2. Academic Validation
  3. ATG5-dependent autophagy in Sertoli cells protects against cadmium-disrupted blood-testis barrier via perturbing CXCL2/CXCR2 axis

ATG5-dependent autophagy in Sertoli cells protects against cadmium-disrupted blood-testis barrier via perturbing CXCL2/CXCR2 axis

  • Cell Biol Toxicol. 2025 Oct 24;41(1):143. doi: 10.1007/s10565-025-10089-5.
Hao Li # 1 2,  Yi-Fan Hu # 1 3 4,  Xin-Run Wang 1 3,  Jing-Wen Hong 1 3 4,  Zhi-Yang Zhang 1 3 5,  Yu-Hui Zou 1 3,  Xin-Yi Cheng 1 3,  Ye-Xin Luo 1 3,  Xu-Dong Zhang 1 3,  Hua-Long Zhu 1 3,  Yong-Wei Xiong 1 3,  Wei Chang 1 3,  Hua Wang 6 7 8,  Lan Yang 9 10
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, 230000, China.
  • 2 Department of Preventive Medicine, School of Public Health, Wannan Medical College, Anhui Province, Wuhu, 241002, China.
  • 3 Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, 230000, China.
  • 4 Center of Prenatal Diagnosis, Affiliated Wuxi School of Medicine, Wuxi Maternity and Child Health Care Hospital, Jiangnan University, Wuxi, 214000, China.
  • 5 First School of Clinical Medicine, Anhui Medical University, Hefei, 230000, China.
  • 6 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, 230000, China. wanghuadev@ahmu.edu.cn.
  • 7 Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Hefei, 230000, China. wanghuadev@ahmu.edu.cn.
  • 8 Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education, The People's Republic of China, Hefei, 230000, China. wanghuadev@ahmu.edu.cn.
  • 9 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, 230000, China. lilylan5930@sina.com.
  • 10 Center of Prenatal Diagnosis, Affiliated Wuxi School of Medicine, Wuxi Maternity and Child Health Care Hospital, Jiangnan University, Wuxi, 214000, China. lilylan5930@sina.com.
  • # Contributed equally.
PMID: 41131418 DOI: 10.1007/s10565-025-10089-5
Abstract

The blood-testis barrier (BTB), a unique structure established through intercellular connections of Sertoli cells, establishes a protective microenvironment for spermatogenesis and male fertility. Cadmium (Cd), known for its toxicity, is ubiquitously present in the environment. Here, our findings revealed that Cd exposure compromises BTB integrity, as demonstrated by decreased expression of BTB-associated proteins and elevated Dsignal/Dradius values. Mechanistically, we demonstrated that activation of the CXCL2/CXCR2 axis contributes to Cd-induced BTB impairment, as evidenced by experiments using a CXCR2 inhibition model. As key BTB components, Sertoli cells rely on Autophagy to maintain their physiological functions. However, the specific role and mechanism of Sertoli cell Autophagy in Cd-induced BTB damage remain unknown. Notably, our results showed that Autophagy inhibition aggravated the Cd-induced BTB disruption and testicular CXCL2/CXCR2 axis activation in mice, whereas Autophagy activation alleviates Cd-evoked BTB disruption and testicular CXCL2/CXCR2 axis activation. Further verification by Sertoli cell specific Atg5 knockout mouse model showed that the Autophagy suppression exacerbated Cd-induced BTB disruption and upregulated the expression of CXCL2. Collectively, our finding points out that ATG5-dependent Autophagy in Sertoli cells protects against Cd-induced BTB disruption via perturbing CXCL2/CXCR2 axis. Our study not only reveals a novel molecular mechanism underlying Cd-induced reproductive toxicity but also provides potential therapeutic targets for male infertility intervention.

Keywords

ATG5; Autophagy; Blood-testis barrier; CXCL2/CXCR2 axis; Cadmium.

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