Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub-threshold pesticide exposure
Coding region paraoxonase polymorphisms dictate accentuated neuronal reactions in chronic, sub-threshold pesticide exposure
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DOI：
10.1096/fj.05-5576fje
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发表时间：
2006-08-01
期刊：
影响因子：
4.8
通讯作者：
Friedman, Alon
中科院分区：
文献类型：
--
作者：
Browne, R. Orie;Ben Moyal-Segal, Liat;Friedman, Alon
有机磷农药(OPs)是已知的乙酰胆碱酯酶(AChE)抑制剂，在世界范围内被广泛使用。最近的研究集中在AChE/PON1基因座作为环境OP暴露遗传易感性的决定因素。为了探索相应的基因-环境相互作用与脑活动的关系，我们综合了神经生理学、神经心理学、生化和遗传学方法。重要的是，我们发现，亚阈值OP暴露会导致明显的生理后果，这些后果受到遗传因素的显著影响。Loreta的皮质脑电分析显示，暴露个人的海马区、副海马区和扣带皮质中的theta活动显著降低，而前额叶皮质中的β活动增加-已知这些区域在胆碱能相关认知功能中发挥作用。通过神经心理测试，我们发现暴露在视觉记忆中的个体存在明显的缺陷。其他神经心理学测试显示，暴露在与未暴露的个体之间没有显著差异，证明了我们发现的特殊性。血液样本的生化分析显示，长期接触者对氧磷酶和芳香酯酶活性增加，而血清乙酰胆碱酯酶活性降低。值得注意的是，特定的对氧磷酶基因类型被发现与这些暴露相关的血酶活性变化和异常脑电模式有关。因此，涉及AChE/PON1基因的基因-环境相互作用可能是决定对OP暴露的生理反应的因果关系。
Organophosphate pesticides (OPs), known inhibitors of acetylcholinesterase (AChE), are used extensively throughout the world. Recent studies have focused on the ACHE/PON1 locus as a determinant of inherited susceptibility to environmental OP exposure. To explore the relationship of the corresponding gene-environment interactions with brain activity, we integrated neurophysiologic, neuropsychological, biochemical, and genetic methods. Importantly, we found that subthreshold OP exposure leads to discernible physiological consequences that are significantly influenced by inherited factors. Cortical EEG analyses by LORETA revealed significantly decreased theta activity in the hippocampus, parahippocampal regions, and the cingulate cortex, as well as increased beta activity in the prefrontal cortex of exposed individuals-areas known to play a role in cholinergic-associated cognitive functions. Through neuropsychological testing, we identified an appreciable deficit in the visual recall in exposed individuals. Other neuropsychological tests revealed no significant differences between exposed and non-exposed individuals, attesting to the specificity of our findings. Biochemical analyses of blood samples revealed increases in paraoxonase and arylesterase activities and reduced serum acetylcholinesterase activity in chronically exposed individuals. Notably, specific paraoxonase genotypes were found to be associated with these exposure-related changes in blood enzyme activities and abnormal EEG patterns. Thus, gene-environment interactions involving the ACHE/PON1 locus may be causally involved in determining the physiological response to OP exposure.