HSD17B1 Compensates for HSD17B3 Deficiency in Fetal Mouse Testis but Not in Adults

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Hydroxysteroid (17β) dehydrogenase (HSD17B) enzymes are crucial for converting 17-ketosteroids to 17beta-hydroxysteroids, a key step in testosterone biosynthesis.
• Mutations in HSD17B3 lead to female-appearing genitalia in XY individuals due to testosterone deficiency, though puberty can reactivate testosterone production via HSD17B3-independent pathways.
• Hsd17b3 knockout (3-KO) mice exhibit similar endocrine imbalances, with high adult serum androstenedione and testosterone but less severe undermasculinization than humans.

Purpose of the Study:

• To investigate the role of HSD17B1 in compensating for HSD17B3 deficiency in male mice.
• To determine if HSD17B1 is responsible for the residual HSD17B activity in Hsd17b3 knockout male mice.
• To understand the mechanisms of testosterone synthesis in the absence of functional HSD17B1 and HSD17B3.

Main Methods:

• Generation of Hsd17b1 knockout (1-KO) mice by introducing a Ser134Ala mutation.
• Breeding of Hsd17b1 and Hsd17b3 double knockout (DKO) mice.
• Analysis of anogenital distance at birth, adult male reproductive organ weights, spermatogenesis, serum testosterone levels, and steroidogenic enzyme expression.

Main Results:

• Inactivation of both HSD17B3 and HSD17B1 (DKO) led to a significant reduction in fetal testosterone synthesis, resulting in female-like anogenital distance at birth.
• Adult DKO males showed more severe undermasculinization than 3-KO mice, with reduced weights of seminal vesicles, levator ani, epididymis, and testis.
• Despite severe undermasculinization, qualitatively normal spermatogenesis was observed in adult DKO males, and high serum testosterone levels persisted, accompanied by upregulated steroidogenic enzymes.

Conclusions:

• HSD17B1 compensates for HSD17B3 deficiency during fetal development in mouse testes.
• HSD17B1 is not the primary enzyme responsible for testosterone synthesis in adult mice with HSD17B3 deficiency.
• Other enzymes likely facilitate the conversion of androstenedione to testosterone in adult mouse testes, and potentially in human testes as well.