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Tracing novel androgen pathways: deciphering the role of 16α-hydroxylation in human fetal biology

Objective

Steroid hormones, produced by the fetal adrenal, are metabolised by the fetal liver and placenta thereby regulating fetal development. Consequently, these steroids are also implicated in endocrine-related disorders and diseases that present in the fetal and neonatal stage. The major fetal liver cytochrome P450 enzyme, CYP3A7, catalyses the production of 16α-hydroxy-dehydroepiandrosterone (16α-hydroxy DHEA) leading to the biosynthesis of the 16α-hydroxy estrogen of pregnancy, estriol, in the placenta. This 16α-hydroxylation is also mediated by CYP3A4 in neonates, as a switch from the predominant CYP3A7 to CYP3A4 expression occurs after birth. Both enzymes, together with CYP3A5 (expressed in adult livers) are capable of hydroxylating steroid substrates on C16 producing metabolites in the fetal and neonatal stages. Importantly, the major adrenal steroid, 11β-hydroxyandrostenedione (11OHA4), a C11-oxy androgen, is produced in the fetal adrenals and circulatory levels have been quantified at birth. The chemical structure of 11OHA4, possessing no moiety on C16, allows it to be hydroxylated by CYP3A enzymes —producing novel downstream 16α-hydroxylated metabolites. While the contribution of 16α-hydroxy DHEA to fetal biology has been widely reported, the contribution of 16α-hydroxy C11-oxy androgens has not, to date, been characterised. Moreover, these metabolites have not been structurally identified. I hypothesise that C11-oxy androgens are catalysed by CYP3As, producing novel 16α-hydroxy C11-oxy androgens in the liver and the placenta. State-of-the-art high-resolution mass spectrometry platforms will be utilised to identify these novel metabolites and confirm the hypothesis. Significance of the proposed study: This project will advance our current knowledge on the downstream metabolism of the C11-oxy androgens and will characterise a novel steroid pathway in fetal biology, potentially important in human development in health and disease.

Call for proposal

H2020-MSCA-IF-2020
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Coordinator

UNIVERSITAET BERN
Address
Hochschulstrasse 6
3012 Bern
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 191 149,44