2. Academic Validation
  3. Bisphenol A attenuates testosterone production in Leydig cells via the inhibition of NR1D1 signaling

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

  • Chemosphere. 2021 Jan;263:128020. doi: 10.1016/j.chemosphere.2020.128020.
Cuimei Li 1,  Linlin Zhang 1,  Tiantian Ma 1,  Lei Gao 1,  Luda Yang 1,  Meina Wu 2,  Zhaoxia Pang 1,  Xiaoyu Wang 1,  Qiyang Yao 1,  Yaoyao Xiao 1,  Lijia Zhao 1,  Wei Liu 1,  Hongcong Zhao 1,  Caixia Wang 1,  Aihua Wang 3,  Yaping Jin 4,  Huatao Chen 5
Affiliations

Affiliations

  • 1 Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China.
  • 2 Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China.
  • 3 Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China; Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
  • 4 Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China. Electronic address: yapingjin@163.com.
  • 5 Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China; Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China. Electronic address: htchen@nwafu.edu.cn.
PMID: 33297044 DOI: 10.1016/j.chemosphere.2020.128020
Abstract

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.

Keywords

Bisphenol A; Circadian clock; Leydig cells; NR1D1; Testosterone.

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