Developmental vitamin D deficiency increases foetal exposure to testosterone

Abstract

Background Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which are more common in males. The ‘prenatal sex steroid’ hypothesis links excessive sex-steroid exposure during foetal life with the behavioural differences observed in ASD. However, the reason why sex steroid exposure may be excessive remains unclear. Epidemiological studies have identified several environmental risk factors associated with ASD, including developmental vitamin D (DVD) deficiency. We have demonstrated in an animal model that DVD-deficiency is associated with a hyper-inflammatory response in placentas from male but not female foetuses. Vitamin D also regulates the expression of several steroidogenic enzymes in vitro. Therefore using this animal model, we have examined whether DVD-deficiency leads to increased sex-steroid levels in both the maternal and foetal compartments. Methods Female rats are fed a vitamin D deficient diet from 6 weeks before mating until tissue collection at embryonic day 18. We examined the levels of testosterone, androstenedione and corticosterone in maternal plasma, foetal brains and amniotic fluid. We further examined gene expressions of steroidogenic enzymes and DNA methylation of aromatase promoters in foetal brains as a potential molecular mechanism regulating testosterone expression. Results We show that DVD-deficiency increases testosterone levels in maternal blood. We also show elevated levels of testosterone and androstenedione in the amniotic fluid of female but not male DVD-deficient foetuses. Testosterone levels were also elevated in DVD-deficient male brains. Vitamin D, like other steroid-related hormones, regulates gene expression via methylation. Therefore we examined whether the significant elevation in testosterone in male brains was due to such a potential gene-silencing mechanism. We show that the promoter of aromatase was hyper-methylated compared to male controls. Limitations A reduction in aromatase, in addition to causing excessive testosterone, could also lead to a reduction in estradiol which was not examined here. Conclusions This study is the first to show how an epidemiologically established environmental risk factor for ASD may selectively elevate testosterone in male embryonic brains. These findings provide further mechanistic support for the prenatal sex steroid theory of ASD.

Vitamin D and the Central Nervous System: Causative and Preventative Mechanisms in Brain Disorders

“…As juveniles or adults, offspring have social behavioural deficits and alterations in stereotyped behavioural phenotypes of relevance to autism [ 5 , 80 ]. Interestingly, vitamin D deficiency leads to subtle increases in testosterone levels in maternal blood [ 81 ], a finding which has long-been considered a risk-modifying factor in autism [ 82 ]. Additionally, foetal male brains from vitamin D deficient dams have increased testosterone compared to control males.…”

“…Additionally, foetal male brains from vitamin D deficient dams have increased testosterone compared to control males. This study went on to show silencing of the major enzyme involved in testosterone breakdown, aromatase, by hypermethylation of its promoter in the brain may be the mechanism [ 81 ].…”

Developmental Vitamin D Deficiency in Pregnant Rats Does Not Induce Preeclampsia

“…Gestational vitamin D deficiency in mice leads to increased maternal corticosterone levels and down-regulation of placental enzymes which inactivate maternal corticosterone [58]. However, we have consistently observed no effect of vitamin D deficiency on baseline corticosterone levels in pregnant rats [59,60]. Thus, differences between placental architecture and/or hypothalamic-pituitary-adrenocortical axis activation may explain the absence of preeclampsia phenotypes between species when subjected to gestational vitamin D deficiency.…”

Vitamin D Status in Children with Autism Spectrum Disorders: Determinants and Effects of the Response to Probiotic Supplementation

“…On the other hand, a condition of 25(OH)D deficiency, both maternal and in early childhood, could contribute to abnormal brain development favoring ASD onset with a higher incidence in males [11,31]. Accordingly, recent experimental data confirmed that 25(OH)D deficiency increases testosterone levels in maternal blood and male embryonic rat brains [32]. Therefore, a 25(OH)D deficient status could represent a predisposing factor for ASD onset, increasing foetal exposure to testosterone.…”