2. Academic Validation
  3. Increased m6A modification of RNA methylation related to the inhibition of demethylase FTO contributes to MEHP-induced Leydig cell injury☆

Increased m6A modification of RNA methylation related to the inhibition of demethylase FTO contributes to MEHP-induced Leydig cell injury☆

  • Environ Pollut. 2021 Jan 1;268(Pt A):115627. doi: 10.1016/j.envpol.2020.115627.
Tianxin Zhao 1,  Junke Wang 1,  Yuhao Wu 1,  Lindong Han 2,  Jiadong Chen 2,  Yuexin Wei 2,  Lianju Shen 2,  Chunlan Long 2,  Shengde Wu 3,  Guanghui Wei 1
Affiliations

Affiliations

  • 1 Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, 400014, PR China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, PR China.
  • 2 Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, 400014, PR China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, PR China.
  • 3 Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, PR China; Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering, Chongqing, 400014, PR China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, PR China; National Clinical Research Center for Child Health and Disorders, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, PR China; Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, PR China. Electronic address: shengdewu@hospital.cqmu.edu.cn.
PMID: 33010548 DOI: 10.1016/j.envpol.2020.115627
Abstract

N6-methyladenosine (m6A) modification, the most prevalent form of RNA methylation, modulates gene expression post-transcriptionally. Di-(2-ethylhexyl) phthalate (DEHP) is a common environmental endocrine disrupting chemical that induces testicular injury due to the inhibition of the demethylase fat mass and obesity-associated protein (FTO) and increases the m6A modification. How FTO-mediated m6A modification in testicular Leydig cell injury induced by DEHP remains unclear. Here, the TM3 Leydig cell line was treated with mono-(2-ethylhexyl) phthalate (MEHP), the main metabolite of DEHP in the body, as well as FB23-2, an inhibitor of FTO. Decreased levels of testosterone in the culture supernatant, significantly increased Apoptosis, and a remarkable upregulation of global m6A modification were found in both TM3 cells treated with MEHP and FB23-2. Transcriptome sequencing showed that both treatments significantly induced apoptosis-associated gene expression. Methylated RNA immunoprecipitation sequencing showed that the Leydig cell injury induced by upregulated m6A modification could be associated with multiple physiological disorders, including histone acetylation, Reactive Oxygen Species biosynthesis, MAPK signaling pathway, hormone secretion regulation, Autophagy regulation, and male gonadal development. Overall, the inhibition of FTO-mediated up-regulation of m6A could be involved in MEHP-induced Leydig cell Apoptosis.

Keywords

Fat mass and obesity-associated protein; Leydig cells; Mono-(2-ethylhexyl) phthalate; N(6)-methyladenosine; RNA methylation.

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