2. Academic Validation
  3. Florasulam impairs Leydig cell function by blocking autophagic flux and triggering PERK-eIF2α-ATF4-CHOP-mediated ER stress

Florasulam impairs Leydig cell function by blocking autophagic flux and triggering PERK-eIF2α-ATF4-CHOP-mediated ER stress

  • Ecotoxicol Environ Saf. 2026 Jan 15:310:119826. doi: 10.1016/j.ecoenv.2026.119826.
Wenting Ye 1,  Jiawei Duan 1,  Jiangpeng Wu 1,  Songyu Huang 1,  Xiao Chen 1,  Yan Sun 1,  Xiaojian Yang 1,  Hongru Lin 1,  Jing Cai 1,  Haiping Wen 1,  Siyu Xia 2,  Yali Song 3
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine, Dongguan Key Laboratory for Innovative Research on Integrated Traditional Chinese and Western Medicine for the Diagnosis and Treatment of Infertility, Institute of Reproductive Genetics, Dongguan Maternal and Child Health Care Hospital, Dongguan, Guangdong Province 523000, China.
  • 2 Center for Reproductive Medicine, Dongguan Key Laboratory for Innovative Research on Integrated Traditional Chinese and Western Medicine for the Diagnosis and Treatment of Infertility, Institute of Reproductive Genetics, Dongguan Maternal and Child Health Care Hospital, Dongguan, Guangdong Province 523000, China. Electronic address: [email protected].
  • 3 Center for Reproductive Medicine, Dongguan Key Laboratory for Innovative Research on Integrated Traditional Chinese and Western Medicine for the Diagnosis and Treatment of Infertility, Institute of Reproductive Genetics, Dongguan Maternal and Child Health Care Hospital, Dongguan, Guangdong Province 523000, China. Electronic address: [email protected].
PMID: 41643304 DOI: 10.1016/j.ecoenv.2026.119826
Abstract

Environmental herbicides are increasingly recognized as contributors to male reproductive decline, yet the cellular mechanisms underlying their toxicity remain poorly defined. Here we show that Florasulam, a widely used triazolopyrimidine sulfonanilide Herbicide, directly disrupts Leydig cell homeostasis and steroidogenic function. Florasulam reduces TM3 Leydig cell viability and promotes Apoptosis, accompanied by decreased expression of the anti-apoptotic protein Bcl-2 and the steroidogenic enzyme HSD3B2. Transcriptomic profiling reveals early suppression of autophagy-related pathways together with enrichment of endoplasmic reticulum (ER) stress signatures. Consistent with these findings, Florasulam inhibits autophagic flux, marked by p62 accumulation, reduced LC3-II levels, and diminished autophagosome formation, and simultaneously activates the PERK-eIF2α-ATF4-CHOP signaling cascade indicative of unresolved ER stress. Pharmacological restoration of Autophagy with Rapamycin or Torin1 attenuates ER stress and significantly reduces Apoptosis. These results identify a critical autophagy-ER stress axis underlying Florasulam-induced Leydig cell injury and provide mechanistic insight into the reproductive risks associated with Herbicide exposure.

Keywords

Autophagy inhibition; ER stress; Florasulam; Leydig cells; Reproductive toxicity.

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