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Vitamin D deficiency worsens maternal diabetes induced neurodevelopmental disorder by potentiating hyperglycemia-mediated epigenetic changes

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  • Yujie Liang, Shenzhen Institute of Mental Health & Shenzhen Kangning Hospital, Shenzhen, China.
  • ,
  • Hong Yu, Foshan University
  • ,
  • Xiaoyin Ke, Shenzhen Institute of Mental Health & Shenzhen Kangning Hospital, Shenzhen, China.
  • ,
  • Darryl Eyles, Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Richlands, 4076, Queensland, Australia.
  • ,
  • Ruoyu Sun, Foshan University
  • ,
  • Zichen Wang, Shenzhen Institute of Mental Health & Shenzhen Kangning Hospital, Shenzhen, China.
  • ,
  • Saijun Huang, Foshan University
  • ,
  • Ling Lin, Shenzhen Institute of Mental Health & Shenzhen Kangning Hospital, Shenzhen, China.
  • ,
  • John J McGrath
  • Jianping Lu, Shenzhen Institute of Mental Health & Shenzhen Kangning Hospital, Shenzhen, China.
  • ,
  • Xiaoling Guo, Foshan University
  • ,
  • Paul Yao, Shenzhen Institute of Mental Health & Shenzhen Kangning Hospital, Shenzhen, China.

Many studies have shown that vitamin D (VD) deficiency may be a risk factor for neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, although causative mechanisms remain unknown. In this study, we investigated the potential role and effect of VD on maternal diabetes induced autism-related phenotypes. The in vitro study found that enhancing genomic VD signaling by overexpressing the VD receptor (VDR) in human neural progenitor cells ACS-5003 protects against hyperglycemia-induced oxidative stress and inflammation by activating Nrf2 and its target genes, including SOD2 and HMOX1, and accordingly, VDR gene knockdown worsens the problem. In the two in vivo models we explored, maternal diabetes was used to establish an animal model of relevance to ASD, and mice lacking 25-hydroxyvitamin D 1-alpha-hydroxylase (the rate-limiting enzyme in the synthesis of 1,25(OH)2D3) were used to develop a model of VD deficiency (VDD). We show that although prenatal VDD itself does not produce ASD-relevant phenotypes, it significantly potentiates maternal diabetes induced epigenetic modifications and autism-related phenotypes. Postnatal manipulation of VD has no effect on maternal diabetes induced autism-related phenotypes. We conclude that VDD potentiates maternal diabetes induced autism-related phenotypes in offspring by epigenetic mechanisms. This study adds to other preclinical studies linking prenatal VDD with a neurodevelopmental disorder.

OriginalsprogEngelsk
TidsskriftAnnals of the New York Academy of Sciences
Vol/bind1491
Nummer1
Sider (fra-til)74-88
Antal sider15
ISSN0077-8923
DOI
StatusUdgivet - maj 2021

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