Mild Maternal Hypothyroxinemia During Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring
| Autor: | Saori Kase, Nobuyuki Shibusawa, Masanobu Yamada, Yoshihiro Ogawa, Xunmei Yuan, Kazuhiko Tagawa, Yasuyo Nakajima, Miho Hamaguchi, Kenichi Kawahori, Nozomi Hanzawa, Hitoshi Okazawa, Koshi Hashimoto, Kazutaka Tsujimoto, Kyota Fujita |
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| Rok vydání: | 2018 |
| Předmět: |
endocrine system
medicine.medical_specialty endocrine system diseases Offspring Endocrinology Diabetes and Metabolism Central nervous system 030209 endocrinology & metabolism Biology Hippocampal formation Hippocampus 03 medical and health sciences Mice 0302 clinical medicine Endocrinology Hypothyroidism Pregnancy Internal medicine medicine Animals Maze Learning Behavior Animal Brain-Derived Neurotrophic Factor Thyroid DNA Methylation medicine.disease Thyroxine medicine.anatomical_structure Hypothyroxinemia Prenatal Exposure Delayed Effects Rotarod Performance Test DNA methylation Female 030217 neurology & neurosurgery Hormone |
| Zdroj: | Thyroid : official journal of the American Thyroid Association. 28(3) |
| ISSN: | 1557-9077 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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