Early life exposure to agricultural pesticides and functional brain imaging in young adults

摘要 有机磷(OP)农药是广泛使用的杀虫剂。自1999年以来，我们的健康中心 萨利娜母亲和儿童评估(CHAMACOS)研究一直在评估以下物质对健康的影响 在加利福尼亚州农业萨利纳斯山谷，约600名墨西哥裔美国青年出生时使用了有机磷杀虫剂。 我们已经报道了产前接触有机磷农药与较差的认知功能和行为能力的关系 从儿童早期到青春期的问题。使用神经成像进行进一步的研究对于 阐明：1)OP对大脑的哪些结构和功能有不利影响；以及2)OP相关 对大脑功能的影响，在使用标准神经行为测试的研究中可能没有检测到。只有两个 神经影像研究报告了与早期生命有机磷农药暴露的相关性。第一个包括一群 40名纽约市儿童，他们发现产前接触OP毒死蜱与减少 结构磁共振成像显示额叶、颞叶和顶叶的皮质厚度 (核磁共振)。在95名CHAMACOS参与者中，我们发现怀孕期间居住在靠近OP的地方 与功能性近红外光谱(FNIRS)观察到的大脑激活模式的改变有关 在执行职能的任务中。这些初步发现需要在更大的样本中得到证实 在大脑发育的关键窗口期间进行高质量的暴露评估。在这个项目中，我们建议 研究生命早期接触有机磷农药对神经激活模式和功能的影响 在整个CHAMACOS青年队列(18-19岁)之间的连接性。我们收集了 使用功能近红外光谱(FNIRS)的神经成像数据--一种成本独特的fMRI替代方法 以及实地研究的便利优势--在CHAMACOS队列的458名参与者中。我们 评估受试者完成下列任务时前额叶、颞叶和顶叶脑区的神经活动 认知灵活性、工作记忆和语言理解。对于约300名CHAMACOS参与者，我们 已经在母亲产前和早期分析了二烷基磷酸盐(DAP)，这是一种非特异性OP生物标记物 儿童(6个月-5岁)尿样。对于所有458名参与者，我们估计接触到 基于居民区对农业有机磷农药的接近程度的单种有机磷农药及其混合物 使用加州独特的农药使用报告(PUR)数据库的应用程序。尿DAP和PUR数据 提供补充暴露措施，以便更全面地审查 在发展的关键时期，来自不同来源的有机磷农药。对于这个项目，我们建议 对这些多维数据进行密集处理，并调查与早期生命操作的关联 使用fNIRS研究农药暴露与皮质神经激活和功能连接的关系。我们的建议 这将是使用功能神经成像来评估农药暴露影响的最大规模的研究，也是第一个 应用fNIRS技术定位与环境暴露相关的神经发育损害。

ABSTRACT Organophosphate (OP) pesticides are widely used insecticides. Since 1999, our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study has been assessing the health effects of OP pesticides among a birth cohort of ~600 Mexican American youth in California’s agricultural Salinas Valley. We have reported associations of prenatal OP pesticide exposure with poorer cognitive function and behavioral problems from early childhood through adolescence. Further investigation using neuroimaging is important for elucidating: 1) which structures and functions in the brain are adversely affected by OPs; and, 2) OP-related impacts on brain function that may be undetected in studies using standard neurobehavioral tests. Only two neuroimaging studies report associations with of early life OP pesticide exposure. The first includes a cohort of 40 New York City children, which found associations of prenatal exposure to the OP chlorpyrifos with reduced cortical thickness of frontal, temporal, and parietal regions shown by structural magnetic resonance imaging (MRI). In a subset of 95 CHAMACOS participants we found that residential proximity to OP use during pregnancy was associated with altered brain activation patterns observed with functional near infrared spectroscopy (fNIRS) during tasks of executive function. These preliminary findings warrant corroboration among a larger sample with high quality exposure assessment during critical windows of brain development. In this project, we propose to investigate associations of early life exposure to OP pesticides on neural activation patterns and functional connectivity among the entire CHAMACOS cohort of young adults (18-19 years old).We have collected neuroimaging data using functional near-infrared spectroscopy (fNIRS) – an alternative to fMRI with distinct cost and convenience advantages for field-based research – in 458 participants of the CHAMACOS cohort. We assessed neural activity in the prefrontal, temporal and parietal brain regions as participants complete tasks of cognitive flexibility, working memory, and language comprehension. For ~300 CHAMACOS participants, we have already analyzed dialkyl phosphates (DAPs), non-specific OP biomarkers, in maternal prenatal and early childhood (6 months – 5 years) urinary samples. For all 458 participants, we have estimated exposure to individual OP pesticides and their mixtures based on residential proximity to agricultural OP pesticide applications using California’s unique Pesticide Use Reporting (PUR) database. Urinary DAPs and PUR data provide complementary exposure measures, allowing for a more comprehensive examination of the effects of OP pesticides from different sources during critical periods of development. For this project, we propose to conduct the intensive processing of these multi-dimensional data and investigate associations of early life OP pesticides exposure with cortical neural activation and functional connectivity using fNIRS. Our proposed research will be the largest to assess impacts of pesticide exposure using functional neuroimaging, and the first to apply fNIRS technology to localize impairments in neurodevelopment related to an environmental exposure.