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  3. Plin4 exacerbates cadmium-decreased testosterone level via inducing ferroptosis in testicular Leydig cells

Plin4 exacerbates cadmium-decreased testosterone level via inducing ferroptosis in testicular Leydig cells

  • Redox Biol. 2024 Oct:76:103312. doi: 10.1016/j.redox.2024.103312.
Xu-Dong Zhang 1,  Jian Sun 1,  Xin-Mei Zheng 1,  Jin Zhang 1,  Lu-Lu Tan 1,  Long-Long Fan 1,  Ye-Xin Luo 1,  Yi-Fan Hu 1,  Shen-Dong Xu 1,  Huan Zhou 1,  Yu-Feng Zhang 1,  Hao Li 1,  Zhi Yuan 1,  Tian Wei 1,  Hua-Long Zhu 2,  De-Xiang Xu 2,  Yong-Wei Xiong 3,  Hua Wang 4
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, and Center for Big Data and Population Health of IHM, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • 2 Department of Toxicology, School of Public Health, and Center for Big Data and Population Health of IHM, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China.
  • 3 Department of Toxicology, School of Public Health, and Center for Big Data and Population Health of IHM, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China. Electronic address: xiongyongweidev@126.com.
  • 4 Department of Toxicology, School of Public Health, and Center for Big Data and Population Health of IHM, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China. Electronic address: wanghuadev@ahmu.edu.cn.
PMID: 39173539 DOI: 10.1016/j.redox.2024.103312
Abstract

Strong evidence indicates that environmental stressors are the risk factors for male testosterone deficiency (TD). However, the mechanisms of environmental stress-induced TD remain unclear. Based on our all-cause male reproductive cohort, we found that serum ferrous iron (Fe2⁺) levels were elevated in TD donors. Then, we explored the role and mechanism of Ferroptosis in environmental stress-reduced testosterone levels through in vivo and in vitro models. Data demonstrated that Ferroptosis and lipid droplet deposition were observed in environmental stress-exposed testicular Leydig cells. Pretreatment with ferrostatin-1 (Fer-1), a specific Ferroptosis inhibitor, markedly mitigated environmental stress-reduced testosterone levels. Through screening of core genes involved in lipid droplets formation, it was found that environmental stress significantly increased the levels of perilipins 4 (PLIN4) protein and mRNA in testicular Leydig cells. Further experiments showed that Plin4 siRNA reversed environmental stress-induced lipid droplet deposition and Ferroptosis in Leydig cells. Additionally, environmental stress increased the levels of METTL3, METTL14, and total RNA m6A in testicular Leydig cells. Mechanistically, S-adenosylhomocysteine, an inhibitor of METTL3 and METTL14 heterodimer activity, restored the abnormal levels of Plin4, Fe2⁺ and testosterone in environmental stress-treated Leydig cells. Collectively, these results suggest that Plin4 exacerbates environmental stress-decreased testosterone level via inducing Ferroptosis in testicular Leydig cells.

Keywords

Environment stress; Ferroptosis; Lipid droplet; Perilipins; Testosterone deficiency; m6A modification.

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