Impact of peroxisomal metabolism in germ and Leydig cells on overall testis functions and male fertility

过氧化体缺乏症的人类疾病表现为一系列导致男性不育的睾丸病理，其分子机制尚不清楚。因此，我们对不同细胞类型的小鼠和人类睾丸中的过氧化物体进行了表征，并确定了过氧化物体蛋白组成的高度异质性，并揭示了Sertoli细胞过氧化物体对于维持正常的精子发生和性腺类固醇代谢的整体调控是必不可少的。由于生殖细胞和间质细胞的过氧化体代谢对整体睾丸功能的影响尚不清楚，我们将建立过氧化酶体缺陷的PEX13KO小鼠模型，以探讨1)精原细胞和精子细胞中的过氧化体代谢与生殖细胞分化和男性生育的相关性，以及2)间质细胞中的过氧化体代谢与雄激素合成、旁分泌和内分泌控制睾丸功能的相关性。表型分析将包括睾丸样本的组织病理学特征、标记酶的分析、类固醇和其他与过氧化酶体相关的代谢物的生化测量、mRNA表达谱以及器官和原代细胞培养的体外研究。3)重要成果将转移到人体睾丸和血液样本的分析中。

Human disorders with peroxisomal deficiency show a range of testicular pathologies leading to male infertility, the molecular pathogenesis of which is not yet understood. We have therefore characterised peroxisomes and identified a strong heterogeneity of peroxisomal protein composition in distinct cell types of mouse and human testis and revealed that Sertoli cell peroxisomes are essential for the maintenance of regular spermatogenesis and the overall regulation of gonadal steroid metabolism. Since the impact of peroxisomal metabolism of germ and Leydig cells on overall testicular functions is not yet understood, we will establish PEX13KO-mouse models with peroxisome deficiency to investigate the relevance of peroxisomal metabolism 1) in spermatogonia and spermatids for germ cell differentiation and for male fertility, and 2) in Leydig cells for androgen synthesis, paracrine and endocrine control of testicular functions. The phenotypic analyses will include the histopathological characterisation of testis samples, analysis of marker enzymes, biochemical measurements of steroids and other peroxisome-related metabolites, mRNAexpression profiling and in vitro studies on organotypic and primary cell cultures. 3) Important results will be transferred to the analyses of human testis and blood samples.