Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.
Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds.
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DOI：
10.3389/fnins.2016.00590
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发表时间：
2016
影响因子：
4.3
通讯作者：
Pieper AA
中科院分区：
文献类型：
--
作者：
Voorhees JR;Rohlman DS;Lein PJ;Pieper AA
有机磷化合物广泛用作杀虫剂、增塑剂和燃料添加剂。这些化合物有效抑制乙酰胆碱酯酶（AChE），这种酶使神经元突触处的乙酰胆碱失活，急性暴露于高OP水平可导致人类和动物的胆碱能危机。有证据进一步表明，反复暴露于较低的OP水平，不足以引起胆碱能危机，在职业环境中经常遇到，也对人们构成严重风险。例如，多项流行病学研究已经确定了职业OP暴露与神经退行性疾病、精神疾病和感觉运动缺陷之间的关联。对这些流行病学发现背后的基础科学机制进行严格的科学调查需要有效的临床前模型，其中严格管制的暴露范例可能与神经毒性相关。在这里，我们回顾了目前在该领域使用的职业OP暴露的实验模型。我们发现，模拟职业OP暴露的动物研究确实显示了神经毒性的证据，并且这些模型的利用有助于阐明OP诱导的神经系统后遗症的机制。尽管如此，仍有必要开展进一步的工作，以评估接触水平、保护方法和治疗策略，这些因素结合在一起，可能有助于修改全球改善工作场所条件的指导方针。
Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.