Lawrence Ben M, O'Donnell Liza, Gannon Anne-Louise, Skerrett-Byrne David A, Parameswaran Shanmathi, Abbott Imogen, Smith Sarah, Handelsman David J, Rebourcet Diane, Smith Lee B
College of Engineering, Science and Environment, The University of Newcastle, Callaghan, New South Wales 2308, Australia.
School of BioSciences, The University of Melbourne, Parkville, Victoria 3010, Australia.
Endocrinology. 2025 Apr 22;166(6). doi: 10.1210/endocr/bqaf078.
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.
从历史上看，17β-羟类固醇脱氢酶3型（HSD17B3）被认为是负责睾丸睾酮生成的关键酶。在人类中，HSD17B3的功能丧失突变会损害产前生活中的睾酮生成，导致46,XY个体中雄激素依赖性组织发育受损。然而，HSD17B3缺乏的雄性小鼠表现出正常的睾丸睾酮浓度、正常的生殖器官发育且具有生育能力，这表明小鼠表达其他能够进行睾丸睾酮合成的羟类固醇脱氢酶。本研究旨在调查17β-羟类固醇脱氢酶12型（HSD17B12）是否能弥补Hsd17b3基因敲除（KO）小鼠中HSD17B3的缺失，HSD17B12在小鼠中可将雄烯二酮转化为睾酮，但在人类中则不能。我们使用CRISPR/Cas9将小鼠HSD17B12中负责将雄烯二酮转化为睾酮的氨基酸替换为人类酶的氨基酸，该人类酶的氨基酸可阻止雄烯二酮用作底物。当将这种Hsd17b12突变引入Hsd17b3 KO小鼠时，雄性小鼠表现出正常的生殖道，但睾丸睾酮生成减少，随之精囊重量减轻。这表明在没有HSD17B3的情况下，HSD17B12有助于睾酮生成，但其他酶也必定有作用。因此，我们对其他睾丸羟类固醇脱氢酶进行了定量，发现Hsd17b3 KO睾丸中HSD17B7的mRNA和蛋白质明显上调。我们证实小鼠而非人类的HSD17B7可在体外产生睾酮。我们得出结论，与人类相比，小鼠在通过羟类固醇脱氢酶进行睾酮生成方面表现出更大的可塑性，以支持雄激素作用和雄性生育能力。
