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

• DOI: 10.1038/s42003-019-0618-9
• Publication Date: 2019-11-05T11:12:36Z
• 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
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Estradiol; Gene Expression Profiling; Ovariectomy; Estrogen Receptor alpha; Epithelial Cells; Endocrine Disruptors; Fibroblasts; Article; 3. Good health; Mice; 03 medical and health sciences; Mammary Glands, Animal; Halogenated Diphenyl Ethers; Animals; Humans; Female; RNA-Seq; Single-Cell Analysis; Receptors, Progesterone; Flame Retardants

AbstractMenopause 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.