Mild Maternal Hypothyroxinemia During Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring

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Abstract
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 gene (Bdnf), which plays a crucial role in CNS development. However, the underlying molecular mechanisms remain unclear. Methods: We administered 0.025% (w/v) thiamazole (MMI) to dams from two weeks prior to conception until delivery and succeeded in inducing mild maternal hypothyroxinemia during pregnancy. We measured serum thyroid hormone and thyrotropin (thyroid-stimulating hormone: TSH) levels of the offspring derived from dams with mild maternal hypothyroxinemia, which were referred to as M offspring and the control offspring (C offspring). At 70 days after birth (d70), we performed several behavior tests to the offspring. We also evaluated gene expression and DNA methylation status 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 d28 and d70. Results: We found no significant differences in serum thyroid hormone or TSH levels between M and C offspring at d28 and d70. 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 in C offspring at d28. At d70, 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. We also found persistent DNA hypermethylation 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. Conclusions: Mild maternal hypothyroxinemia induces persistent DNA hypermethylation in Bdnf exon IV in offspring as epigenetic memory, which may result in long-term cognitive disorders.

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