significantly increased within 1 mm from the developing epithelium in BPA-exposed females (squares), compared with controls (circles). **,P <0.02; ***, P < 0.005. Copyright 2007, The Endocrine Society, (A–F) and (I) reprinted with permission [55]

Figure 2. Effects of exposure to 250ng BPA/kg/day on mice exposed from E8 to E18

Carmine –stained whole mounts of E18 4th mammary gland of controls (A), and BPA exposed embryos (B). Note the increased size of the epithelial cords, compared with controls. Lumen formation in E18 mouse mammary glands is inhibited by BPA treatment. Lumen formation [arrow] was observed in 38% of control animals (C) but in none of the histological sections of animals exposed in utero to 250ng BPA/kg BW/day from E9(D). Scale bars represent 100μm. Copyright 2007, The Endocrine Society, reprinted with permission [55]

Figure 3. BPA exposure increases the number of progesterone receptor positive cells as seen in sections stained with an antibody against PR

Sections from an inguinal mammary gland of a mouse exposed from E8 to birth showing a cluster of PR positive cells at one month of age indicating a presumptive branching point (arrow) (A), Copyright 2005, The Endocrine Society reprinted with permission [57]; a control (B), and a mouse exposed to BPA from conception to weaning show a differential staining pattern of PR expression (C) Copyright 2011, The Endocrine Society reprinted with permission [58]. Note that the ducts of the mammary glands of BPA-exposed mice contain more PR-positive luminal epithelial cells than the unexposed controls

Figure 4. Prenatal exposure to BPA results in increased branching in adulthood

Photomicrographs of mammary gland whole mounts of 4 month old control mice (A) and mice exposed to 250ng BPA/kg bw/d from E8 to birth (B). Scale bar represents 1 mm.

Figure 5. Beaded ducts in whole-mounted mouse mammary glands from BPA-exposed offspring

Mammary glands from control mice do not develop beaded ducts (A); glands from exposed females do. Panel B shows a mammary gland from a 9 month-old female exposed to BPA during perinatal development (E8 to PND21) containing beaded ducts. Beads are marked by arrowheads. Inset illustrates a higher magnification of a beaded duct. In comparison to a normal duct (C), confocal images of beaded ducts in BPA-exposed females (D) demonstrate the presence of cells obliterating the ductal lumen. Areas with cells inside the ductal lumen are marked by yellow arrows. All photographed mammary glands were stained with carmine alum. Magnification: A and B = 32x; C and D = 200x. Adapted from from Reproductive Toxicology [61] with permission from Elsevier. (E) Histology section of ductal contents stained with H&E.

Figure 6

Proposed causal links tying BPA exposure, mammary gland development and carcinogenesis: BPA binds to the ERs present in the primary mesenchyme which alters the peri-ductal stroma, increasing peri-ductal collagen deposition and thus tissue rigidity. Increased rigidity is known to block or delay lumen formation. BPA also induces adipocyte differentiation in the primary periductal stroma and fat pad, which in turn causes increased duct elongation and branching. These changes lead to an increased sensitivity to mammotropic hormones such as estrogens and progesterone and likely to prolactin. The solid arrows link observations at E18 with postulated causal links. Dashed arrows link the observed effects at E18 with effects observed during puberty and adulthood. Not represented here are the effects of BPA on the hypothalamus, where it alters the control of ovarian cyclicity and likely the control of prolactin production.

References

1. Sallout B, Walker M. The fetal origin of adult diseases. Journal of Obstetrics and Gynaecology. 2003;23:555–60. - PubMed
1. Barker DJP, Hanson MA. Altered regional blood flow in the fetus: the origins of cardiovascular disease? Acta Paediatricia. 2004;93:1559–60. - PubMed
1. Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm count and disorders of the male reproductive tract? Lancet. 1993;341:1392–95. - PubMed
1. Skakkebaek NE, Meyts ER, Jorgensen N, et al. Germ cell cancer and disorders of spermatogenesis: an environmental connection? APMIS. 1998;106:3–12. - PubMed
1. Markey CM, Rubin BS, Soto AM, Sonnenschein C. Endocrine disruptors from Wingspread to environmental developmental biology. J Steroid Biochem Molec Biol. 2003;83:235–44. - PubMed

Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors - PubMed (original) (raw)