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，并且与 OP 化学战剂具有共同的作用机制。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积聚，导致最初的过度刺激，最终导致 ACh 受体耗尽。毒死蜱 (CPF) 是全球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) 酶代谢为具有毒理学活性的毒死蜱 (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。 CYP2B6（主要负责 CPF 生物活化的 CYP 酶）的遗传变异性因此可能是毒性的个体差异的原因。据推测，人类 CYP2B6 中已知的功能多态性将表现出 CPF 生物活化至 CPF-O 的动力学的变异性，并且 CYP2B6个体的基因型与其对 CPF 毒性的相对易感性有关。当前提案的目标是使用体外技术来研究 CYP2B6 的不同流行亚型，并观察与正常野生型酶相比这些遗传变体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学的药代动力学/药效 (PBPK/PD) 模型，用于检查 CYP2B6 基因型与人群中效应和毒性生物标志物之间的相关性。了解个体间变异背后的机制有可能改善当前的风险评估工作，这些工作严重依赖动物数据并使用群体驱动的范式，并使用不确定因素来解释人们对个体之间的变异性知之甚少。此外，人们对长期接触 CPF 和其他 OP 化合物与多种神经系统疾病和其他疾病之间的潜在关联知之甚少。拟议的研究将确定对介导 CPF 毒性很重要的遗传因素，阐明基因与环境的相互作用，这将有助于继续努力调查易感人群中 CPF 暴露与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) 农药在全球范围内大量使用，并构成重大健康风险，特别是在可能缺乏个人防护装备 (PPE) 和其他安全法规的欠发达国家。识别和保护最易受影响的人群可以改善预防性医疗保健并降低风险。需要了解个体差异的潜在生物学机制来识别那些最有 CPF 毒性风险的个体。