孕期轻度砷暴露与学龄前儿童认知损伤及其胎盘甲状腺激素受体信号下调诱导炎症反应的中介作用研究

Exposure to low level arsenic during pregnancy is a major international public health concern and exposure to less than the current “safe range of arsenic” could also cause adverse fetal growth and development after birth. This is a population-based birth cohort study which recruited total 3 273 eligible mother-and-singleton-offspring pairs. The objective of this project was to analyze the association between arsenic exposure during pregnancy and 5-year-old pre-school children's cognitive function impairment and the sensitive period of effect. Based on the established human placenta specimens by this cohort, both of nested case-control study and cohort study were used to analyze the differences of the expression levels about thyroid hormone receptor signals, multiple inflammatory factors and multiple growth factors in placentas between preschool children with and without cognitive dysfunction and between different arsenic exposure groups, the objective of which was in order to clarify the role of placental endocrine dysfunction caused by placental inflammatory response induced by down-regulation of placental TRs signals in the relation between arsenic exposure during pregnancy and children's cognitive function impairment. We verified the protective effect of placental TRs signals in placental endocrine function damage mediated by placental inflammation using human placental trophoblast cells with TRs gene silencing in vitro. The study will not only broaden the etiology between prenatal exposure to arsenic and children's cognitive impairment, but also can provide a basis for hazard, prevention and control about early exposure to low level arsenic during pregnancy.

孕期轻度砷暴露是重大公共卫生问题，低于目前界定的“安全范畴”内的暴露水平也可对胎儿宫内及其出生后的生长发育造成不良影响。本课题依托已建立的马鞍山优生优育出生队列3273对单胎活产母婴队列人群，评价孕期轻度砷暴露与5岁儿童认知功能损伤的关联及作用敏感期；采用巢式—病例对照研究和队列研究有机结合的方法，依托该队列已建立的人胎盘标本库，分析比较队列内认知功能异常与正常儿童间、不同砷暴露水平组间胎盘TRs信号、胎盘炎性因子、胎盘生长因子表达水平的差异，阐明胎盘TRs信号下调诱导胎盘炎症致胎盘内分泌功能不全在联结孕期轻度砷暴露与儿童认知功能损伤中的作用；体外染毒TRs基因沉默的人胎盘滋养细胞，验证胎盘TRs信号对炎症介导的胎盘内分泌功能损害的保护作用。本研究不但可拓宽孕期砷暴露对儿童认知功能损伤的病因学视野，还可为孕期轻度砷暴露的危害、预防和控制提供新的依据。

孕期轻度砷暴露是重大公共卫生问题，低于目前界定的“安全范畴”内的暴露水平也可对胎儿宫内及其出生后的生长发育造成不良影响。本项目主要依托马鞍山优生优育出生队列3273名单胎活产人群，研究了孕期环境砷暴露对6月龄儿童神经发育情况及学龄前儿童认知功能发育情况的不良影响作用，证实儿童宫内砷暴露可导致其出生后神经发育迟缓：与低水平砷暴露组相比，校正所有潜在混杂因素后，相对中、高水平砷暴露组6月龄婴儿个人—社会能区疑似发育迟缓的风险显著增加；敏感性分析还表明，不断放窄婴儿五个能区发育迟缓的界定标准，这一效应仍然非常显著，且这一效应具有性别特异性，女童显著；脐血砷暴露水平与学龄前儿童认知功能五个维度得分中流体推理指数及工作记忆指数呈负相关，关联系数具有临界统计学意义。上述结果提示：由于儿童赶上生长现象，宫内砷暴露的神经毒性作用随着儿童年龄的增长可能会有所缓解。此外，孕期多种砷暴露指标均可对新生儿甲状腺功能具有直接的损害作用（减少新生儿FT4的水平，或增加新生儿TSH的水平），且这种损害作用不以损害母体的甲状腺功能为介导，在多种金属元素联合暴露（As、Hg、Cd与Se）的情况下，砷仍然具有主导作用；但孕期环境砷暴露水平并不引起胎盘炎性因子表达水平的改变，从而提示环境水平的砷暴露对儿童神经发育的损害效应可能主要源于砷的内分泌干扰效应。动物实验结果发现，在高于环境砷暴露水平条件下，孕期砷暴露可导致仔鼠空间学习记忆能力障碍，并致母代鼠胎盘总厚度、胎盘迷路层厚度、迷路层厚度/胎盘总厚度比值下降，胎盘的血窦面积减小且胎盘发生氧化应激。项目结果拓宽了孕期不同砷暴露水平对子代认知功能损伤的病因学视野，为孕期砷暴露的危害、预防和控制提供了新的依据。

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