Abstract：
The global challenge of male infertility is escalating, notably due to the decreased testosterone (T) synthesis in testicular Leydig cells under stress, underscoring the critical need for a more profound understanding of its regulatory mechanisms. CREBZF, a novel basic region-leucine zipper transcription factor, regulates testosterone synthesis in mouse Leydig cells in vitro; however, further validation through in vivo experiments is essential. Our study utilized Cyp17a1-Cre to knock out CREBZF in androgen-synthesis cells and explored the physiological roles of CREBZF in fertility, steroid hormone synthesis, and behaviors in adult male mice. Conditional knockout (cKO) CREBZF did not affect fertility and serum testosterone level in male mice. Primary Leydig cells isolated from CREBZF-cKO mice showed impaired testosterone secretion and decreased mRNA levels of Star, Cyp17a1, and Hsd3b1. Loss of CREBZF resulted in thickening of the adrenal cortex, especially X-zone, with elevated serum corticosterone and dehydroepiandrosterone levels and decreased serum dehydroepiandrosterone sulfate levels. Immunohistochemical staining revealed increased expression of StAR, Cyp11a1, and 17β-Hsd3 in the adrenal cortex of CREBZF-cKO mice, while the expression of AR was significantly reduced. Along with the histological changes and abnormal steroid levels in the adrenal gland, CREBZF-cKO mice showed higher anxiety-like behavior and impaired memory in the elevated plus maze and Barnes maze, respectively. In summary, CREBZF is dispensable for fertility, and CREBZF deficiency in Leydig cells promotes adrenal function in adult male mice. These results shed light on the requirement of CREBZF for fertility, adrenal steroid synthesis, and stress response in adult male mice, and contribute to understanding the crosstalk between testes and adrenal glands.
摘要：
男性不育的全球挑战正在升级，特别是由于睾丸睾丸间质细胞在压力下的睾酮（T）合成减少，强调迫切需要对其监管机制有更深刻的理解。CREBZF,一种新的碱性区域-亮氨酸拉链转录因子，在体外调节小鼠睾丸间质细胞的睾酮合成；然而，通过体内实验进一步验证是必不可少的。我们的研究利用Cyp17a1-Cre敲除雄激素合成细胞中的CREBZF，并探索CREBZF在生育中的生理作用。类固醇激素合成，和成年雄性小鼠的行为。条件敲除(cKO)CREBZF不影响雄性小鼠的生育力和血清睾酮水平。从CREBZF-cKO小鼠分离的原代Leydig细胞显示睾酮分泌受损和Star的mRNA水平降低,Cyp17a1和Hsd3b1。CREBZF缺失导致肾上腺皮质增厚，尤其是X区，血清皮质酮和脱氢表雄酮水平升高，血清硫酸脱氢表雄酮水平降低。免疫组织化学染色显示StAR的表达增加，CREBZF-cKO小鼠肾上腺皮质中的Cyp11a1和17β-Hsd3，而AR的表达显著降低。随着肾上腺的组织学改变和激素水平异常，CREBZF-cKO小鼠在高架迷宫和巴恩斯迷宫中表现出更高的焦虑样行为和记忆受损，分别。总之,CREBZF对生育来说是可有可无的，Leydig细胞中的CREBZF缺乏促进成年雄性小鼠的肾上腺功能。这些结果揭示了CREBZF对生育率的要求，肾上腺类固醇合成，和成年雄性小鼠的应激反应，并有助于理解睾丸和肾上腺之间的串扰。
