1. Academic Validation
  2. Tris(2-ethylhexyl) phosphate induces cytotoxicity in TM3 Leydig cells by modulating autophagy and endoplasmic reticulum stress

Tris(2-ethylhexyl) phosphate induces cytotoxicity in TM3 Leydig cells by modulating autophagy and endoplasmic reticulum stress

  • Ecotoxicol Environ Saf. 2024 May 21:279:116462. doi: 10.1016/j.ecoenv.2024.116462.
Wenqiao Zhang 1 Yali Song 2 Letai Yi 3 Jinhuan Ou 4 Junhui Chen 4 Wei Zhang 4 Qinglian Wen 5 Chuanbin Yang 6 Jigang Wang 7
Affiliations

Affiliations

  • 1 Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 2 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong 523125, China.
  • 3 Medicine Innovation Center for Nationalities, Inner Mongolia Medical University, Hohhot 010110, China.
  • 4 Department of Critical Medicine, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital; the Second Clinical Medical College of Jinan University; the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, Guangdong, China.
  • 5 Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan 646000, China. Electronic address: wenqinglian@swmu.edu.cn.
  • 6 Department of Critical Medicine, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital; the Second Clinical Medical College of Jinan University; the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, Guangdong, China. Electronic address: h1094103@connect.hku.hk.
  • 7 Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan 646000, China; Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan, Guangdong 523125, China; Department of Critical Medicine, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital; the Second Clinical Medical College of Jinan University; the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, Guangdong, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: jgwang@icmm.ac.cn.
Abstract

Tris (2-ethylhexyl) phosphate (TEHP) is a frequently used organophosphorus flame retardant with significant ecotoxicity and widespread human exposure. Recent research indicates that TEHP has reproductive toxicity. However, the precise cell mechanism is not enough understood. Here, by using testicular mesenchymal stromal TM3 cells as a model, we reveal that TEHP induces Apoptosis. Then RNA Sequencing analysis, immunofluorescence, and western blotting results show that THEP inhibits Autophagy flux and enhances endoplasmic reticulum (ER) stress. Moreover, the activation of the ER stress is critical for TEHP-induced cell injury. Interestingly, TEHP-induced ER stress is contributed to autophagic flux inhibition. Furthermore, pharmacological inhibition of Autophagy aggravates, and activation of Autophagy attenuates TEHP-induced Apoptosis. In summary, these findings indicate that TEHP triggers Apoptosis in mouse TM3 cells through ER stress activation and Autophagy flux inhibition, offering a new perspective on the mechanisms underlying TEHP-induced interstitial cytotoxicity in the mouse testis.

Keywords

Autophagy; Endoplasmic reticulum stress; Reproductive toxicity; Tris (2-ethylhexyl) phosphate.

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