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Developmental vitamin D deficiency increases foetal exposure to testosterone
Molecular Autism ( IF 6.3 ) Pub Date : 2020-12-10 , DOI: 10.1186/s13229-020-00399-2
Asad Amanat Ali 1 , Xiaoying Cui 1, 2 , Renata Aparecida Nedel Pertile 1 , Xiang Li 1 , Gregory Medley 1 , Suzanne Adele Alexander 1, 2 , Andrew J O Whitehouse 3 , John Joseph McGrath 1, 2, 4 , Darryl Walter Eyles 1, 2
Affiliation  

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. 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. 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. A reduction in aromatase, in addition to causing excessive testosterone, could also lead to a reduction in estradiol which was not examined here. 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.

中文翻译:

发育性维生素 D 缺乏会增加胎儿对睾酮的暴露

自闭症谱系障碍 (ASD) 是一组神经发育障碍,在男性中更为常见。“产前性类固醇”假说将胎儿时期过度使用性类固醇与 ASD 中观察到的行为差异联系起来。然而,性类固醇暴露过量的原因尚不清楚。流行病学研究已经确定了几个与 ASD 相关的环境风险因素,包括发育性维生素 D (DVD) 缺乏症。我们已经在动物模型中证明,DVD 缺陷与男性而非女性胎儿胎盘的过度炎症反应有关。维生素 D 还调节体外几种类固醇生成酶的表达。因此使用这个动物模型,我们已经检查了 DVD 缺陷是否会导致母体和胎儿隔室中性类固醇水平的增加。从交配前 6 周到胚胎第 18 天收集组织,雌性大鼠被喂食缺乏维生素 D 的饮食。我们检查了母体血浆、胎儿大脑和羊水中的睾酮、雄烯二酮和皮质酮水平。我们进一步检查了胎儿大脑中类固醇生成酶的基因表达和芳香酶启动子的 DNA 甲基化,作为调节睾酮表达的潜在分子机制。我们表明 DVD 缺乏会增加母体血液中的睾酮水平。我们还显示,女性而非男性 DVD 缺陷胎儿的羊水中睾酮和雄烯二酮水平升高。在缺乏 DVD 的男性大脑中,睾酮水平也升高。维生素D,像其他类固醇相关激素一样,通过甲基化调节基因表达。因此,我们检查了男性大脑中睾丸激素的显着升高是否是由于这种潜在的基因沉默机制。我们表明,与男性对照相比,芳香酶的启动子是高度甲基化的。芳香化酶的减少,除了导致睾酮过多外,还可能导致雌二醇的减少,此处未进行检查。这项研究首次展示了 ASD 的流行病学确定的环境风险因素如何选择性地提高男性胚胎大脑中的睾丸激素。这些发现为 ASD 的产前性类固醇理论提供了进一步的机制支持。因此,我们检查了男性大脑中睾酮的显着升高是否是由于这种潜在的基因沉默机制。我们表明,与男性对照相比,芳香酶的启动子是高度甲基化的。芳香化酶的减少,除了导致睾酮过多外,还可能导致雌二醇的减少,此处未进行检查。这项研究首次展示了 ASD 的流行病学确定的环境风险因素如何选择性地提高男性胚胎大脑中的睾丸激素。这些发现为 ASD 的产前性类固醇理论提供了进一步的机制支持。因此,我们检查了男性大脑中睾酮的显着升高是否是由于这种潜在的基因沉默机制。我们表明,与男性对照相比,芳香酶的启动子是高度甲基化的。芳香化酶的减少,除了导致睾酮过多外,还可能导致雌二醇的减少,此处未进行检查。这项研究首次展示了 ASD 的流行病学确定的环境风险因素如何选择性地提高男性胚胎大脑中的睾丸激素。这些发现为 ASD 的产前性类固醇理论提供了进一步的机制支持。除了导致睾丸激素过多外,还可能导致雌二醇减少,此处未进行检查。这项研究首次展示了 ASD 的流行病学确定的环境风险因素如何选择性地提高男性胚胎大脑中的睾丸激素。这些发现为 ASD 的产前性类固醇理论提供了进一步的机制支持。除了导致睾丸激素过多外,还可能导致雌二醇减少,此处未进行检查。这项研究首次展示了 ASD 的流行病学确定的环境风险因素如何选择性地提高男性胚胎大脑中的睾丸激素。这些发现为 ASD 的产前性类固醇理论提供了进一步的机制支持。
更新日期:2020-12-10
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