2. Academic Validation
  3. Di-(2-ethylhexyl) phthalate exposure induces premature testicular senescence by disrupting mitochondrial respiratory chain through STAT5B-mitoSTAT3 in Leydig cell

Di-(2-ethylhexyl) phthalate exposure induces premature testicular senescence by disrupting mitochondrial respiratory chain through STAT5B-mitoSTAT3 in Leydig cell

  • Geroscience. 2024 Mar 19. doi: 10.1007/s11357-024-01119-x.
Haiming Cao # 1 2,  Qigen Xie # 1 3,  Peng Luo # 1,  Jiaqi Chen # 4,  Kai Xia 5,  Lin Ma 6,  Demeng Chen 7,  Chunhua Deng 1,  Zi Wan 8
Affiliations

Affiliations

  • 1 The Andrology Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.
  • 2 The Reproductive Andrology Clinic, the Seventh Affiliated Hospital of Sun Yat-Sen University, 628 Zhenyuan Road, 518000, Shenzhen, Guangdong, China.
  • 3 The Department of Pediatric Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
  • 4 The Urology Department, Affiliated Sanming First Hospital, Fujian Medical University, Sanming, 365000, Fujian, China.
  • 5 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.
  • 6 The Reproductive Center, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518000, Guangdong, China.
  • 7 Translational Medicine Center, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.
  • 8 The Andrology Department, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China. zi_wan2012@163.com.
  • # Contributed equally.
PMID: 38499958 DOI: 10.1007/s11357-024-01119-x
Abstract

Di-(2-ethylhexyl) phthalate (DEHP), a prevalent plasticizer, is known to have endocrine-disrupting effects on males and cause reproductive toxicity. There were causal effects of DEHP on testosterone levels in the real world by Mendelian randomization analysis. Exposure to DEHP during the preadult stage might lead to premature testicular senescence, but the mechanisms responsible for this have yet to be determined. In this study, we administered DEHP (300 mg/kg/day) to male C57BL/6 mice from postnatal days 21 to 49. The mice were kept for 6 months without DEHP. RNA Sequencing was conducted on testicular tissue at PNM6. The results indicated that DEHP hindered testicular development, lowered serum testosterone levels in male mice, and induced premature testicular senescence. TM3 Leydig cells were exposed to 300 μM of mono(2-ethylhexyl) phthalate (MEHP), the bioactive metabolite of DEHP, for 72 h. The results also found that DEHP/MEHP induced senescence in vivo and in vitro. The mitochondrial respiratory chain was disrupted in Leydig cells. The expression and stability of STAT5B were elevated by MEHP treatment in TM3 cells. Furthermore, p-ERK1/2 was significantly decreased by STAT5B, and mitochondria-STAT3 (p-STAT3 ser727) was significantly decreased due to the decrease of p-ERK1/2. Additionally, the senescence level of TM3 cells was decreased and treated with 5 mM NAC for 1 h after MEHP treatment. In conclusion, these findings provided a novel mechanistic understanding of Leydig cells by disrupting the mitochondrial respiratory chain through STAT5B-mitoSTAT3.

Keywords

DEHP; Mitochondrial respiratory chain; ROS; Senescence.

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