Mild maternal hypothyroxinemia during pregnancy induces persistent DNA hypermethylation in the hippocampal brain-derived neurotrophic factor gene in mouse offspring
Mild maternal hypothyroxinemia during pregnancy induces persistent DNA hypermethylation in the hippocampal brain-derived neurotrophic factor gene in mouse offspring
复制标题
妊娠期间轻度母亲低甲状腺素血症会导致小鼠后代海马脑源性神经营养因子基因持续DNA高甲基化
作者：
Kawahori K;Hashimoto K;Yuan X;Tsujimoto K;Hanzawa N;Hamaguchi M;Kase S;Fujita K;Tagawa K;Okazawa H;Nakajima Y;Shibusawa N;Yamada M;Ogawa Y
背景：甲状腺激素对于中枢神经系统（CNS）的正常发育至关重要。实验啮齿动物表明，即使怀孕期间母体甲状腺激素循环中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，导致不可逆转的认知缺陷。这可能是由于海马脑源性神经营养因子基因Bdnf的表达持续减少，该基因在中枢神经系统发育中发挥着至关重要的作用。然而，潜在的分子机制仍不清楚。方法：从受孕前两周到分娩，对母鼠施用噻唑啉（MMI；0.025％[w/v]），成功诱导妊娠期间母亲轻度低甲状腺素血症。测量了患有轻度母体低甲状腺素血症的母鼠（M后代）和对照后代（C后代）的血清甲状腺激素和促甲状腺素水平。出生后70天，对后代进行了多项行为测试。还评估了第28天和第70天子代海马Bdnfexon IV启动子区域的基因表达和DNA甲基化状态，该区域主要负责神经活动依赖性Bdnf基因表达。结果：第28天和第70天M和C子代之间血清甲状腺激素或促甲状腺素水平没有发现显着差异。 后代在行为测试中表现出学习能力受损。第 28 天时，M 后代中的海马稳态 Bdnfexon IV 表达显着弱于 C 后代。第 70 天时，M 后代和 C 后代中基础水平的海马 Bdnfexon IV 表达相当。然而，在行为测试后，M 后代明显弱于 C 后代。与C子代相比，M子代海马Bdnfexon IV启动子区也存在持续性DNA高甲基化，这可能导致M子代Bdnfexon IV表达减弱。结论：母体轻度低甲状腺素血症可诱导子代Bdnfexon IV持续性DNA高甲基化， 表观遗传记忆，可能导致长期认知障碍。
Background: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 geneBdnf, which plays a crucial role in CNS development. However, the underlying molecular mechanisms remain unclear.Methods: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 ofBdnfexon IV, which is largely responsible for neural activity-dependentBdnfgene expression, in the hippocampus of the offspring at day 28 and day 70.Results: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-stateBdnfexon IV expression was significantly weaker in M offspring than it was in C offspring at day 28. At day 70, hippocampalBdnfexon 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 ofBdnfexon IV in the hippocampus of M offspring compared to that of C offspring, which may cause the attenuation ofBdnfexon IV expression in M offspring.Conclusions:Mild maternal hypothyroxinemia induces persistent DNA hypermethylation inBdnfexon IV in offspring as epigenetic memory, which may result in long-term cognitive disorders.