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

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. Although prenatal vitamind D deficiency (VDD) alone in these models would not appear to enhance autism‐related molecular and behavioral phenotypes, it significantly potentiated maternal diabetes induced autism‐related phenotypes in the offspring through modulation of epigenetic modifications in neurons. VD may act as an environmental modulator of maternal diabetes but perhaps other epidemiologically validated risk factors for autism. Our work further supports a role for prenatal VDD in autism and perhaps should be considered in the context of other developmental risk factors.