2. Academic Validation
  3. Di-(2-ethylhexyl) phthalate exposure leads to ferroptosis via the HIF-1α/HO-1 signaling pathway in mouse testes

Di-(2-ethylhexyl) phthalate exposure leads to ferroptosis via the HIF-1α/HO-1 signaling pathway in mouse testes

  • J Hazard Mater. 2022 Mar 15:426:127807. doi: 10.1016/j.jhazmat.2021.127807.
Yuhao Wu 1,  Junke Wang 2,  Tianxin Zhao 3,  Jiadong Chen 1,  Lian Kang 1,  Yuexin Wei 1,  Lindong Han 1,  Lianju Shen 1,  Chunlan Long 1,  Shengde Wu 4,  Guanghui Wei 5
Affiliations

Affiliations

  • 1 Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China.
  • 2 Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China; Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 4 Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China. Electronic address: [email protected].
  • 5 Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, China. Electronic address: [email protected].
PMID: 34863575 DOI: 10.1016/j.jhazmat.2021.127807
Abstract

Di-(2-ethylhexyl) phthalate (DEHP) is an extensively used plasticizer and has been shown to cause reproductive dysfunction in humans and model Animals. However, the exact mechanisms of testicular injury induced by DEHP exposure have not been fully clarified. Using gas chromatography-mass spectrometry, we found that mono-2-ethylhexyl ester (MEHP, a major biometabolite of DEHP) and DEHP concentrations were elevated in mouse serum after DEHP exposure. Using RNA-seq, we found that Ferroptosis and HIF-1 signaling pathways might be involved in testicular injury due to prepubertal DEHP exposure. Subsequent Western blotting, ferrous iron and MDA measurements, and immunofluorescence of testicular sections verified the RNA-seq findings. Consistently, based on the RNA-seq findings, we found that Ferroptosis and HIF-1 signaling pathways might play crucial roles in Leydig and Sertoli cell injury due to MEHP exposure in vitro. Further experiments also confirmed Ferroptosis in Leydig and Sertoli cells. Using Western blotting, cellular immunofluorescence and ChIP-qPCR, we found that MEHP exposure caused HIF-1α accumulation and stabilization, resulted in HIF-1α translocation into the nucleus, and induced HIF-1α/Hmox1 binding in Leydig and Sertoli cells. To clarify whether HIF-1α plays a pivotal role in MEHP-induced Ferroptosis, we knocked out HIF-1α using the CRISPR/Cas9 technique. We found that HIF-1α knockout rescued MEHP-induced Ferroptosis. In summary, our findings certified that prepubertal DEHP exposure led to Ferroptosis in mouse testes via the HIF-1α/HO-1 signaling pathway.

Keywords

Di-(2-ethylhexyl) phthalate; Ferroptosis; HIF-1α; Testis.

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