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Stress response abnormalities transgenerationally inherited via miR-23 downregulation are restored by a methyl modulator during the lactation period

Published online by Cambridge University Press:  29 November 2023

Takahiro Nemoto Open the ORCID record for Takahiro Nemoto [Opens in a new window] ,
Yuki Morita  and
Yoshihiko Kakinuma
Takahiro Nemoto*
Affiliation:
Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo, Japan
Yuki Morita
Affiliation:
Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo, Japan
Yoshihiko Kakinuma
Affiliation:
Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo, Japan
*
Corresponding author: T. Nemoto; Email: taknemo@nms.ac.jp
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Abstract

Low birthweight rats due to fetal undernutrition sustain higher corticosterone levels when exposed to stress. This is due to the upregulated expression of the pituitary-specific Gas5, a long noncoding RNA (lncRNA) that acts as a glucocorticoid receptor decoy and then competitively inhibiting the binding of glucocorticoids to DNA. However, the mechanism of Gas5 lncRNA upregulation remains unclear. Therefore, using the fetal undernourished model, we identified the factors that regulated Gas5 lncRNA expression and examined their effect on subsequent generations. We found that the expression levels of miR-23 was significantly lower in low birth-weight rats compared with controls. The expression of miR-23 was significantly lower and the expression levels of Gas5 lncRNA were significantly higher in the pituitary gland of low birth-weight offspring of the F2 and F3 generations compared with controls. The methyl modulator intervention in lactating F0 maternal rats restored miR-23 and Gas5 lncRNA expressions not only in F1, F2 and F3 offspring. Moreover, the intervention reduced circulating corticosterone levels and gene expressions in the pituitary gland after restraint stress exposure. In conclusion, miR-23-mediated alterations of the stress response are inherited and restored by methyl modulator intervention during lactation.

Keywords

TransgenerationalglucocorticoidMicroRNApituitarynutrition
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 14 , Issue 5 , October 2023 , pp. 678 - 686
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Copyright
© The Author(s), 2023. Published by Cambridge University Press in association with The International Society for Developmental Origins of Health and Disease (DOHaD)

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