Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities

Abstract

Population studies show worrisome trends towards earlier breast development, difficulty in breastfeeding, and increasing rates of breast cancer in young women. Multiple epidemiological studies have linked these outcomes with chemical exposures, and experimental studies have shown that many of these chemicals generate similar effects in rodents, often by disrupting hormonal regulation. These endocrine-disrupting chemicals (EDCs) can alter the progression of mammary gland (MG) development, impair the ability to nourish offspring via lactation, increase mammary tissue density, and increase the propensity to develop cancer. However, current toxicological approaches to measuring the effects of chemical exposures on the MG are often inadequate to detect these effects, impairing our ability to identify exposures harmful to the breast and limiting opportunities for prevention. This paper describes key adverse outcomes for the MG, including impaired lactation, altered pubertal development, altered morphology (such as increased mammographic density), and cancer. It also summarizes evidence from humans and rodent models for exposures associated with these effects. We also review current toxicological practices for evaluating MG effects, highlight limitations of current methods, summarize debates related to how effects are interpreted in risk assessment, and make recommendations to strengthen assessment approaches. Increasing the rigor of MG assessment would improve our ability to identify chemicals of concern, regulate those chemicals based on their effects, and prevent exposures and associated adverse health effects.

Keywords: Endocrine disrupting chemical; Test guideline; Thelarche; Weaning; Window of susceptibility.

Fig. 1

Mammary gland whole mounts provide detailed morphology and evidence of functional alterations. a Traditional histological sections of MG tissue. Classical transverse cross-section of the MG including skin (top; required by some test guidelines) shows very little visible MG epithelial cells for evaluation. Longitudinal section (bottom) of the MG presents larger area and more epithelial structures than transverse cross-section, but ductal tree structure may not be able to be evaluated. Figure adapted from Davis and Fenton, 2013 with permission [206]. b Impairment of lactation. MG whole mounts from mouse dams dosed with vehicle (left) or 200 μg BPS/kg/day (right) from gestation day 8 through lactation day 21. On lactation day 21, the vehicle-treated MG (left) remained full of an expansive network of lobuloalveolar units, whereas the BPS-exposed MG contained stunted and/or regressed alveolar buds. Magnification 6 × . (Unpublished, LN Vandenberg). c MG whole mounts from mice exposed to 5 mg/kg/day PFOA in utero and during lactation (lower panels) showed delays in ductal elongation, ductal branching, and terminal end bud formation relative to controls (upper panels). Developmental delays were apparent at puberty (PND22) and persisted into adulthood at PND63. At 18 months of age, epithelial density remained reduced in PFOA-exposed mice and lesions become apparent (arrow). Magnification 2.5 × for PND22, 5 × for PND42, 5 × for PND63, 1.6 × for 18 months. Figure adapted from White et al. 2009 with permission [69]. d Intraductal hyperplasia (beaded ducts) in MG whole mounts in female mice perinatally exposed to BPA (gestation day 8 to PND21). Unlike controls (upper left whole mount and lower left fluorescence; 9-month-old mice), the ductal lumens of BPA-treated mice (upper right whole mount (9-month) and lower middle (3-month) and right (9-month) fluorescence) contained cellular infiltrates, creating a “beaded” appearance. Upper panels magnification 32 × , lower panels magnification 200 × . Figure adapted from Vandenberg et al. 2008 with permission [227]. e Ductal carcinoma in situ. Top panel: Whole mount of a MG from a rat exposed to 2.5 μg BPA/kg/day from gestation day 9 until PND1, treated with a subcarcinogenic dose of MNU (20 mg/kg) at 50 days of age, and sacrificed 20 weeks after MNU injection. The arrow points to a lesion in a whole mount. No lesions were observed in the vehicle-treated animals. Scale bar = 1 mm. Bottom panel: H&E staining of the tumor removed from the lesion in the top panel. Scale bar = 200 μm. (Unpublished, AM Soto)