Browne R Orie, Moyal-Segal Liat Ben, Zumsteg Dominik, David Yaron, Kofman Ora, Berger Andrea, Soreq Hermona, Friedman Alon
Department of Physiology, Soroka University Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
FASEB J. 2006 Aug;20(10):1733-5. doi: 10.1096/fj.05-5576fje. Epub 2006 Jun 28.
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.
有机磷酸酯类农药（OPs）是已知的乙酰胆碱酯酶（AChE）抑制剂，在全球广泛使用。最近的研究聚焦于ACHE/PON1基因座，将其作为遗传性易感性环境OP暴露的决定因素。为了探究相应的基因 - 环境相互作用与脑活动的关系，我们整合了神经生理学、神经心理学、生物化学和遗传学方法。重要的是，我们发现阈下OP暴露会导致明显的生理后果，且这些后果受到遗传因素的显著影响。通过LORETA进行的皮层脑电图分析显示，暴露个体的海马体、海马旁区域和扣带回皮层的θ活动显著降低，前额叶皮层的β活动增加，而这些区域已知在胆碱能相关认知功能中发挥作用。通过神经心理学测试，我们发现暴露个体在视觉回忆方面存在明显缺陷。其他神经心理学测试显示，暴露个体与未暴露个体之间没有显著差异，这证明了我们研究结果的特异性。对血样的生化分析显示，长期暴露个体的对氧磷酶和芳基酯酶活性增加，血清乙酰胆碱酯酶活性降低。值得注意的是，发现特定的对氧磷酶基因型与这些与暴露相关的血液酶活性变化和异常脑电图模式有关。因此，涉及ACHE/PON1基因座的基因 - 环境相互作用可能因果性地参与决定对OP暴露的生理反应。
