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

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

Steroid hormones play crucial roles in human fetal development as they bind and activate receptors which regulate key biological processes. These steroid hormones are also important after birth. During fetal development, a specific class of steroid hormones, termed androgens, are produced by the fetal adrenal and metabolised by the fetal liver and placenta. This biological route from the fetal adrenal through the fetal liver to the placenta is especially important, as an imbalance in androgen levels are implicated in endocrine-related disorders and diseases that present in the fetal and neonatal stages. In the fetal liver, an enzyme termed cytochrome P450 3A7, CYP3A7, catalyses the production of unique hydroxylated androgens. This same process is also mediated by CYP3A4 in neonates, as a switch from the predominant CYP3A7 to CYP3A4 activity occurs after birth, and while both hepatic enzymes metabolise androgens, only a few downstream hydroxylated androgen metabolites are currently known. The project “Tracing novel androgen pathways in human fetal biology: SHOXY” aimed to identify novel hydroxylated androgens and to characterise their metabolic pathway in human fetal biology. The characterization of these androgens and their downstream metabolites could prove integral to our understanding of the transition from the fetal to the neonatal stage and endocrine-related disorders that present at these stages. Ultimately, this project permitted an in-depth investigation into the hepatic metabolism of androgens specific to human fetal development, with an expected far-reaching impact on fetal and neonatal endocrinology. The scientific objectives of this Marie Skłodowska-Curie Action (MSCA) were to investigate (a) the biosynthesis of hydroxylated androgens by hepatic CYP3A enzymes; (b) the efficiency of these conversions by CYP3A7 compared to CYP3A4; and (c) the conversions in in vitro cell models and systems. The overarching goal of this action was to combine steroid science, protein chemistry and analytical chemistry to describe the role of androgens in fetal development! The training objectives of this MSCA were to (a) enhance the bioinformatic and analytical skills of the fellow, together with the networking skills of the fellow through the establishment of national and international collaborations; and (b) transfer the knowledge of adrenal steroidogenesis and mass spectrometric analysis of steroid metabolites from the fellow to the host institution, in the form of establishing analytical methods.

Data: CORDIS, © European Union