Genetic analysis of organophosphate metabolism in NC farmworkers

描述（由申请人提供）：农场工人暴露于农药是一个广泛承认的环境健康问题（Arabian等人，2002年; Arabian & Quandt 2003年; Reeves & Schafer 2003年; Arabian等人，2006年b）。有机磷（OP）杀虫剂是最广泛使用的杀虫剂之一，并且包括毒死蜱、二嗪农、乐果、二磺草酮和灭多威。暴露于有机磷农药对人体健康有害（Reigart & Roberts，1999年），有限暴露的直接影响包括皮疹、恶心和视力模糊，大量暴露的直接影响包括丧失知觉、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。农场工人及其家人接触农药的来源包括职业、准职业、居住和环境因素（Fenske等人，2000年; Arbor等人，2006 c; Quandt等人，2006年）。农场工人几乎无法控制他们的接触（Austin等人，2001年），并且在工作场所很少有机会在回家前换掉工作服和淋浴（美国总审计局（GAO）2000年; Arabian等人，2001年）。农场工人可利用的住房通常位于施用农药的田地附近（住房援助理事会2001; Early等人，2006）并且通常是不合格的，具有导致住宅杀虫剂施用的侵染（Quandt等人，2004; Early等人，2006年）。农场工人及其配偶往往得不到保护自己及其家人免受接触所需的信息（Ardegan等人，1999; Rao等人，2006年）。农药接触的有效剂量显然取决于最初的环境接触，但也受个人代谢和排泄毒素的先天能力的影响。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。这些基因中的几个聚集在同一染色体区域，表明可能是由这些基因内或之间的遗传变异介导的潜在的共同调控机制。据报道，PON 1的多态性与PON 1酶的水平相关（例如，（Holland等人，2006）），表明遗传变异有助于该酶的水平或活性。全面分析整个PON基因座，包含PON 1，PON 2和PON 3，是必要的，以确定个人的单核苷酸多态性（SNP）或SNP的组合，有助于OP代谢的个体差异。有人认为，较低水平的PON 1活性导致OP暴露的损害作用的风险增加。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基因座的遗传变异，以确定慢性有机磷暴露对健康产生负面影响的风险最大的个体。农药接触是一个环境健康问题，对农场工人既有急性风险，也有慢性风险。对任何特定个人的风险可以表示为接触量本身与个人能够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来纳州农场工人群体中农药代谢的遗传贡献，以便更全面地了解慢性农药暴露的长期影响潜力。

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.