Abstract：
Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane-associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS-275 (an HDAC1/2/3-specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3-H3K9ac-Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism-mediated cognitive impairment in the offspring.
摘要：
妊娠期亚临床甲状腺功能减退症（SCH）是妊娠期甲状腺功能障碍的最常见形式，会影响胎儿神经系统发育，增加出生后神经发育障碍的风险。然而,母体亚临床甲状腺功能减退症对胎儿脑发育和行为表型影响的机制尚不清楚，需要进一步研究。在这项研究中,我们通过在怀孕期间将母猪暴露于含有50ppm丙基硫氧嘧啶(PTU)的饮用水中,构建了母体亚临床甲状腺功能减退症小鼠模型,并通过行为测试发现其后代伴有严重的认知缺陷.机械上,妊娠期SCH导致子代海马中HDAC1/2/3的蛋白表达和活性上调。ChIP分析显示，神经颗粒蛋白（Ng）启动子上的H3K9ac在SCH后代的海马中减少，随着Ng蛋白的显著减少，导致突触可塑性标志物PSD95（突触后密度中的膜相关蛋白）和SYN（突触素，突触前末端的特定标记)，突触可塑性受损.此外,MS-275（HDAC1/2/3特异性抑制剂）对SCH后代的给药减轻了后代的突触可塑性受损和认知功能障碍。因此，我们的研究提示,母体亚临床甲状腺功能减退症可能通过HDAC1/2/3-H3K9ac-Ng通路介导后代认知功能障碍.我们的研究有助于理解母体亚临床甲状腺功能减退症介导的后代认知障碍的信号机制。
