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目的 探讨α-酮戊二酸(α-KG)对孕期砷暴露导致子代肝脏脂质沉积中的保护作用及机制。方法 SPF级8周龄癌症研究所(ICR)小鼠，雌雄2∶1交配后得到孕鼠共32只，将孕鼠随机分为4组：对照组、砷组、α-KG组、砷+α-KG组。在妊娠第0～16天(GD0～GD16)，砷组和砷+α-KG组每天饮水暴露亚砷酸钠(NaAsO2)15 mg/L,α-KG组和砷+α-KG组使用α-KG(2 g/kg)每天进行灌胃。在GD16收集胎鼠肝脏，并测量胎鼠体质量与顶臀长；转录组分析对照组和砷组基因表达差异；液相色谱-串联质谱法(LC-MS/MS)检测胎鼠肝脏总三酰甘油(TGs)水平及其亚型；油红O染色观察肝脏组织病理变化；实时定量聚合酶链式反应(qPCR)检测胎鼠磷酸肌醇3-激酶(PI3K)、蛋白激酶B(AKT)、脂质代谢相关基因的表达水平。结果 转录组学分析显示，孕期砷暴露后导致胎肝2 144个基因下调和1 675个基因上调；与对照组相比，砷组胎鼠体质量和顶臀长降低(PTuKey<0.05)，肝脏TGs水平升高(PTuKey<0.05)；油红O染色结果显示，脂滴明显增加(PTuKey<0.01);qPCR检测结果显示脂质合成相关基因表达显著上调(PTuKey<0.05),β-氧化以及脂质降解相关基因表达下降(PTuKey<0.05),PI3K、AKT转录水平降低(PTuKey<0.05)。与砷组相比，砷+α-KG组胎鼠体质量和顶臀长增加(PTuKey<0.05)；肝脏TGs水平降低(PTuKey<0.05)；油红O染色结果显示，脂滴显著减少(PTuKey<0.01)；脂质合成相关基因表达下调(PTuKey<0.05),β-氧化以及脂质降解相关基因表达上调(PTuKey<0.05),PI3K、AKT转录水平上升(PTuKey<0.05)。结论 α-KG可有效缓解孕期砷暴露导致的子代肝脏脂质沉积，其作用机制可能是通过激活PI3K/AKT，恢复脂质代谢稳态实现的。
Abstract：Objective To investigate the protective effect of α-ketoglutarate(α-KG) on hepatic lipid deposition in offspring caused by arsenic exposure during pregnancy.Methods 8-week-old institute of cancer research(ICR) mice were mated in a ratio of 2∶1 between females and males, and the detection of vaginal plugs confirmed pregnant. A total of 32 pregnant mice were randomly divided into four groups: control group, arsenic group, α-KG group, arsenic+α-KG group. On gestational day 0-16(GD0-GD16), the arsenic and arsenic+α-KG groups were exposed to sodium arsenite(NaAsO2,15 mg/L) in drinking water everyday, and the α-KG and arsenic+α-KG groups were gavaged with α-KG(2 g/kg) everyday. On GD16, pregnant mice were euthanized to collect fetal liver, and fetal body weight and crown-rump length were measured. Gene expression differences between the control group and the arsenic group were analyzed by transcriptome. The total triglycerides(TGs) and subtypes in fetal liver were detected by liquid chromatography tandem mass spectrometry(LC-MS/MS). Oil red O staining was used to observe the histopathological changes in the liver. Quantitative polymerase chain reaction(qPCR) was used to detect the expression level of genes related to lipid synthesis, transport, and degradation, and phosphatidylinositol 3'-kinase/protein kinase B(PI3K/AKT) in the liver of fetus.Results Transcriptomics analysis showed that 2 144 genes were downregulated and 1 675 genes were upregulated in the arsenic exposed fetal liver; body weight and crown-rump length were reduced(PTuKey<0. 05); the level of hepatic TGs was elevated in arsenic group(PTuKey<0. 05); oil-red O staining showed a significant increase in lipid droplets in arsenic group(PTuKey<0. 01); the expression of lipid synthesis-related genes were significantly upregulated(PTuKey<0. 05); the expression of β-oxidation-related genes and lipid degradation-related genes were downregulated(PTuKey<0. 05); the expression of PI3K, AKT decreased (PTuKey<0. 05). Compared with the arsenic group, the body weight and crown-rump length of fetus increased in the arsenic+α-KG group(PTuKey<0. 05); the level of hepatic TGs decreased in the arsenic+α-KG group(PTuKey<0. 05); oil red O staining showed lipid droplets significantly decreased(PTuKey<0. 01); the expression of lipid synthesisrelated genes were downregulated(PTuKey<0. 05), the expression of β-oxidation-related genes and lipid degradationrelated genes were upregulated(PTuKey<0. 05); the expression levels of PI3K and AKT increased(PTuKey<0. 05).Conclusion α-KG alleviated hepatic lipid deposition in offspring exposed to arsenic during pregnancy through ac-tivating PI3K/AKT signaling pathway.
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基本信息:
DOI：10.19405/j.cnki.issn1000-1492.2026.02.006
中图分类号:R714.2
引用信息:
[1]暴双蕊,吴红艳,孙影,等.α-酮戊二酸经PI3K/AKT改善砷诱导的子代肝脂质沉积[J].安徽医科大学学报,2026,61(02):225-232.DOI:10.19405/j.cnki.issn1000-1492.2026.02.006.
基金信息:
国家自然科学基金项目（编号：82173565）; 安徽省高校中青年教师培养行动项目（编号：DTR2023012）; 出生人口健康教育部重点实验室“本科生开放课题”项目（编号：JKBK20249）~~