围产期甲基汞暴露对子代成年大鼠神经递质代谢及学习记忆能力的影响
Effects of Perinatal Methylmercury Exposure on Neurotransmitter Metabolism and the Learning and Memory in Adult Offspring Rats
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摘要: 本研究旨在通过建立围产期甲基汞暴露大鼠模型,探讨神经递质在甲基汞暴露致子代成年大鼠学习记忆损伤中的贡献以及其在辅助判断甲基汞致神经损伤中的作用。八臂迷宫检测子代成年大鼠学习记忆能力;液相色谱-质谱联用仪(liquid chromatography-tandem mass spectrometer, LC-MS/MS)检测子代大鼠血清神经递质水平;冷原子荧光光谱法(cold atomic fluorescence spectrometry, CVAFS)检测子代大鼠脑汞含量;pairwise Pearson相关性分析探讨子代大鼠脑汞含量、神经递质水平、学习记忆能力三者之间的关系,中介效应分析探讨神经递质在围产期甲基汞暴露致子代成年大鼠学习记忆损伤中的作用。结果显示,甲基汞染毒组子鼠工作记忆错误次数(working memory errors, WME)、参考记忆错误次数(reference memory errors, RME)较对照组显著增加,各剂量甲基汞染毒组子鼠脑汞含量均显著高于对照组,且随着染毒剂量的增加,脑汞含量逐渐升高;甲基汞染毒组血清中乙酰胆碱(acetylcholine, ACh)、5-羟色胺(5-hydroxytryptamine, 5-HT)、多巴胺(dopamine, DA)、去甲肾上腺素(noradrenaline, NA)、谷氨酸(glutamate, Glu)水平及Glu/GABA比值显著高于对照组,而肾上腺素(adrenaline, A)和γ-氨基丁酸(γ-aminobutyric acid, GABA)水平显著低于对照组。相关性分析结果显示,子鼠脑汞含量与ACh、5-HT、DA、NA、Glu以及学习记忆损伤参数WME、RME呈正相关,与A、GABA呈负相关。ACh、5-HT、DA、NA、Glu与WME呈正相关,GABA与WME呈负相关;ACh、5-HT、DA、NA、Glu与RME呈正相关,GABA与RME呈负相关。中介分析结果显,5-HT和Glu在甲基汞致子鼠WME增加中起完全中介效应作用。5-HT在甲基汞致子鼠RME增加中起完全中介效应作用;Glu在甲基汞致子鼠RME增加中存在中介效应作用,中介效应值为52.30%。多重中介效应分析结果显示,神经递质在甲基汞暴露致学习记忆能力损伤中不存在多重中介作用。综上所述,神经递质代谢紊乱参与了围产期甲基汞暴露致子代成年大鼠学习记忆能力损伤,动态观察5-HT和Glu表达可辅助判断甲基汞致神经损伤。Abstract: This study aimed to investigate the contribution of neurotransmitters to the learning and memory impairments observed in adult offspring rats exposed to methylmercury (MeHg) and the role of neurotransmitters in MeHg-induced neurological impairments. To this end, a perinatal MeHg exposure rat model was established. The eight-arm maze was used to test the learning and memory ability of adult offspring rats. CVAFS was used to detect the brain mercury content of rats and LC-MS/MS was used to detect the neurotransmitter levels. Pairwise Pearson correlation analysis was performed to analyze the linear correlation between the brain mercury content and neurotransmitter levels. Mediated effects analysis was performed to investigate the role of neurotransmitters in perinatal MeHg exposure-induced learning and memory impairment in rats. The results demonstrated that the number of working memory errors (WME) and reference memory errors (RME) of rats in the MeHg-exposed groups were significantly higher than those in the control group, and the brain mercury levels of the offspring in each MeHg-exposed group were significantly higher than those in the control group, with an increasing trend with increasing treatment dose. The serum levels of acetylcholine (ACh), 5-hydroxytryptamine (5-HT), dopamine (DA), noradrenaline (NA), glutamate (Glu) and Glu/GABA ratio were significantly higher in the MeHg group than in the control group, while the adrenaline (A) and γ-aminobutyric acid (GABA) levels were significantly lower. Correlation analysis revealed that the brain mercury content was positively correlated with the levels of ACh, 5-HT, DA, NA, Glu, and WME, RME, but negatively correlated with A and GABA. ACh, 5-HT, DA, NA and Glu were positively correlated with WME, while GABA was negatively correlated with WME. ACh, 5-HT, DA, NA and Glu were positively correlated with RME, while GABA were negatively correlated with RME. Mediation analysis results showed that 5-HT and Glu play a completely mediating roles in the increase of WME, 5-HT plays a complete mediating role in the increase of RME; Glu plays a mediating role in the increase of RME, and the mediating effect value was 52.30%. Further analysis revealed no multiple mediating effects of neurotransmitters on the relationship between MeHg treatment and learning memory impairments. In conclusion, an imbalance in neurotransmitter metabolism is involved in the effect of perinatal MeHg exposure on impaired learning and memory in adult offspring rats. 5-HT and Glu are expected to serve as biomarkers for the determination of MeHg-induced neurotoxicity.
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Key words:
- MeHg /
- rats /
- neurotoxicity /
- brain /
- neurotransmitters
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