基于出生队列研究妊娠期农药复合暴露对儿童神经行为发育的影响及表观遗传学机制

The mixed pesticides are applied widespread in China, organophosphate pesticides (OPs) and pyrethroid pesticides (PYRs) have been developed and used extensively. Our previous studies have demonstrated much higher pesticide exposure levels among people in China than those reported in developed countries. Since pesticides could pass through the placental barrier and blood–brain barrier, fetal period probably was the critical time window of the effects of the co-exposure of OPs and PYRs on children’s neurodevelopment. China is still in the early stages in this respect,and the mechanism is unclear.Evidence showed that placenta may play an important role in central nervous system development through adaptive responses to the maternal environment, and might be a useful surrogate tissue to explore fetal brain development. Placental epigenetic patterning of glucocorticoid response genes and brain-derived neurotrophic factor (BDNF) signaling pathways might be the key mechanisms which are related with infant neurobehavior development. Based on our “Laizhou Bay Birth Cohort”,we enrolled pregnant women and investigated both in utero OPs and PYRs exposure levels through the pregnancy and their possible relationship with children’s performance at 12 and 24 months of age based on the Gesell Developmental Schedule. Pyrosequencing was used to quantify levels of methylation at CpG sites within the promoter regions of HSD11B2, NR3C1 and BDNF, and of the repetitive element(LINE-1) in placenta. In conclusion, we will focus on the mechanism of epigenetic changes affecting neurobehavior development caused by prenatal pesticides co-exposure, and provide a scientific evidence for early prevention and intervention on children’s health in China.

我国混配农药使用普遍，有机磷农药（OPs）与拟除虫菊酯类农药（PYRs）是其中使用量最大的两种农药。本课题组前期研究发现我国普通人群OPs与PYRs暴露水平远高于发达国家。由于农药可通过胎盘屏障和血脑屏障，因而妊娠期农药复合暴露对子代神经发育的影响备受关注。国内此方面研究较少且机制不明。目前发现胎盘在介导孕期环境暴露所致胎儿适应性的神经发育方面发挥着重要作用，可作为胎儿神经发育研究的替代组织。孕期胎盘糖皮质激素代谢通路与脑源性神经营养因子相关表观遗传学改变可能是其关键机制。本研究依托“莱州湾出生队列”，探索妊娠期农药复合暴露水平与特征，评估妊娠期农药复合暴露对婴幼儿神经行为发育的影响，并结合妊娠期胎盘特定基因与全基因组甲基化改变，深入探讨妊娠期农药复合暴露对婴幼儿神经行为发育影响的表观遗传学机制，为揭示农药复合暴露在神经发育关键期对婴幼儿神经发育影响的作用机制提供科学依据。

我国混配农药使用普遍，有机磷农药（OPs）与拟除虫菊酯类农药（PYRs）是其中使用量最大的两种农药。由于农药可通过胎盘屏障和血脑屏障，因而妊娠期农药复合暴露对子代神经发育的影响备受关注。本研究依托“莱州湾出生队列”，评估妊娠期农药复合暴露对婴幼儿神经行为发育的影响，探索胎盘糖皮质激素代谢通路与脑源性神经营养因子相关表观遗传学改变在农药暴露对儿童神经行为发育中是否具有影响。本研究共纳入379名同时完成OPs和PYRs尿液代谢产物的孕妇，其中有289名1岁婴儿和262名2岁幼儿完成了神经发育的评估[格赛尔发育量表（Gesell Developmental Schedules, Gesell）]，包括粗动作能、精细动作能、应物能、言语能和应人能。采用焦磷酸盐测序技术检测142例胎盘BDNF, HSD11B2, NR3C1和LINE1基因的甲基化水平。结果发现，妊娠期有机磷农药和拟除虫菊酯类农药对1岁、2岁婴幼儿的神经行为发育均具有影响，且存在性别差异。两种农药对儿童神经行为的改变具有交互作用。胎盘LINE1基因启动子区的甲基化水平与1岁、2岁婴幼儿的神经行为发育呈显著负相关，提示胎盘基因甲基化水平改变在有机磷农药影响婴幼儿神经行为发育过程中可能发挥某种作用。上述结果为揭示农药复合暴露在神经发育关键期影响婴幼儿神经发育的作用机制提供了一定科学依据，该结果尚需进一步扩大样本量、优化实验条件进行验证。