PON1 and Developmental Sensitivity to OP Pesticides

描述（由申请人提供）：最近的研究表明，孕妇和儿童普遍暴露于有机磷农药（OP）。然而，在相同的暴露量下，一些个体可能更容易受到OPs的不利影响，这取决于他们的基因组成和编码关键代谢酶的基因的表达。例如，人类酶对氧磷酶（PON1）对各种OPs的解毒效率不同，这取决于192位的主要多态性和启动子和编码区的其他多态性。作为CHAMACOS纵向出生队列研究的一部分，我们调查了生活在加利福尼亚州萨利纳斯山谷农业社区的-500名怀孕拉丁妇女及其子女的OP暴露和健康影响。初步数据表明，该队列中的OP暴露超过了国家参考水平，并且母体OP尿代谢物水平与妊娠期缩短和新生儿异常反射有关。来自130个母体和脐带血样本的初步数据显示，新生儿的PON1活性低于母亲，这表明他们可能更容易受到OPs的不利影响。因此，基因型、酶活性和年龄的差异可能导致对OP暴露的不同敏感性。在拟议的研究中，我们将利用CHAMACOS队列中广泛的生物库和生长和神经发育数据。我们的目标是：1)为拉丁裔人群创建PON1基因单倍型图谱；2)研究出生至24个月婴儿PON1酶活性的个体发生；3)确定PON1基因型是否与母体和脐带血中OP农药相关；4)确定PON1是否改变OP暴露与胎儿生长、妊娠期长短和神经发育的关系。为了实现这些目标，我们将对CHAMACOS母亲和儿童进行5种PON1多态性（192,55,-108,-909,-162）的基因分型；测定12个月和24个月时产妇、脐带和儿童血液中四种底物特异性PON1酶活性（芳基酯酶、对氧磷酶、重氮磷酶、毒死蜱氧磷酶）；测量脐带血和母体血中的OPs。这项研究将有助于确定更容易受到接触OP的健康影响的人类亚群。这些数据将支持国家儿童研究计划，确定易受化学战剂影响的亚群体，并为实施《食品质量保护法》提供决策依据。

DESCRIPTION (provided by applicant): Recent studies demonstrate widespread organophosphate pesticide (OP) exposures to pregnant women and children. However, given the same exposure, some individuals may be more susceptible to the adverse effects of OPs depending on their genetic makeup and expression of genes encoding key metabolic enzymes. For example, the human enzyme paraoxonase (PON1) detoxifies various OPs with different efficiency depending on the main polymorphism at position 192 and others along promoter and coding regions. As part of the CHAMACOS longitudinal birth cohort study, we have investigated OP exposures and health effects in -500 pregnant Latina women and their children living in the agricultural community of the Salinas Valley, CA. Initial data suggest that OP exposure in this cohort exceed national reference levels, and that maternal OP urinary metabolite levels were associated with shortened gestation and abnormal reflexes in neonates. Preliminary data from 130 maternal and cord blood samples show that newborns had lower PON1 activity than their mothers, suggesting they may be more susceptible to the adverse effects of OPs. Thus, differences in genotype, enzyme activity, and age may contribute to differential sensitivity to OP exposures. In the proposed study, we will take advantage of an extensive biorepository and data on growth and neurodevelopment from the CHAMACOS cohort. Our objectives are: 1) to create a PON1 gene haplotype map for this Latino population; 2) to examine the ontogeny of PON1 enzyme activity in infants from birth through 24 months; 3) to establish whether PON1 genotype is associated with OP pesticides in maternal and cord blood; and 4) to determine whether PON1 modifies the relationship of OP exposure and fetal growth, length of gestation and neurodevelopment. To address these aims, we will genotype CHAMACOS mothers and children for five PON1 polymorphisms (192, 55, -108, -909, -162); measure four substrate-specific PON1 enzyme activities (arylesterase, paraoxonase, diazoxonase, chlorpyrifos oxonase) in maternal, cord and child blood at 12 and 24 months; and measure OPs in cord and maternal bloods. This study will help identify human subpopulations more susceptible to the health impact of OP exposure. These data will support planning for the National Children's Study, identify subpopulations susceptible to chemical warfare agents, and inform policy decisions for implementation of the Food Quality Protection Act.