Functional Analysis of HSD17B3-Deficient Male Mice Reveals Roles for HSD17B7 and HSD17B12 in Testosterone Biosynthesis
Year: 2025
Type: article
Abstract: Historically, 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) was thought to be the key enzyme responsible for testicular testosterone production. In humans, loss-of-function mutations in HSD17B3 impair testosterone production during prenatal life leading to impaired development of androgen-dependent tissues in 46,XY individuals. However, male mice with HSD17B3 deficiency exhibit normal testicular testosterone concentrations, normal development of reproductive organs and are fertile, suggesting that mice express other hydroxysteroid dehydrogenase enzymes capable of testicular testosterone synthesis. This study aimed to investigate whether 17β-hydroxysteroid dehydrogenase type 12 (HSD17B12), which can convert androstenedione to testosterone in mice but not in humans, compensates for the lack of HSD17B3 in Hsd17b3 knockout (KO) mice. We used CRISPR/Cas9 to substitute the amino acid in mouse HSD17B12 that is responsible for its ability to convert androstenedione to testosterone with the amino acid of the human enzyme that prevents androstenedione being used as a substrate. When this Hsd17b12 mutation was introduced into Hsd17b3 KO mice, males exhibited normal reproductive tracts but reduced testicular testosterone production with a consequential reduction in seminal vesicle weight. This suggests HSD17B12 contributes toward testosterone production in the absence of HSD17B3, but other enzymes must also contribute. We therefore quantified other testicular hydroxysteroid dehydrogenases, finding that HSD17B7 mRNA and protein was markedly upregulated in Hsd17b3 KO testes. We confirmed that mouse, but not human, HSD17B7 can produce testosterone in vitro. We conclude that compared to humans, mice exhibit increased plasticity in testosterone production via hydroxysteroid dehydrogenase enzymes to support androgen action and male fertility.
Source: Endocrinology
Institutions: The University of Melbourne, University of Newcastle Australia, Griffith University, Hudson Institute of Medical Research, Monash University, Hunter Medical Research Institute, Helmholtz Munich, German Center for Diabetes Research, The University of Sydney, Concord Repatriation General Hospital, Anzac Research Institute, Inserm, École des Hautes Études en Santé Publique, Institut de Recherche en Santé, Environnement et Travail, Université de Rennes
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,750
OpenAlex ID: W4410187336