Rzeszotek Sylwia, Kolasa Agnieszka, Pilutin Anna, Misiakiewicz-Has Kamila, Sielatycka Katarzyna, Wiszniewska Barbara
Department of Histology and Embryology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland.
Institute of Biology, Faculty of Exact and Natural Sciences, University of Szczecin, 71-415 Szczecin, Poland.
Biomedicines. 2022 Oct 27;10(11):2725. doi: 10.3390/biomedicines10112725.
Finasteride (Fin) causes androgen imbalance by inhibiting the conversion of testosterone (T) to its more active metabolite, dihydrotestosterone (DHT). Androgen receptors (AR) are present (e.g., in hepatocytes), which have well-developed endoplasmic reticulum (ERet). Cellular protein quality control is carried out by ERet in two paths: (i) unfolded protein response (UPR) and/or (ii) endoplasmic reticulum associated degradation (ERAD). ERet under continuous stress can generate changes in the UPR and can direct the cell on the pathway of life or death. It has been demonstrated that genes involved in ERet stress are among the genes controlled by androgens in some tissues. Oxidative stress is also one of the factors affecting the functions of ERet and androgens are one of the regulators of antioxidant enzyme activity. In this paper, we discuss/analyze a possible relationship between androgen imbalance in paternal generation with ERet stress and liver disorders in both paternal and filial generation. In our rat model, hyperglycemia and subsequent higher accumulation of hepatic glycogen were observed in all filial generation obtained from females fertilized by Fin-treated males (F1:Fin). Importantly, genes encoding enzymes involved in glucose and glycogen metabolism have been previously recognized among UPR targets.
非那雄胺（Fin）通过抑制睾酮（T）向其活性更强的代谢产物双氢睾酮（DHT）的转化，导致雄激素失衡。雄激素受体（AR）存在（例如，在肝细胞中），其内质网（ERet）发育良好。细胞蛋白质质量控制由内质网通过两条途径进行：（i）未折叠蛋白反应（UPR）和/或（ii）内质网相关降解（ERAD）。持续应激下的内质网可导致未折叠蛋白反应发生变化，并可引导细胞走向生存或死亡途径。已经证明，内质网应激相关基因是某些组织中受雄激素调控的基因之一。氧化应激也是影响内质网功能的因素之一，而雄激素是抗氧化酶活性的调节因子之一。在本文中，我们讨论/分析了父代雄激素失衡与内质网应激以及父代和子代肝脏疾病之间的可能关系。在我们的大鼠模型中，在由经非那雄胺处理的雄性大鼠受精的雌性大鼠所产生的所有子代（F1：Fin）中，均观察到高血糖以及随后肝糖原的更高积累。重要的是，参与葡萄糖和糖原代谢的酶的编码基因先前已被确认为未折叠蛋白反应的靶点。
