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

Area of Science:

• Endocrinology
• Molecular Biology
• Reproductive Science

Background:

• 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) is crucial for human testosterone synthesis.
• HSD17B3 deficiency in humans causes impaired androgen-dependent tissue development.
• Male mice lacking HSD17B3 show normal reproductive development, suggesting alternative pathways.

Purpose of the Study:

• Investigate the role of 17β-hydroxysteroid dehydrogenase type 12 (HSD17B12) in compensating for HSD17B3 deficiency in mice.
• Determine if other hydroxysteroid dehydrogenases contribute to testosterone production in Hsd17b3 knockout mice.

Main Methods:

• Utilized CRISPR/Cas9 gene editing to modify mouse HSD17B12.
• Generated Hsd17b3 knockout mice with a mutated Hsd17b12 gene.
• Quantified hydroxysteroid dehydrogenase expression (mRNA and protein) in mouse testes.
• Performed in vitro assays to assess testosterone production capacity.

Main Results:

• Mice with Hsd17b12 mutation in an Hsd17b3 knockout background had reduced testicular testosterone and seminal vesicle weight.
• HSD17B7 mRNA and protein were significantly upregulated in Hsd17b3 knockout testes.
• Mouse HSD17B7, but not human HSD17B7, demonstrated in vitro testosterone production.

Conclusions:

• HSD17B12 contributes to testosterone production in mice lacking HSD17B3.
• HSD17B7 also plays a compensatory role in mouse testicular testosterone synthesis.
• Mice exhibit greater enzymatic plasticity for testosterone production compared to humans, ensuring male fertility.