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Alternative (backdoor) androgen production and masculinization in the human fetus

View ORCID ProfilePeter J O’Shaughnessy, Jean Philippe Antignac, Bruno Le Bizec, Marie-Line Morvan, Konstantin Svechnikov, Olle Söder, Iuliia Savchuk, Ana Monteiro, Ugo Soffientini, View ORCID ProfileZoe C Johnston, View ORCID ProfileMichelle Bellingham, View ORCID ProfileDenise Hough, Siladitya Bhattacharya, View ORCID ProfileNatasha Walker, View ORCID ProfilePanagiotis Filis, View ORCID ProfilePaul A Fowler
doi: https://doi.org/10.1101/365122
Peter J O’Shaughnessy
1Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Rd, Glasgow, G61 1QH UK
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  • ORCID record for Peter J O’Shaughnessy
Jean Philippe Antignac
2Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA), UMR Oniris-INRA 1329, Université Bretagne Loire, Nantes F-44307, France
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Bruno Le Bizec
2Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA), UMR Oniris-INRA 1329, Université Bretagne Loire, Nantes F-44307, France
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Marie-Line Morvan
2Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA), UMR Oniris-INRA 1329, Université Bretagne Loire, Nantes F-44307, France
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Konstantin Svechnikov
3Department of Women’s and Children’s Health, Pediatric Endocrinology Unit, Karolinska Institute and University Hospital, Q2:08, Stockholm, Sweden
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Olle Söder
3Department of Women’s and Children’s Health, Pediatric Endocrinology Unit, Karolinska Institute and University Hospital, Q2:08, Stockholm, Sweden
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Iuliia Savchuk
3Department of Women’s and Children’s Health, Pediatric Endocrinology Unit, Karolinska Institute and University Hospital, Q2:08, Stockholm, Sweden
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Ana Monteiro
1Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Rd, Glasgow, G61 1QH UK
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Ugo Soffientini
1Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Rd, Glasgow, G61 1QH UK
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Zoe C Johnston
1Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Rd, Glasgow, G61 1QH UK
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Michelle Bellingham
1Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Rd, Glasgow, G61 1QH UK
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Denise Hough
1Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Rd, Glasgow, G61 1QH UK
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Siladitya Bhattacharya
4Institute of Applied Health Sciences, Aberdeen, AB25 2ZD, UK
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Natasha Walker
5Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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Panagiotis Filis
5Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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Paul A Fowler
5Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen, AB25 2ZD, UK
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Abstract

Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production but little is known about the synthesis of backdoor androgens despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human male fetuses using multi-dimensional and high-resolution mass-spectrometry. Results show that androsterone is the principal backdoor androgen in the fetal circulation and that DHT is undetectable (<1ng/ml). Backdoor pathway intermediates are found primarily in the placenta and fetal liver with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are mostly undetectable in the fetal testes. This is consistent with transcript levels of enzymes involved in the backdoor pathway (SRD5A1, AKR1C2/4, CYP17A1), as measured by qPCR. These data identify androsterone as the predominant backdoor androgen in the human fetus and show that it is formed primarily in non-gonadal tissue with placental progesterone the likely substrate. Masculinization of the human fetus depends, therefore, on androgen synthesis by both the fetal testes and non-gonadal tissues leading to DHT formation at the genital tubercle. Our findings provide, for the first time, a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans

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Posted July 09, 2018.
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Alternative (backdoor) androgen production and masculinization in the human fetus
Peter J O’Shaughnessy, Jean Philippe Antignac, Bruno Le Bizec, Marie-Line Morvan, Konstantin Svechnikov, Olle Söder, Iuliia Savchuk, Ana Monteiro, Ugo Soffientini, Zoe C Johnston, Michelle Bellingham, Denise Hough, Siladitya Bhattacharya, Natasha Walker, Panagiotis Filis, Paul A Fowler
bioRxiv 365122; doi: https://doi.org/10.1101/365122
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Alternative (backdoor) androgen production and masculinization in the human fetus
Peter J O’Shaughnessy, Jean Philippe Antignac, Bruno Le Bizec, Marie-Line Morvan, Konstantin Svechnikov, Olle Söder, Iuliia Savchuk, Ana Monteiro, Ugo Soffientini, Zoe C Johnston, Michelle Bellingham, Denise Hough, Siladitya Bhattacharya, Natasha Walker, Panagiotis Filis, Paul A Fowler
bioRxiv 365122; doi: https://doi.org/10.1101/365122

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