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 st...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-12-01
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| Series: | Molecular Autism |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13229-020-00399-2 |
| _version_ | 1818928907929255936 |
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| author | Asad Amanat Ali Xiaoying Cui Renata Aparecida Nedel Pertile Xiang Li Gregory Medley Suzanne Adele Alexander Andrew J. O. Whitehouse John Joseph McGrath Darryl Walter Eyles |
| author_facet | Asad Amanat Ali Xiaoying Cui Renata Aparecida Nedel Pertile Xiang Li Gregory Medley Suzanne Adele Alexander Andrew J. O. Whitehouse John Joseph McGrath Darryl Walter Eyles |
| author_sort | Asad Amanat Ali |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T03:36:22Z |
| format | Article |
| id | doaj.art-a436e4938f5b4e999bdefc2fdf672edb |
| institution | Directory Open Access Journal |
| issn | 2040-2392 |
| language | English |
| last_indexed | 2024-12-20T03:36:22Z |
| publishDate | 2020-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Autism |
| spelling | doaj.art-a436e4938f5b4e999bdefc2fdf672edb2022-12-21T19:54:52ZengBMCMolecular Autism2040-23922020-12-0111111310.1186/s13229-020-00399-2Developmental vitamin D deficiency increases foetal exposure to testosteroneAsad Amanat Ali0Xiaoying Cui1Renata Aparecida Nedel Pertile2Xiang Li3Gregory Medley4Suzanne Adele Alexander5Andrew J. O. Whitehouse6John Joseph McGrath7Darryl Walter Eyles8Queensland Brain Institute, The University of QueenslandQueensland Brain Institute, The University of QueenslandQueensland Brain Institute, The University of QueenslandQueensland Brain Institute, The University of QueenslandQueensland Brain Institute, The University of QueenslandQueensland Brain Institute, The University of QueenslandTelethon Kids Institute, The University of Western AustraliaQueensland Brain Institute, The University of QueenslandQueensland Brain Institute, The University of QueenslandAbstract 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.https://doi.org/10.1186/s13229-020-00399-2Developmental vitamin D deficiencyAutismTestosteroneAromataseMethylationAnimal model |
| spellingShingle | Asad Amanat Ali Xiaoying Cui Renata Aparecida Nedel Pertile Xiang Li Gregory Medley Suzanne Adele Alexander Andrew J. O. Whitehouse John Joseph McGrath Darryl Walter Eyles Developmental vitamin D deficiency increases foetal exposure to testosterone Molecular Autism Developmental vitamin D deficiency Autism Testosterone Aromatase Methylation Animal model |
| title | Developmental vitamin D deficiency increases foetal exposure to testosterone |
| title_full | Developmental vitamin D deficiency increases foetal exposure to testosterone |
| title_fullStr | Developmental vitamin D deficiency increases foetal exposure to testosterone |
| title_full_unstemmed | Developmental vitamin D deficiency increases foetal exposure to testosterone |
| title_short | Developmental vitamin D deficiency increases foetal exposure to testosterone |
| title_sort | developmental vitamin d deficiency increases foetal exposure to testosterone |
| topic | Developmental vitamin D deficiency Autism Testosterone Aromatase Methylation Animal model |
| url | https://doi.org/10.1186/s13229-020-00399-2 |
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