Dataset Information

Identifying a novel hydroxysteroid dehydrogenase enzyme that is capable of testosterone biosynthesis in the mouse

ABSTRACT: Androgens, such as testosterone and dihydrotestosterone (DHT), are essential for male sexual development, masculinisation, spermatogenesis, and general lifelong health. Androgens are predominantly synthesised in the testes of mice (~95%) by highly specialised cells known as the Leydig cells. There are two known androgen production pathways in the testes of mice: (i) the canonical pathway which synthesises testosterone which can be used as a substrate for the more potent DHT, and (ii) the alternate pathway which can synthesise DHT without the need for testosterone. The HSD17B3 enzyme is a key enzyme in the canonical pathway which converts androstenedione into testosterone and the SRD5A1 enzyme is the predominant 5α-reductase in the testes that converts androgen precursors into the alternate pathway. HSD17B3 deficiency in humans results in a disorder of sexual development with 46,XY individuals appearing with female or ambiguous external genitalia whilst having Wolffian internal structures. However, in contrast to humans, Hsd17b3 knockout (KO) mice can be identified as male from birth and throughout adulthood, remain fertile and have normal intratesticular testosterone levels indicating that compensatory mechanisms are apparent in the mouse. What these compensatory mechanisms are, be other enzymes, or other androgen production pathways, remains unknown. We have generated a mouse model incorporating wild-type (WT), Hsd17b3 KO and Hsd17b3; Srd5a1 double (d)KO mice. Proteomic analysis has been performed on WT, Hsd17b3 KO and dKO whole testis tissue to identify potential androgen compensatory mechanisms in the mouse and pathways that are impacted by the removal of the HSD17B3 or both the HSD17B3 and SRD5A1 proteins. The total proteins detected across the three groups were 2,892, 3,041, and 2813 in WT, Hsd17b3 KO and dKO testes, respectively.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Testis

SUBMITTER: David Skerrett-Byrne

LAB HEAD: Professor Lee Smith

PROVIDER: PXD050748 | Pride | 2025-05-12

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	Ben_HSSR_Testis_284_20220928102654.raw	Raw
	Ben_HSSR_Testis_286_20220928115939.raw	Raw
	Ben_HSSR_Testis_291_20220928054835.raw	Raw
	Ben_HSSR_Testis_298_20220928011019.raw	Raw
	Ben_HSSR_Testis_332_20220928133225.raw	Raw

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Publications

Functional Analysis of HSD17B3-Deficient Male Mice Reveals Roles for HSD17B7 and HSD17B12 in Testosterone Biosynthesis.

Lawrence Ben M BM O'Donnell Liza L Gannon Anne-Louise AL Skerrett-Byrne David A DA Parameswaran Shanmathi S Abbott Imogen I Smith Sarah S Handelsman David J DJ Rebourcet Diane D Smith Lee B LB

Endocrinology 20250401 6

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, suggestin ...[more]

PMID: 40336300

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