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.

A novel function of R-spondin1 in regulating estrogen receptor expression independent of Wnt/β-catenin signaling

“…In contrast, ER - luminal cells did not respond to RSPO1 stimulation ( Figure 1—figure supplement 1c ). Estrogen (Estradiol-E2, E2) is one of the few known upstream regulator of Esr1 ( Chu et al, 2007 ; Kanaya et al, 2019 ). Thus, E2 (1 μM) was used as control to show the extent of Esr1 activation.…”

Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing

“…Surrounding the epithelial cells are various stromal cells, including fibroblasts, vascular/lymphatic cells, immune cells, and adipocytes. Although initial scRNA-seq studies provided valuable knowledge of mammary epithelia in early and adult development ( Bach et al, 2017 ; Giraddi et al, 2018 ; Nguyen et al, 2018 ; Pal et al, 2017 ; Wuidart et al, 2018 ), characterization of stromal cells has been limited ( Han et al, 2018 ; Kanaya et al, 2019 ; Tabula Muris Consortium, 2018 , 2020 ).…”

Nutritional Regulation of Mammary Gland Development and Milk Synthesis in Animal Models and Dairy Species

“…For example, a recent study suggested that the expression of miRNAs could be specific to different cells [ 181 ]. The access to single cell RNA-seq, already used in breast cancer studies [ 182 , 183 ], will provide a deeper understanding of fine regulatory mechanisms of milk synthesis.…”