PON1 and Developmental Sensitivity to OP Pesticides

描述(由申请人提供)：最近的研究表明，孕妇和儿童广泛接触有机磷农药(OP)。然而，在相同的暴露条件下，一些人可能更容易受到有机磷农药的不利影响，这取决于他们的基因构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)对不同的OP具有不同的解毒效率，这取决于192位的主要多态以及启动子和编码区的其他多态。作为CHAMACOS纵向出生队列研究的一部分，我们调查了居住在加利福尼亚州萨利纳斯山谷农业社区的500名拉美孕妇及其子女的OP暴露及其对健康的影响。初步数据表明，该队列中OP的暴露水平超过了国家参考水平，母亲的OP尿代谢物水平与妊娠缩短和新生儿的异常反射有关。来自130个母亲和脐带血样本的初步数据显示，新生儿的PON1活性低于他们的母亲，这表明他们可能更容易受到有机磷农药的不利影响。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队列中关于生长和神经发育的广泛生物信息库和数据。我们的目标是：1)为这一拉丁裔人群创建PON1基因单倍型图谱；2)检查婴儿从出生到24个月的PON1酶活性的个体发育；3)确定PON1基因是否与母亲和脐带血中的OP杀虫剂有关；以及4)确定PON1是否改变OP暴露与胎儿生长、妊娠长度和神经发育的关系。为了达到这些目标，我们将对CHAMACOS母亲和儿童的五个PON1基因多态性(192、55、-108、-909、-162)进行基因分型；在12个月和24个月时检测母亲、脐带血和儿童血液中四种底物特异性PON1酶的活性(芳香酯酶、对氧磷酶、重氮酶和毒死蜱酶)；并检测脐带血和母血中的OP。这项研究将有助于确定对OP暴露的健康影响更敏感的人类亚群。这些数据将支持国家儿童研究的规划，确定易受化学战剂影响的亚群，并为实施《食品质量保护法》的政策决策提供参考。

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.