Abstract：
Hydroxysteroid (17β) dehydrogenase (HSD17B) enzymes convert 17-ketosteroids to 17beta-hydroxysteroids, an essential step in testosterone biosynthesis. Human XY individuals with inactivating HSD17B3 mutations are born with female-appearing external genitalia due to testosterone deficiency. However, at puberty their testosterone production reactivates, indicating HSD17B3-independent testosterone synthesis. We have recently shown that Hsd17b3 knockout (3-KO) male mice display a similar endocrine imbalance, with high serum androstenedione and testosterone in adulthood, but milder undermasculinization than humans. Here, we studied whether HSD17B1 is responsible for the remaining HSD17B activity in the 3-KO male mice by generating a Ser134Ala point mutation that disrupted the enzymatic activity of HSD17B1 (1-KO) followed by breeding Hsd17b1/Hsd17b3 double-KO (DKO) mice. In contrast to 3-KO, inactivation of both HSD17B3 and HSD17B1 in mice results in a dramatic drop in testosterone synthesis during the fetal period. This resulted in a female-like anogenital distance at birth, and adult DKO males displayed more severe undermasculinization than 3-KO, including more strongly reduced weight of seminal vesicles, levator ani, epididymis, and testis. However, qualitatively normal spermatogenesis was detected in adult DKO males. Furthermore, similar to 3-KO mice, high serum testosterone was still detected in adult DKO mice, accompanied by upregulation of various steroidogenic enzymes. The data show that HSD17B1 compensates for HSD17B3 deficiency in fetal mouse testis but is not the enzyme responsible for testosterone synthesis in adult mice with inactivated HSD17B3. Therefore, other enzymes are able to convert androstenedione to testosterone in the adult mouse testis and presumably also in the human testis.
摘要：
羟基类固醇（17β）脱氢酶（HSD17B）酶将17-酮类固醇转化为17β-羟基类固醇，睾酮生物合成的重要步骤。具有失活HSD17B3突变的人类XY个体由于睾酮缺乏而出生时具有女性外观的外生殖器。然而,在青春期他们的睾丸激素生产重新激活，表明不依赖HSD17B3的睾酮合成。我们最近发现Hsd17b3基因敲除（3-KO）雄性小鼠表现出类似的内分泌失调，在成年期有高血清雄烯二酮和睾酮，但比人类更温和的男子气概。这里,在3-KO雄性小鼠中,我们通过产生破坏HSD17B1(1-KO)酶活性的Ser134Ala点突变,然后饲养Hsd17b1/Hsd17b3双KO(DKO)小鼠,研究了HSD17B1是否与剩余的HSD17B活性有关.与3-KO相比，小鼠中HSD17B3和HSD17B1的失活导致胎儿期睾酮合成急剧下降。这导致了出生时女性般的肛门生殖器距离，成年DKO男性比3-KO表现出更严重的男子气概不足，包括更强烈地减少精囊的重量，左撇子,附睾,和睾丸。然而,在成年DKO男性中检测到正常的精子发生。此外，类似于3-KO小鼠，在成年DKO小鼠中仍然检测到高血清睾酮，伴随着各种类固醇生成酶的上调。数据显示,HSD17B1补偿胎儿小鼠睾丸中的HSD17B3缺乏,但不是在具有灭活HSD17B3的成年小鼠中负责睾酮合成的酶。因此,其他酶能够在成年小鼠睾丸中以及可能在人类睾丸中将雄烯二酮转化为睾丸激素。
