Genetic analysis of organophosphate metabolism in NC farmworkers

描述（由申请人提供）：农场工人接触农药是一个公认的环境健康问题（Arcury et al., 2002; Arcury & Quandt 2003; Reeves & Schafer 2003; Arcury et al., 2006）。有机磷（OP）杀虫剂是使用最广泛的杀虫剂之一，包括毒死蜱、二嗪农、乐果、二硫磷和磷。接触有机磷农药对人体健康有害（Reigart & Roberts， 1999年），少量接触的直接影响包括皮疹、恶心和视力模糊，大量接触的直接影响包括失禁、昏迷和死亡。暴露的延迟效应可能包括不育、出生缺陷、癌症和神经退行性疾病。农场工人及其家庭的农药暴露来源包括职业、准职业、居住和环境因素（Fenske等人，2000；Arcury等人，2006；Quandt等人，2006）。农场工人几乎无法控制他们的暴露（Austin等人，2001年），并且在回家之前，在工作场所更换工作服和淋浴的机会有限（美国总审计局，2000年）；Arcury et al., 2001)。提供给农场工人的住房通常位于施用农药的田地附近（住房援助委员会2001年；Early等人，2006年），而且通常不符合标准，虫害导致居民使用农药（Quandt等人，2004年；Early等人，2006年）。农场工人及其配偶往往没有获得保护自己和家人免受暴露所需的信息（Arcury等人，1999；Rao等人，2006）。农药暴露的有效剂量显然取决于最初的环境暴露，但它也受到个人先天代谢和排泄毒素能力的影响。OP农药的代谢主要由细胞色素P450家族中的特定蛋白质和对氧磷酶类分子决定。这些基因中的一些聚集在同一染色体区域，表明可能存在共同的调控机制，可能是由这些基因内部或基因之间的遗传变异介导的。据报道，PON1的多态性与PON1酶的水平相关（例如，（Holland等人，2006）），这表明遗传变异有助于这种酶的水平或活性。对包含PON1、PON2和PON3的整个PON位点进行综合分析，对于确定导致OP代谢个体差异的单个单核苷酸多态性（snp）或snp组合是必要的。有研究表明，较低水平的PON1活性导致暴露于OP的破坏性影响的风险增加。本研究的目的是彻底表征参与OP代谢的特定p450基因和整个PON位点的遗传变异，以确定那些最容易受到慢性有机磷暴露负面健康影响的个体。农药接触是一个对农场工人具有急性和慢性风险的环境健康问题。对任何特定个体的风险可以表示为接触量本身与个体代谢和解毒农药的速度之间的相互作用。为了充分了解农药暴露与行为或环境因素之间的联系，分析必须能够考虑农药代谢的遗传变异性。本研究的目的是评估北卡罗莱纳州农场工人群体中农药代谢的遗传贡献，以便更全面地了解长期接触农药的潜在长期影响。

DESCRIPTION (provided by applicant): Farmworker exposure to pesticides is a widely acknowledged environmental health problem (Arcury et al., 2002; Arcury & Quandt 2003; Reeves & Schafer 2003; Arcury et al., 2006b). Organophosphorus (OP) insecticides are among the most widely used pesticides, and include chlorpyrifos, diazinon, dimethoate, disulfoton, and phosmet. Exposure to OP pesticides is detrimental to human health (Reigart & Roberts 1999), with immediate effects of limited exposure including rash, nausea, and blurry vision, and immediate effects of significant exposure including loss of continence, coma, and death. Delayed effects of exposure may include sterility, birth defects, cancer, and neurodegenerative disease. Sources of pesticide exposure among farmworkers and their families include occupational, para-occupational, residential, and environmental factors (Fenske et al., 2000; Arcury et al., 2006c; Quandt et al., 2006). Farmworkers have little to no control of their exposure (Austin et al., 2001), and have limited access to facilities at work for changing out of work clothes and showering before coming home (United States General Accounting Office (GAO) 2000; Arcury et al., 2001). The housing available to farmworkers is often located near fields to which pesticides are applied (Housing Assistance Council 2001; Early et al., 2006) and is generally substandard, with infestations that lead to residential pesticide application (Quandt et al., 2004; Early et al., 2006). Farmworkers and their spouses are often not provided with the information they need to protect themselves and their families from exposure (Arcury et al., 1999; Rao et al., 2006). The effective dose of pesticide exposure is clearly dependent on the initial environmental exposure, but it is also influenced by an individual's innate ability to metabolize and excrete the toxins. Metabolism of OP pesticides is primarily determined by specific proteins in the cytochrome P450 family and the paraoxonase class of molecules. Several of these genes are clustered in the same chromosomal region, indicating a potential common regulatory mechanism, which may be mediated by genetic variation within or between these genes. Polymorphisms in PON1 have been reported to be correlated with the levels of PON1 enzyme (e.g., (Holland et al., 2006)), suggesting that genetic variation contributes to the level or activity of this enzyme. A comprehensive analysis of the entire PON locus, containing PON1, PON2, and PON3, is necessary to identify the individual single nucleotide polymorphisms (SNPs) or combinations of SNPs that contribute to individual variability in OP metabolism. It has been suggested that lower levels of PON1 activity lead to an increased risk of the damaging effects of OP exposure. The goal of this study is to thoroughly characterize genetic variation of the specific p450 genes involved in OP metabolism and the entire PON locus in an effort to identify those individuals most at risk to the negative health effects of chronic organophosphate exposure. Pesticide exposure is an environmental health problem with both acute and chronic risks to farmworkers. The risk to any given individual can be expressed as an interaction between the quantity of the exposure itself and the rate at which that individual is able to metabolize and detoxify the pesticide. To fully understand the links between pesticide exposure and behavior or environmental factors, analyses must be able to consider genetic variability in pesticide metabolism. The goal of this study is to evaluate the genetic contribution of pesticide metabolism in a population of North Carolina farmworkers, in order to gain a more complete understanding of the potential for long term effects of chronic pesticide exposure.