生命早期有机磷农药暴露及PON1状态对儿童神经行为发育影响的前瞻性研究

Organophosphate pesticides (OPs) are the most widely used pesticides in China, leaving the country with severe pollution problems. Since OPs could pass through the placental barrier and blood-brain barrier, early life period probably was the critical time window of the effects of OPs on children’s neurobehavioral development. Our previous studies have demonstrated much higher OP exposure levels among susceptible populations including pregnant women and children in China than those reported in developed countries. Our previous studies also have demonstrated that prenatal OP exposure could adversely affect children's neurobehavioral development at 2 years of age and PON1 genotype is critical to individual's susceptibility to OP exposure. Thus, we believe that OPs may work through PON1 status and result in adverse neurobehavioral development. Based on the “Laizhou Bay Birth Cohort” , we enrolled pregnant women and children and measured OP exposure levels in maternal and child urine at 1, 2 and 5 years of age by using gas chromatography-mass spectrometry and investigated the effects of OP exposure on children’s performance at 1 and 2 years of age based on the Gesell Developmental Schedule, as well as at 5 years of age based on the Wechsler Preschool and Primary Scale of Intelligence to explore the critical window period of OP exposure on neurobehavioral development. Further, we assess the potential effects of PON1 status (including genotype and phenotype) on associations between maternal OP exposure levels during pregnancy and neurobehavioral development. In conclusion, the present study will provide a scientific basis for preventive management and healthy assurance among Chinese pregnant women and children.

我国有机磷农药（OPs）使用普遍，污染问题严重。由于OPs可通过胎盘屏障及血脑屏障，因此生命早期OPs暴露对儿童神经行为发育的影响备受关注。我们的前期研究发现我国孕妇及儿童OPs暴露水平远高于发达国家，出生前OPs暴露可影响2岁儿童神经行为发育，并发现对氧磷酶（PON1）的基因型可影响人群对OPs的易感性。因此我们相信PON1在OPs的神经发育毒性中起重要作用。本研究依托已建立的“莱州湾出生队列”，采用气相色谱-质谱串联法检测孕妇及1岁、2岁、5岁儿童尿液OPs代谢产物水平，阐明生命早期多时点OPs暴露水平；评估1岁、2岁、5岁儿童神经行为发育水平；明确OPs暴露与儿童神经行为发育的关联性，探索OPs暴露对神经行为发育影响的关键窗口期；并探讨PON1状态（活性、水平、基因型和甲基化水平）在人群对OPs的神经发育毒性易感性中的作用。本研究将为制定干预措施，保障妇女儿童健康提供科学依据。

目的：分析出生前后有机磷农药（organophosphate pesticides，OPs）暴露对幼儿神经行为发育的影响。探讨孕妇对氧磷酶1（paraoxonase 1，PON1）在人群对OPs的神经发育毒性易感性中的作用。.方法：依托莱州湾出生队列，招募孕妇，随访至5岁幼儿，评估幼儿神经行为发育水平。采用气相色谱-质谱串联法检测孕妇及幼儿尿液中OPs的DAP代谢物，采用DNA测序技术检测母PON1-108、PON1192、PON155位点基因型，并采用焦磷酸测序法检测母PON1甲基化程度。运用线性回归模型评价OPs暴露对神经行为发育的影响，探讨不同PON1基因型中，OPs暴露对神经行为发育的影响。.结果：（1）出生前DEs水平（DEs = DEP + DETP）及DAPs水平（DAPs = DMP + DMTP + DEP + DETP）与2岁幼儿应人能负相关。（2）出生后24个月DMs水平（DMs = DMP + DMTP）与2岁幼儿应物能正相关。（3）在母PON1-108CC的2岁幼儿中：出生前DMs水平与应人能负相关。在母PON1192QQ的2岁幼儿中：出生前DMs水平、DAPs水平与粗动作能负相关，出生前DMs水平、DEs水平、DAPs水平与应人能负相关。在母PON155LM的2岁幼儿中：出生前DMs水平与精细动作能负相关。（4）PON1甲基化程度在人群对OPs的神经发育毒性易感性中的作用不明确。.结论：出生前OPs暴露与幼儿神经行为发育负相关，并且在母PON1–108CC、PON1192QQ、PON155LM的幼儿中，该影响更为明显。