The Impact of Genetic Variability on Human Susceptibility to Chlorpyrifos

遗传变异对人类对毒死蜱敏感性的影响

• 批准号: 8256238
• 负责人: Alice Langford Crane
• 金额: $ 3.22万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256238
• 关键词: Accounting; Acetylcholine; Acetylcholinesterase; Address; Agricultural Workers; Biological; Biological Markers; Blood; COS Cells; Caring; Cells; Chemical Warfare Agents; Chlorpyrifos; Cholinergic Receptors; Cholinesterase Inhibitors; Chronic; Complementary DNA; Country; Cytochrome P450; Data; Dermal; Disease; Dose; Drug Kinetics; Enzyme Kinetics; Enzymes; Equipment; Exhibits; Exposure to; Genetic; Genetic Polymorphism; Genotype; Goals; Health; Healthcare; High Pressure Liquid Chromatography; Human; In Vitro; Incubated; Individual; Interdisciplinary Study; Kinetics; Knowledge; Link; Liver; Mediating; Metabolic Biotransformation; Metabolism; Muscle; Neurologic; Neurons; Neurotransmitters; O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; Organophosphorus Compounds; Outcome; Parents; Pesticides; Play; Poison; Population; Predisposition; Preparation; Prevalence; Production; Protein Isoforms; Public Health; Regulation; Relative (related person); Reporting; Research; Risk; Risk Assessment; Role; Safety; Synapses; Techniques; Testing; Time; Toxic effect; Uncertainty; Variant; animal data; base; cohort; exhaustion; exposed human population; gene environment interaction; genetic variant; human CYP2B6 protein; hydroxypyridine; improved; in vivo; interest; models and simulation; mutant; neurobehavioral; neurotoxicity; pharmacodynamic model; response; simulation; urinary

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.

描述（由申请人提供）：有机磷（OP）农药在世界范围内广泛使用，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）和丁酰胆碱酯酶（BChE）。这种抑制的最重要的结果是神经递质乙酰胆碱（ACh）在神经元和肌肉突触中的积累，导致最初的过度刺激，随后是ACh受体的最终耗尽。毒死蜱（Chlorpyrifos，CPF）是世界上最常用的有机磷农药之一。与许多OP农药一样，CPF是一种前毒物，必须主要通过肝脏中的细胞色素p450（CYP 450）酶代谢为具有毒理学活性的毒死蜱氧（CPF-O），以发挥毒性作用。CPF-O是一种有效的胆碱酯酶（ChE）抑制剂。因此，CYP 2B 6（主要负责CPF生物活化的CYP酶）的遗传变异性可解释个体间毒性的变异性。据推测，人CYP 2B 6中已知的功能多态性将表现出CPF生物活化为CPF-O的动力学变异性，个体的CYP 2B 6基因型将与其对CPF毒性的相对易感性相关。当前提案的目的是使用体外技术研究CYP 2B 6的不同流行亚型，并观察这些遗传变体与正常变体相比的任何酶动力学改变，并将这些动力学参数纳入基于生理学的药代动力学/药效学（PBPK/PD）模型，以检查人群中CYP 2B 6基因型与效应和毒性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，并使用群体驱动的范式，其中不确定性因素用于解释对个体间变异性知之甚少。此外，慢性暴露于CPF和其他OP化合物与多种神经系统和其他疾病的潜在关联尚不清楚。拟议的研究将确定在介导CPF毒性方面重要的遗传因素，澄清基因-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）农药在世界范围内大量使用，并构成重大健康风险，特别是在可能缺乏个人防护设备（PPE）和其他安全法规的欠发达国家。确定和保护最易受感染的人群可以改善预防性保健并减少风险。需要了解个体间变异性的潜在生物学机制，以确定CPF毒性风险最大的个体。