Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
FASEB J. 2024 Jun 30;38(12):e23736. doi: 10.1096/fj.202400389R.
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.
妊娠亚临床甲状腺功能减退症（SCH）是妊娠期间最常见的甲状腺功能障碍形式，可影响胎儿神经系统发育，并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大脑发育和行为表型的影响机制尚不清楚，需要进一步研究。在这项研究中，我们通过在妊娠期间让母鼠饮用含有 50ppm 丙基硫氧嘧啶（PTU）的水来构建母体亚临床甲状腺功能减退症的小鼠模型，发现其后代通过行为测试伴随着严重的认知缺陷。从机制上讲，妊娠期 SCH 导致后代海马体中 HDAC1/2/3 的蛋白表达和活性上调。ChIP 分析显示，SCH 后代海马体中 Ng 启动子上的 H3K9ac 减少，Ng 蛋白显著减少，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（突触小泡蛋白，突触前末端的特异性标志物）的表达水平降低，突触可塑性受损。此外，向 SCH 后代施用 MS-275（一种 HDAC1/2/3 特异性抑制剂）可缓解后代的突触可塑性受损和认知功能障碍。因此，我们的研究表明，母体亚临床甲状腺功能减退症可能通过 HDAC1/2/3-H3K9ac-Ng 途径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损伤的信号机制。
