Single-cell RNA-sequencing analysis of estrogen- and endocrine-disrupting chemical-induced reorganization of mouse mammary gland.

Abstract

Menopause is a critical window of susceptibility for its sensitivity to endocrine disrupting chemicals due to the decline of endogenous estrogen. Using a surgical menopausal (ovariectomized) mouse model, we assessed how mammary tissue was affected by both 17β-estradiol (E2) and polybrominated diphenyl ethers (PBDEs). As flame retardants in household products, PBDEs are widely detected in human serum. During physiologically-relevant exposure to E2, PBDEs enhanced E2-mediated regrowth of mammary glands with terminal end bud-like structures. Analysis of mammary gland RNA revealed that PBDEs both augmented E2-facilitated gene expression and modulated immune regulation. Through single-cell RNA sequencing (scRNAseq) analysis, E2 was found to induce Pgr expression in both Esr1+ and Esr1- luminal epithelial cells and Ccl2 expression in Esr1+ fibroblasts. PBDEs promote the E2-AREG-EGFR-M2 macrophage pathway. Our findings support that E2 + PBDE increases the risk of developing breast cancer through the expansion of estrogen-responsive luminal epithelial cells and immune modulation.

• Authors: Noriko Kanaya, Gregory Chang, Xiwei Wu, Kohei Saeki, Lauren Bernal, Hyun-Jeong Shim, Jinhui Wang, Charles Warden, Takuro Yamamoto, Jay Li, June-Soo Park, Timothy Synold, Steve Vonderfecht, Michele Rakoff, Susan L Neuhausen, Shiuan Chen
• Journal: Communications biology (Commun Biol) Vol. 2 Pg. 406 ( 2019) ISSN: 2399-3642 [Electronic] England
• PMID: 31701034 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019.

Chemical References

• Endocrine Disruptors
• Esr1 protein, mouse
• Estrogen Receptor alpha
• Flame Retardants
• Halogenated Diphenyl Ethers
• Receptors, Progesterone
• Estradiol
• pentabromodiphenyl ether

Topics

• Animals
• Endocrine Disruptors (toxicity)
• Epithelial Cells (drug effects, metabolism, pathology)
• Estradiol (toxicity)
• Estrogen Receptor alpha (metabolism)
• Female
• Fibroblasts (drug effects, metabolism, pathology)
• Flame Retardants (toxicity)
• Gene Expression Profiling
• Halogenated Diphenyl Ethers (toxicity)
• Humans
• Mammary Glands, Animal (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Ovariectomy
• RNA-Seq
• Receptors, Progesterone (metabolism)
• Single-Cell Analysis