The Impact of Genetic Variability on Human Susceptibility to Chlorpyrifos

描述(申请人提供)：有机磷(OP)杀虫剂在世界范围内被广泛使用，并与OP化学战剂具有共同的机制。这些化合物抑制乙酰胆碱酯酶(AChE)和丁基胆碱酯酶(BChE)。这种抑制的最重要结果是神经递质乙酰胆碱(ACh)在神经元和肌肉突触中积累，导致最初的过度刺激，随后ACh受体最终耗尽。毒死蜱(CPF)是世界上最常用的有机磷农药之一。与许多OP杀虫剂一样，CPF是一种前毒物，必须通过肝脏中的细胞色素P450(CYP)酶代谢成具有毒理活性的毒死蜱(CPF-O)，才能发挥毒性作用。CPF-O是一种有效的胆碱酯酶(ChE)抑制剂。因此，主要负责CPF生物激活的CYP酶可能解释了毒性的个体间差异。假设已知的人类CYP2B6功能多态将显示CPF生物激活为CPF-O的动力学差异，个体的CYP2B6基因将与其对CPF毒性的相对易感性有关。目前建议的目标是使用体外技术来研究不同流行的CYP2B6亚型，并观察这些遗传变异与正常、野生型酶相比的任何改变的酶动力学，并将这些动力学参数纳入基于生理的药代动力学/药效学(PBPK/PD)模型中，以检验在人类群体中CYP2B6基因与效应和毒性的生物标志物之间的相关性。了解个体间变异性背后的机制有可能改善目前的风险评估工作，这些工作严重依赖动物数据，并使用具有不确定性因素的总体驱动范式来解释对个体变异性了解较少的情况。此外，慢性接触CPF和其他OP化合物与多种神经和其他疾病的潜在联系还知之甚少。这项拟议的研究将确定在调节CPF毒性方面重要的遗传因素，阐明基因-环境相互作用，这将有助于继续努力调查CPF暴露与易感人群中某些健康终点之间的联系。 公共卫生相关性：毒死蜱(CPF)和其他有机磷(OP)杀虫剂在全球范围内大量使用，对健康构成重大风险，特别是在可能缺乏个人防护装备(PPE)和其他安全法规的欠发达国家。确定和保护最易受影响的人群可以改善预防性保健，降低风险。需要了解个体间变异的潜在生物学机制，以确定哪些个体面临CPF毒性的最大风险。

DESCRIPTION (provided by applicant): Organophosphorus (OP) pesticides are extensively used worldwide and share a common mechanism with OP chemical warfare agents. These compounds inhibit the enzymes acetylcholinesterase (AChE) and butylrylcholinesterase (BChE). The most important result of this inhibition is the accumulation of the neurotransmitter acetylcholine (ACh) in neuronal and muscular synapses leading to an initial overstimulation, followed by eventual exhaustion of ACh receptors. Chlorpyrifos (CPF) is one of the most commonly used OP pesticides worldwide. Like many OP pesticides, CPF is a pro-poison and must be metabolized to the toxicologically active Chlorpyrifos oxon (CPF-O), primarily by cytochrome p450 (CYP) enzymes in the liver, to exert toxic effects. CPF-O is a potent cholinesterase (ChE) inhibitor. Genetic variability in CYP2B6, the CYP enzyme primarily responsible for CPF bioactivation may therefore account for interindividual variability in toxicity It is hypothesized that known functional polymorphisms in human CYP2B6 will exhibit variability in the kinetics for the bioactivation of CPF to CPF-O and that the CYP2B6 genotype of an individual will be related to their relative susceptibility to CPF toxicity. The objectives of the current proposal are to use in vitro techniques to study different prevalent isoforms of CYP2B6 and observe any altered enzyme kinetics of these genetic variants as compared to the normal, wild-type enzymes and to incorporate these kinetic parameters into a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model to examine the correlation between CYP2B6 genotype and biomarkers of effect and toxicity in a human population. Understanding the mechanisms behind interindividual variability has the potential to improve current risk assessment efforts, which rely heavily on animal data and use population- driven paradigms with uncertainty factors used to account for poorly understood variability among individuals. In addition, the potential association of chronic exposure to CPF and other OP compounds with a multitude of neurological and other diseases is poorly understood. The proposed study will identify genetic factors that are important in mediating CPF toxicity, clarifying gene-environment interactions which will help the continuing efforts to investigate the link between CPF exposure and certain health endpoints in susceptible populations. PUBLIC HEALTH RELEVANCE: Chlorpyrifos (CPF) and other organophosphorus (OP) pesticides are heavily used worldwide and pose significant health risks, particularly in underdeveloped countries where personal protective equipment (PPE) and other safety regulations may be lacking. Identification and protection of the most susceptible populations can improve preventative health care and reduce risks. Knowledge of underlying biological mechanisms of interindividual variability is needed to identify those individuals most at risk for CPF toxicity.