2. Academic Validation
  3. The role of inositol-requiring enzyme 1α in gestational arsenic-induced α-KG collapse in male offspring

The role of inositol-requiring enzyme 1α in gestational arsenic-induced α-KG collapse in male offspring

  • Ecotoxicol Environ Saf. 2025 Oct 15:305:119188. doi: 10.1016/j.ecoenv.2025.119188.
Shuang-Rui Bao 1,  Hong-Yan Wu 1,  Tong Zhan 1,  Ying Sun 1,  Qian Yang 1,  Ya-Ping Song 1,  Zhi-Yan Wan 1,  Xin-Ru Liang 1,  Wen-Yi Chen 2,  Li Tao 3,  Yuan-Bao Xu 4,  De-Xiang Xu 5,  Cheng Zhang 6
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China.
  • 2 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, Anhui 230032, China.
  • 3 The Second Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
  • 4 The First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
  • 5 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, Anhui 230032, China. Electronic address: xudex@126.com.
  • 6 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, Hefei 230032, China; MOE Key Laboratory of Population Health Across Life Cycle, Hefei, Anhui 230032, China. Electronic address: zhangchengdev@126.com.
PMID: 41066812 DOI: 10.1016/j.ecoenv.2025.119188
Abstract

Arsenic，a well-documented environmental contaminant, has been associated with hepatic metabolism dysregulation. Previous study found arsenic exposure during pregnancy induced hepatic lipid accumulation in female offspring through α-ketoglutarate(α-KG) reduction. However, the mechanism of arsenic-reduced α-KG content remains unclear. In this study, in vivo experiments were conducted to investigate endoplasmic reticulum (ER) stress activation in arsenic-exposed offspring, while experiments in vitro were to investigate the role of ER stress in arsenic-reduced α-KG content. Our findings revealed gestational arsenic exposure reduced the hepatic α-KG level in male offspring. Mechanistically, arsenic exposure triggered ER stress, as evidenced by the activation of ER stress sensor inositol-requiring enzyme 1α (IRE1α). To confirm the effect of ER stress in arsenic impeded α-KG content, 4-phenylbutyric acid (4-PBA), an accepted inhibitor of ER stress, was used to treat AML12 cells. The results showed 4-PBA pretreatment upregulated the expression of α-KG synthase and mitigated the depletion of α-KG content. Moreover, IRE1α siRNA pretreatment markedly reversed arsenic-reduced α-KG content in AML12 cells. As above, Arsenic exposure reduced α-KG content via activating IRE1α signaling. ER stress maybe the potential mechanism of arsenic exposure impaired α-KG level in male offspring. This study provided novel insights into the toxicological mechanisms whereby maternal environmental exposure programed metabolic disorders in offspring.

Keywords

Arsenic; inositol-requiring enzyme 1α; isocitrate dehydrogenase; α-ketoglutarate.

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