胎盘甲状腺素受体信号介导拟除虫菊酯诱发胎儿生长受限的机制

Our previous animal experiments have demonstrated that fenvalerate exposure during pregnancy induces fetal growth restriction in mice. In the present study, we propose a scientific hypothesis, that is, pyrethroid induces placenta dysfunction and fetal growth restriction through disrupting placental thyroid hormone receptor signaling. First, based on the established Ma' anshan birth corhort, we will examine the association betwwen pyrethroid urine metabolites concentration of 3000 pregnant women and fetal growth restriction. Second, to explore the role of placenta thyroid hormone receptor signaling interference on triggering fetal rat growth restriction, we will detect the effects of maternal fenveralate exposure on placeta thyroid hormone receptor signaling im mice; to demonstrate the role of placenta thyroid hormone receptor signaling in fenveralate-induced deficits in placeta function, we will investigate its effects of fenveralate on gene regulation related human placenta trophocyte transport, endocrine and barrier function under the condition of Thyroid hormone receptor gene silencing. Finally, to verify the role of hyroid hormone receptor signaling on regulating placenta and fetal development, we will analyse the association among fetal growth restriction, placenta thyroid hormone receptor signaling disruption and placental dysfunction through nested case－control study design; to further demonstrate the mechanism that placental thyroid hormone receptor signaling mediates pyrethroid-induced fetal growth restriction, we will investgate the association among pyrethroids exposure, placenta thyroid hormone receptor signal disruption and placental dysfunction. This study will provide the scientific basis for a new mechanism of fetal growth restriction induced by pyrethroid exposure during pregnancy.

前期动物实验证实孕期氰戊菊酯暴露诱发胎鼠生长受限。本课题假设：拟除虫菊酯通过干扰胎盘甲状腺素受体信号导致胎盘功能障碍和胎儿生长受限。本课题分析3000孕妇尿液拟除虫菊酯代谢物浓度与胎儿生长受限之间的关联；检测氰戊菊酯对小鼠胎盘甲状腺素受体信号的干扰作用，阐明胎盘甲状腺素受体受损在氰戊菊酯诱发胎鼠生长受限中的作用；观察甲状腺素受体基因沉默与否条件下氰戊菊酯对人胎盘滋养细胞物质转运、内分泌和屏障相关基因的调控作用，阐明胎盘甲状腺素受体信号在氰戊菊酯干扰胎盘功能中的作用；采用巢式病例-对照设计，分析胎儿生长受限与胎盘甲状腺素受体信号受损和胎盘功能障碍的关联，验证甲状腺素受体信号在调节胎盘和胎儿发育中的作用；分析拟除虫菊酯暴露与胎盘甲状腺素受体信号受损和胎盘功能障碍的关联，验证胎盘甲状腺素受体信号介导拟除虫菊酯诱发胎儿生长受限的机制。本课题为阐明孕期拟除虫菊酯暴露诱发胎儿生长受限的新机制提供依据。

氰戊菊酯是典型的Ⅱ型拟除虫菊酯杀虫剂，因其广泛应用而成为重要的环境污染物。前期动物实验证实孕期氰戊菊酯暴露诱发胎鼠生长受限。通过课题组4年研究，验证了课题假设：拟除虫菊酯通过干扰胎盘甲状腺素受体信号导致胎盘功能障碍和胎儿生长受限。本课题分析孕妇尿液拟除虫菊酯代谢物浓度与胎儿宫内生长受限之间的关联；检测氰戊菊酯对小鼠胎盘甲状腺素受体信号的干扰作用，阐明胎盘甲状腺素受体受损在氰戊菊酯诱发胎儿生长受限中的作用；分析拟除虫菊酯暴露与胎盘甲状腺素受体信号受损和胎盘功能障碍的关联，验证胎盘甲状腺素受体信号介导拟除虫菊酯诱发胎儿生长受限的机制。课题组还进一步研究了孕期拟除虫菊酯暴露诱发胎儿生长受限后对子代神经行为发育的长期影响；探讨了孕期拟除虫菊酯暴露对胎盘和子代发育的损害及其远期作用、孕期拟除虫菊酯暴露对胎盘甲状腺素受体信号的干扰作用，揭示了孕后期是拟除虫菊酯暴露诱导宫内生长受限的关键时间窗；进一步探讨环境相关低剂量拟除虫菊酯暴露对子代认知和行为发育的影响，揭示海马甲状腺激素信号在青春期低剂量拟除虫菊酯暴露损害神经行为发育中发挥着重要作用。在该项目资助下，课题组还进一步探讨了发育关键期暴露拟除虫菊酯对子代神经行为发育的影响和代际效应，揭示拟除虫菊酯暴露通过干扰海马甲状腺激素受体信号损伤雌性子代学习和记忆能力。本课题为最终阐明发育关键期拟除虫菊酯暴露诱发胎儿生长受限及其对神经行为发育的长期影响和可能分子机制提供依据。