Bisphenol A attenuates testosterone production in Leydig cells via the inhibition of NR1D1 signaling

Dec 10, 2020Chemosphere

Bisphenol A reduces testosterone production in male hormone-producing cells by blocking NR1D1 signaling

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

BPA treatment significantly reduced testosterone production in mouse Leydig cells.

BPA decreases the transcription levels of the NR1D1 and steroidogenic genes (Hsd3b2 and Hsd17b3) in TM3 cells.
Increased levels of other circadian clock genes (Per2 and Dbp) were observed following BPA treatment.
BPA downregulated NR1D1 and StAR protein expression while upregulating BMAL1 protein in TM3 cells.
Intraperitoneal BPA injection led to a marked decline in NR1D1 and StAR protein levels and steroidogenic gene transcription in mouse testes.
Serum testosterone levels were drastically reduced in BPA-treated mice.
The NR1D1 agonist SR9009 enhanced testosterone production in TM3 cells and partially reversed the effects of BPA.

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Bisphenol A (BPA) is an endocrine-disrupting compound that impairs testosterone synthesis in male mammals. A circadian clock gene deficiency leads to diminished fertility and even infertility in male mice. However, whether circadian clock signaling pathways mediate the suppressive effect of BPA on testosterone synthesis in Leydig cells (LCs) remains unknown. The present study aims to detect the effect of BPA on cellular circadian clock and testosterone synthesis in mouse LCs, and examine the mechanisms underlying NR1D1 signaling. BPA treatment significantly attenuated the transcription levels of Nr1d1 and steroidogenic genes (Hsd3b2 and Hsd17b3) in TM3 cells, but increased other circadian clock gene levels (Per2 and Dbp). BPA treatment also significantly downregulated NR1D1 and StAR protein expression, but upregulated BMAL1 protein expression in TM3 cells. Furthermore, there was a marked decline in testosterone production in BPA-treated TM3 cells. Intraperitoneal injection of BPA profoundly reduced NR1D1 and StAR protein levels and steroidogenic gene transcription levels (Cyp11a1, Hsd3b2, and Hsd17b3), while enhancing BMAL1 protein and other circadian clock gene (Per2 and Dbp) levels in mouse testes. Notably, serum testosterone levels were also drastically reduced in BPA-treated mice. Moreover, SR9009, an NR1D1 agonist, augmented testosterone production in TM3 cells via elevated expression of steroidogenic genes (StAR, Cyp11a1 and Hsd17b3). Conversely, Nr1d1 knockdown inhibited testosterone accumulation and attenuated steroidogenic gene expression. Moreover, treatment with SR9009 partially reversed the BPA effect on the circadian clock and testosterone production. Taken together, our study demonstrates that BPA perturbs testosterone production, at least partially, via inhibiting NR1D1 signaling in LCs.

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Bisphenol A attenuates testosterone production in Leydig cells via the inhibition of NR1D1 signaling

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