Microcystin-LR inhibits testosterone synthesis via reactive oxygen species-mediated GCN2/eIF2α pathway in mouse testes

  • Sci Total Environ. 2021 Aug 10:781:146730. doi: 10.1016/j.scitotenv.2021.146730.
Lan Gao  1 ,  Jing Chen  2 ,  Jian Li  2 ,  An-Qi Cui  2 ,  Wei-Wei Zhang  2 ,  Xiu-Liang Li  2 ,  Jing Wang  2 ,  Xiao-Yi Zhang  2 ,  Ye Zhao  3 ,  Yuan-Hua Chen  2 ,  Cheng Zhang  2 ,  Hua Wang  4 ,  De-Xiang Xu  5
Affiliations
  • 1. Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 2. Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
  • 3. Department of Nuclear Medicine, Anhui Medical University, Hefei 230032, China.
  • 4. Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
  • 5. Department of Toxicology & Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China. Electronic address: [email protected].
PMID: 33798882 DOI: 10.1016/j.scitotenv.2021.146730
Abstract

Previous studies demonstrated that microcystin-leucine-arginine (MC-LR) disrupted testosterone (T) synthesis, but the underlying mechanisms are not entirely elucidated. This study aims to explore the role of Reactive Oxygen Species (ROS)-mediated GCN2/eIF2α activation on MC-LR-induced disruption of testicular T synthesis. Male mice were intraperitoneally injected with MC-LR (0 or 20 μg/kg) daily for 5 weeks. Serum T was decreased in MC-LR-exposed mice (0.626 ± 0.122 vs 24.565 ± 8.486 ng/ml, P < 0.01), so did testicular T (0.667 ± 0.15 vs 8.317 ± 1.387 ng/mg protein, P < 0.01). Steroidogenic proteins including StAR, CYP11A1 and CYP17A1 were downregulated in MC-LR-exposed mouse testes and TM3 cells. Mechanistically, p-GCN2 and p-eIF2α were elevated in MC-LR-exposed TM3 cells. GCN2iB attenuated MC-LR-induced GCN2 and eIF2α phosphorylation in TM3 cells. Moreover, GCN2iB attenuated MC-LR-induced downregulation of steroidogenic proteins in TM3 cells. Further analysis found that cellular ROS were elevated and HO-1 was upregulated in MC-LR-exposed TM3 cells. PBN rescued MC-LR-induced activation of GCN2/eIF2α signaling in TM3 cells. Additionally, pretreatment with PBN attenuated MC-LR induced downregulation of steroidogenic proteins and synthases in TM3 cells. These results suggest that ROS-mediated GCN2/eIF2α activation contributes partially to MC-LR-caused downregulation of steroidogenic proteins and synthases. The present study provides a new clue for understanding the mechanism of MC-LR-induced endocrine disruption.

Keywords
GCN2/eIF2α signaling; Leydig cell; MC-LR; Reactive oxygen species; Testosterone synthesis.
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