PBDEs exposure reshapes non-epithelial compartments of the menopaused murine mammary gland

Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants and are linked to breast carcinogenesis. While PBDEs have been reported to be the ligands of steroid hormone receptors, including estrogen receptor (ER), evaluation of the impact of PBDE exposure in a physiologically and environmentally relevant model has been lacking. In this study, we aimed to examine effects of both low-dose, long-term exposure (environmental) and high-dose, short-term exposure (experimental) of PBDEs on the mammary gland during and after gradual ovarian function loss, when the organ becomes hypersensitive to external stimuli.  Following treatment with 4-vinylcyclohexene diepoxide (VCD) that causes follicle-depletion in the ovary, mice had experimental PBDEs exposure during peri- or post-menopausal periods, or environmental PBDEs exposure during post-menopausal period with various combinations of 17β-estradiol and progesterone administration. The mammary glands significantly regressed by the VCD treatment, which was more evident at the post-menopausal period. All PBDE exposures did not augment or compromise the macroscopic ductal reorganization resulting from the VCD and/or hormonal treatments. Single-cell RNA sequencing revealed that the experimental PBDE exposure during the post-menopausal period caused specific transcriptomic changes in the non-epithelial compartment such as Errfi1 upregulation in fibroblasts. The environmental PBDE exposure resulted in similar transcriptomic changes, but to a lesser extent. Therefore, PBDEs may affect the post-menopausal gland through including   impacts on the non-epithelial compartments. Low dose PBDE exposure, which is presumably equivalent to the maximum environmental exposure in humans, can also exert similar influences.