ODP263 A Nonbiased Single-Cell Transcriptomic Analysis of Mouse Mammary Gland after Low Dose/Long Term vs. High Dose/Short Term Exposure to PBDEs

Abstract

Introduction

Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants and associated with breast carcinogenesis. In this study, we examined the effects of PBDEs during the menopausal transition in a 4-vinylcyclohexene diepoxide (VCD)-induced mouse menopause model, which presents a follicle-depleted and ovary-intact animal that closely approximate the gradual menopause transition in humans. The aim of this study was to compare the impacts of PBDE exposures on the mammary gland at the macroscopic gland structures and the single-cell resolution under three treatment schedules.

Materials and Methods

We treated nine-week-old female C57BL/6 mice with VCD (160 mg/kg) for 15 days. Then, the animals had high dose PBDE exposure for 1 week during peri- (Perimenopause/High group) or post-menopausal periods (Menopause/High group). The third group was exposed to low dose PBDE (the 1/20th of the high dose) for 20 weeks during the postmenopausal period (Menopause/Low group). In each group, the mice received various combinations of 17B-estradiol and progesterone treatments simultaneously. Our experimental design allowed us to directly compare the effects of PBDE under three potential exposure conditions.

Results

The mammary glands significantly regressed by the VCD treatment, more evident at the postmenopausal period. All PBDE exposures did not augment or compromise the macroscopic ductal reorganization resulting from the VCD and/or hormonal treatments. Single-cell sequencing revealed that the PBDE exposure in the Menopause/High group caused specific transcriptomic changes in the non-epithelial compartment such as Errfi1 upregulation in fibroblasts and AY036118 downregulation in multiple cell types. The PBDE exposure in the Menopause/Low group resulted in similar transcriptomic changes to a lesser extent.

Conclusion

PBDEs may affect the postmenopausal gland through impacts on the non-epithelial compartments. Low dose PBDE exposure, which is presumably equivalent to the maximum environmental exposure in humans, can exert the influences.

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