α-酮戊二酸对妊娠期砷暴露引起的母体脂质稳态和线粒体状态紊乱的影响

Effect of α-ketoglutarate on maternal lipid homeostasis and mitochondrial status perturbed by gestational arsenic exposure

α-酮戊二酸对妊娠期砷暴露引起的母体脂质稳态和线粒体状态紊乱的影响

Authors:Tong Zhan,Shuang-Rui Bao,Ying Sun,Hong-Yan Wu,Wen-Kang Tao,Xin-Ru Liang,Zhi-Yan Wan,Qian Yang,Hua Wang,Yi-Chao Huang,Jian-Qing Wang,De-Xiang Xu,Cheng Zhang

Source：Biochimica et Biophysica Acta-molecular And Cell Biology of Lipids

PMID:40680987

DOI:10.1016/j.bbalip.2025.159665

Abstract

Arsenic is a common environmental toxicant with known hepatotoxic effects, yet its impact on maternal lipid metabolism during pregnancy remains poorly understood. In this study, we established a pregnant mouse model to investigate the effects of gestational arsenic exposure and the potential protective role of α-ketoglutarate (α-KG), a key tricarboxylic acid (TCA) cycle intermediate. In the first experiment, arsenic exposure led to significant disruptions in maternal serum and hepatic lipid profiles. Mechanistically, arsenic reduced hepatic α-KG concentrations, impaired mitochondrial ultrastructure, altered mitochondria-related gene expression, induced oxidative stress, and decreased multiple TCA cycle intermediates, collectively indicating compromised mitochondrial function. In the second experiment, α-KG supplementation during gestation effectively restored hepatic α-KG levels and reversed arsenic-induced lipid metabolic imbalances. Moreover, α-KG preserved mitochondrial morphology, normalized the expression of mitochondrial genes, alleviated oxidative stress, and partially rescued the levels of disrupted TCA intermediates. These results suggest that arsenic disrupts maternal lipid homeostasis primarily through mitochondrial dysfunction and oxidative stress, and that α-KG supplementation can alleviate these disturbances by supporting mitochondrial function. Although the exact molecular mechanisms require further clarification, our findings highlight the potential therapeutic role of α-KG in maintaining maternal lipid metabolic health during arsenic exposure during pregnancy.

Keywords:Arsenic; Lipid; Mitochondrion; Pregnancy; α-Ketoglutarate

摘要

砷是一种常见的环境毒物，具有已知的肝毒性作用，但其对妊娠期间母体脂质代谢的影响仍知之甚少。在本研究中，我们建立了一种妊娠小鼠模型，以探讨妊娠期砷暴露的影响以及α-酮戊二酸(α-KG）的潜在保护作用，α-KG是三羧酸循环(TCA循环）的关键中间产物。在第一个实验中，砷暴露导致母体血清和肝脏脂质谱发生显著紊乱。机制上，砷降低了肝脏α-KG浓度，损害了线粒体超微结构，改变了与线粒体相关的基因表达，诱导了氧化应激，并减少了多种三羧酸循环中间产物，这些变化共同表明线粒体功能受损。在第二个实验中，妊娠期间补充α-KG有效恢复了肝脏α-KG水平，并逆转了砷诱导的脂质代谢失衡。此外，α-KG维持了线粒体形态，恢复了线粒体相关基因的表达，缓解了氧化应激，并部分恢复了受损的TCA中间代谢物水平。这些结果表明，砷主要通过线粒体功能障碍和氧化应激扰乱母体脂质稳态，而α-KG补充可通过支持线粒体功能缓解这些扰动。尽管确切的分子机制需要进一步澄清，但我们的发现突出了α-KG在妊娠期砷暴露过程中维持母体脂质代谢健康方面的潜在治疗作用。

关键词：砷；脂质；线粒体；妊娠；α-酮戊二酸