Exposure to the Endocrine Disruptor, Propylparaben, During Pregnancy and Lactation, Alters Typical Parity-Induced Reorganization of the Mouse Mammary Gland

Abstract

The mammary gland is a hormone sensitive organ that is susceptible to endocrine disrupting chemicals (EDCs) during several vulnerable periods, including pregnancy and lactation. Mammary gland reorganization during pregnancy and lactation is hormone driven and provides long-term protection against breast cancer risk. It is unknown if EDC exposures during these sensitive windows can alter mammary reorganization to either enhance or offset parity-induced protection against breast cancer. Here, we examined effects of propylparaben (PP), a common preservative used in personal care products and foods with estrogen receptor (ER) agonist properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10,000 µg/kg/day PP throughout pregnancy and lactation. These doses were selected for their relevance to human exposures. We also included an unexposed nulliparous female group to evaluate the typical changes associated with parity. Five weeks post-involution (and five weeks after the last PP exposure), mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. We found that PP reduced many of the typical morphological effects of parity on the mammary gland, resulting in intermediate phenotypes for ductal density and total epithelial structures. Notably, we found increased proliferation in PP-treated mammary glands, despite decreased ductal epithelial volume relative to parous controls. Mammary glands from PP-treated females also had alterations in the expression of ERα-mediated genes, including PgR (the gene that encodes progesterone receptor) and Igf1, with expression levels that were intermediate to both nulliparous and parous control mice. Finally, PP reduced the effect of parity on several immune cell types in the mammary gland including B cells, T-cells, and M2 macrophages. These results suggest that PP, at levels relevant to human exposure, can disrupt the normal response to parity in the mouse mammary gland, including persistent alterations to mammary gland structures. Future studies should address whether PP exposures disturb the protective effects of pregnancy on mammary cancer risk.