生命早期农药暴露谱对儿童神经行为发育的影响及其分子机制

A large amount of pesticides are widely used in China every year, bringing severe pesticide pollution problems. Pregnant women and children are exposed to multiple types of pesticide inevitably. Our preliminary study results have demonstrated the pesticide internal exposure levels among pregnant women and children are much higher in several regions of China than in developed countries, with multi-exposure to pesticides as the dominant exposure pattern. We also found that the exposure during early life to certain pesticides with potential neurodevelopmental toxicity was significantly related to the intellective development in offspring. Therefore, it is urgent in the field of public health to elaborate the China-specific characteristics of pesticide exposure during early life and its effect on children’s neurobehavioral development. Based on the established prospective large-sample-size birth cohort which collects questionnaires and bio-samples from both pregnant women and children at designed time spots during the whole pregnancy and early childhood, we will analyze the characteristics of multiple exposure to pesticides during early life, and try to demonstrate their relationship with children’s neurobehavioral development. By simulating the actual exposure level of pesticide that will be obtained from our cohort, we will base on the metabolic disorder leading to abnormal neurodevelopment to establish a pesticide-exposing rat model to illuminate the mechanism underlying the neurobehavioral developmental toxicity caused by multi-exposure to pesticides during early life. This study will not only clarify the impact of pesticide multi-exposure during early life on children’s neurobehavioral development and the mechanism underlying, but also propel the revision on criterion in pesticide application and provide a scientific basis for the measures on early prevention and intervention.

我国农药使用面广量大，污染问题突出，妊娠期妇女和儿童不可避免暴露于多种农药。项目组前期研究发现我国多地区孕妇及儿童农药内暴露水平远高于发达国家，呈混合暴露模式，且子代在生命早期暴露于具有潜在神经发育毒性的农药与其智力发育密切相关。因此，关注具有中国特点的生命早期农药暴露谱，阐明其对儿童神经行为发育的影响，是公共卫生领域亟待解决的重大科学问题。本项目将依托大型前瞻性出生队列，在妊娠期、儿童期多时点采集信息和样本，分析生命早期农药暴露谱特征，阐述其与儿童神经行为发育的关系。模拟人群实际农药暴露情况，以引起神经发育异常的代谢紊乱机制为切入点，通过建立大鼠染毒模型，阐明生命早期农药暴露谱的神经行为发育毒作用机制。本研究不仅将阐明生命早期农药暴露谱对儿童神经行为发育的影响及其机制，更将推动我国在农药限量标准上的发展，为制定早期预防和干预措施提供重要参考和依据。

本项目依托多中心大型前瞻性出生队列，阐明我国孕期农药混合暴露的模式、水平及暴露途径；明确生命早期关键农药混合暴露对儿童神经行为发育影响及量效关系；利用多种动物模型进行机制探索，阐述生命早期农药混合染毒对子代神经行为发育的毒作用机制。在项目实施阶段，项目组依据全球大型出生队列联盟（ECHIBG）实施标准建设出生队列，建立标准化的队列数据库与生物样本库；基于气相色谱-三重四级杆串联质谱（GC-MS/MS）等平台，建立并优化多套基于血清的农药内暴露高灵敏度检测和分析方法，并严格质控；通过对目标农药的危害识别、剂量-反应关系评定、暴露评估和危险度表征分析，构建目标农药暴露致儿童神经行为发育异常的风险评估模型，并进一步探索多类混合暴露模型在农药混合暴露对子代神经行为发育异常影响中的应用；采用神经干细胞、斑马鱼、小鼠染毒模型，阐明孕期目标农药暴露对子代神经行为发育异常发生的影响和分子机制。综上，本项目以人群队列研究和动物实验研究为模型，互为提示和验证，揭示了生命早期农药暴露谱对儿童神经行为发育的影响及其分子机制，为我国农药限量标准的制定提供理论依据，为儿童神经发育异常的早期干预和预防提供重要的研究基础。项目实施以来，已发表标注基金号SCI论著19篇，其中JCR Q1区的17篇， IF > 7的10篇，获得国家发明专利4件，制定江苏省地方标准1件。项目负责人主编《Early-life Environmental Exposure and Disease - Facts and Perspectives》，副主编《出生队列建设标准与适宜技术》等。