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

Kenichi Kawahori, Koshi Hashimoto, Xunmei Yuan, Kazutaka Tsujimoto, Nozomi Hanzawa, Miho Hamaguchi, Saori Kase, Kyota Fujita, Kazuhiko Tagawa, Hitoshi Okazawa, Yasuyo Nakajima, Nobuyuki Shibusawa, Masanobu Yamada, Yoshihiro Ogawa

Research output: Contribution to journalArticle

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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: 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. 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-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. 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.

Original languageEnglish
Pages (from-to)395-406
Number of pages12
JournalThyroid
Volume28
Issue number3
DOIs
Publication statusPublished - Mar 2018

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Brain-Derived Neurotrophic Factor
Exons
Thyroid Hormones
Mothers
Pregnancy
DNA
Genes
Thyrotropin
Genetic Promoter Regions
Hippocampus
Central Nervous System
Methimazole
Gene Expression
DNA Methylation
Serum
Epigenomics
Rodentia
Learning
Parturition
Behavior Rating Scale

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Mild Maternal Hypothyroxinemia during Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring. / Kawahori, Kenichi; Hashimoto, Koshi; Yuan, Xunmei; Tsujimoto, Kazutaka; Hanzawa, Nozomi; Hamaguchi, Miho; Kase, Saori; Fujita, Kyota; Tagawa, Kazuhiko; Okazawa, Hitoshi; Nakajima, Yasuyo; Shibusawa, Nobuyuki; Yamada, Masanobu; Ogawa, Yoshihiro.

In: Thyroid, Vol. 28, No. 3, 03.2018, p. 395-406.

Research output: Contribution to journalArticle

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 2018, 'Mild Maternal Hypothyroxinemia during Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring', Thyroid, vol. 28, no. 3, pp. 395-406. https://doi.org/10.1089/thy.2017.0331
Kawahori, Kenichi ; Hashimoto, Koshi ; Yuan, Xunmei ; Tsujimoto, Kazutaka ; Hanzawa, Nozomi ; Hamaguchi, Miho ; Kase, Saori ; Fujita, Kyota ; Tagawa, Kazuhiko ; Okazawa, Hitoshi ; Nakajima, Yasuyo ; Shibusawa, Nobuyuki ; Yamada, Masanobu ; Ogawa, Yoshihiro. / Mild Maternal Hypothyroxinemia during Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring. In: Thyroid. 2018 ; Vol. 28, No. 3. pp. 395-406.
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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: 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. 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-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. 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.",
author = "Kenichi Kawahori and Koshi Hashimoto and Xunmei Yuan and Kazutaka Tsujimoto and Nozomi Hanzawa and Miho Hamaguchi and Saori Kase and Kyota Fujita and Kazuhiko Tagawa and Hitoshi Okazawa and Yasuyo Nakajima and Nobuyuki Shibusawa and Masanobu Yamada and Yoshihiro Ogawa",
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T1 - Mild Maternal Hypothyroxinemia during Pregnancy Induces Persistent DNA Hypermethylation in the Hippocampal Brain-Derived Neurotrophic Factor Gene in Mouse Offspring

AU - Kawahori, Kenichi

AU - Hashimoto, Koshi

AU - Yuan, Xunmei

AU - Tsujimoto, Kazutaka

AU - Hanzawa, Nozomi

AU - Hamaguchi, Miho

AU - Kase, Saori

AU - Fujita, Kyota

AU - Tagawa, Kazuhiko

AU - Okazawa, Hitoshi

AU - Nakajima, Yasuyo

AU - Shibusawa, Nobuyuki

AU - Yamada, Masanobu

AU - Ogawa, Yoshihiro

PY - 2018/3

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N2 - 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: 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. 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-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. 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.

AB - 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: 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. 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-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. 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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