在不同实验动物对OPIDN的敏感性差异中雌激素的作用及机制

Organophosphorus compounds (OPs) are neurotoxic chemicals that are widely used as pesticides, fungicides and herbicides. Besides of acute toxicity, OPs are capable of causing delayed neurological deficits called organophosphate-induced delayed neurotoxicity (OPIDN). Different species have different sensitivity to OPIDN. For example, hens are sensitive to OPIDN whereas rats are not. The mechanism underlying this species difference is still poorly understood. Recent studies found that after OP treatment, serum estrogen level in hens decreased whereas estrogen level in rats increased more than ten times. More and more evidence showed that estrogen, an important female hormone, can promote neuronal cell proliferation and prevent neurodegeneration in both central and peripheral neuronal systems. So we propose that estrogen plays important role in determining the sensitivity of different species to OPIDN. In this project, we are going to use two different animal models,hens and rats, combined with two in vitro neuroblastoma cell culture systems from two different species,which are either sensitive or insensitive to OPIDN, to study the role of estrogen in pathogenesis of OPIDN. This research will help us understand the mechanism underlying the pathogenesis of OPIDN and discover new therapy to prevent and treat OP's toxicity.

有机磷农药可以使人及敏感动物产生迟发性神经病理损伤，即有机磷引起的迟发性神经毒性（OPIDN）。OPIDN具有动物种属敏感性，但这种敏感性差异的机制并不清楚。在鸡这种对OPIDN敏感的动物上，发现接触神经毒性有机磷后血清中雌激素水平下降；而在OPIDN不敏感的动物大鼠上，有机磷染毒会使其血清中雌激素水平有几十倍的上升。此外，很多证据表明，雌激素对于机体神经系统具有保护作用。这些研究强烈提示雌激素可能与OPIDN的动物敏感性相关。本项目使用鸡和大鼠这两种分别对OPIDN敏感和不敏感的动物作为实验动物模型，并选择两种对OPIDN敏感性不同的动物来源的成神经瘤细胞作为细胞模型，研究给予外源性雌激素和雌激素拮抗剂对OPIDN是否存在干预效应及其作用机制，着重了解雌激素在决定OPIDN的动物敏感性差异中的作用机理。研究结果可帮助我们进一步认识OPIDN的发生机制，并为探索其药物预防和治疗提供线索。

有机磷农药可以在人及敏感动物（例如鸡等）上引起迟发性的神经毒性（OPIDN），但是该神经毒性的机制并不清楚。本研究主要在实验动物模型鸡中探索性激素与OPIDN发生之间的关系。研究发现雌激素处理能够加重实验动物鸡的OPIDN症状；而孕激素处理对OPIDN有预防作用，其分子机制可能是通过抑制有机磷诱导的ErbB2/Akt通路的活化，进而提高组成髓鞘的雪旺细胞中S100蛋白的表达，从而恢复髓鞘的结构和功能。该结果揭示了OPIDN发生的分子机制，为进一步研究OPIDN治疗药物奠定了基础。