1 Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University , Tokyo, Japan .
2 Department of Preemptive Medicine and Metabolism, Tokyo Medical and Dental University , Tokyo, Japan .
Thyroid. 2018 Mar;28(3):395-406. doi: 10.1089/thy.2017.0331.
Thyroid hormones are essential for normal development of the central nervous system (CNS). Experimental rodents have shown that even a subtle thyroid hormone insufficiency in circulating maternal thyroid hormones during pregnancy may adversely affect neurodevelopment in offspring, resulting in irreversible cognitive deficits. This may be due to the persistent reduced expression of the hippocampal brain-derived neurotrophic factor gene Bdnf, which plays a crucial role in CNS development. However, the underlying molecular mechanisms remain unclear.
Thiamazole (MMI; 0.025% [w/v]) was administered to dams from two weeks prior to conception until delivery, which succeeded in inducing mild maternal hypothyroxinemia during pregnancy. Serum thyroid hormone and thyrotropin levels of the offspring derived from dams with mild maternal hypothyroxinemia (M offspring) and the control offspring (C offspring) were measured. At 70 days after birth, several behavior tests were performed on the offspring. Gene expression and DNA methylation status were also evaluated in the promoter region of Bdnf exon IV, which is largely responsible for neural activity-dependent Bdnf gene expression, in the hippocampus of the offspring at day 28 and day 70.
No significant differences in serum thyroid hormone or thyrotropin levels were found between M and C offspring at day 28 and day 70. M offspring showed an impaired learning capacity in the behavior tests. Hippocampal steady-state Bdnf exon IV expression was significantly weaker in M offspring than it was in C offspring at day 28. At day 70, hippocampal Bdnf exon IV expression at the basal level was comparable between M and C offspring. However, it was significantly weaker in M offspring than in C offspring after the behavior tests. Persistent DNA hypermethylation was also found in the promoter region of Bdnf exon IV in the hippocampus of M offspring compared to that of C offspring, which may cause the attenuation of Bdnf exon IV expression in M offspring.
Mild maternal hypothyroxinemia induces persistent DNA hypermethylation in Bdnf exon IV in offspring as epigenetic memory, which may result in long-term cognitive disorders.
甲状腺激素对中枢神经系统（CNS）的正常发育至关重要。实验啮齿动物表明，即使在妊娠期间母体循环甲状腺激素中存在轻微的甲状腺激素不足，也可能对后代的神经发育产生不利影响，导致不可逆的认知缺陷。这可能是由于海马脑源性神经营养因子基因 Bdnf 的持续低表达所致，该基因在 CNS 发育中起着至关重要的作用。然而，其潜在的分子机制尚不清楚。
从受孕前两周开始，给母体喂食丙硫氧嘧啶（MMI；0.025%[w/v]），直至分娩，成功地在妊娠期间诱导母体轻度甲状腺功能减退。测量来自母体轻度甲状腺功能减退（M 后代）和对照后代（C 后代）的后代的血清甲状腺激素和促甲状腺激素水平。在出生后 70 天，对后代进行了多项行为测试。还评估了海马体中 Bdnf 外显子 IV 启动子区域的基因表达和 DNA 甲基化状态，Bdnf 外显子 IV 主要负责神经活动依赖性 Bdnf 基因表达。
在第 28 天和第 70 天，M 和 C 后代的血清甲状腺激素或促甲状腺激素水平无显著差异。M 后代在行为测试中表现出学习能力受损。与 C 后代相比，M 后代在第 28 天的海马体 Bdnf 外显子 IV 表达明显较弱。在第 70 天，M 和 C 后代的海马体 Bdnf 外显子 IV 基础水平相当。然而，在行为测试后，M 后代的表达明显弱于 C 后代。与 C 后代相比，M 后代的海马体 Bdnf 外显子 IV 启动子区域也存在持续的 DNA 高甲基化，这可能导致 M 后代 Bdnf 外显子 IV 表达减弱。
母体轻度甲状腺功能减退症会在后代中诱导 Bdnf 外显子 IV 中的持续 DNA 高甲基化，作为表观遗传记忆，这可能导致长期认知障碍。
