An important study demonstrating altered glucose transport and utilisation, predisposing to metabolic disease, in the offspring of Fin treated rats. The alteration of androgen signaling is associated with metabolic endpoints, and is expanded upon as the justification for the investigation and in the discussion:
Generally, testosterone is considered a key factor in gender related metabolic syndrome [19]. The lack of T in castrated rats causes symptoms similar to T2D or MetS, e.g., increased hepatic glucose synthesis (hyperglycaemia) as a consequence of inhibited insulin secretion, Akt phosphorylation, glucose uptake, glycogen synthase activity, GLUT-2 over-expression and glycogen phosphorylase activity in the liver. However, androgen concentration is not the only factor which influences glucose
homeostasis. A key role is also played by the androgen receptor (AR)âa target for T, DHT, and other androgens. Many studies indicate that AR deletion contributes to the development of late visceral obesity with leptin resistance, insulin resistance and increased lipogenesis in adipose tissue and the liver [14]. A lack of androgen receptors in males promotes insulin resistance that could promote T2D development. An experiment carried out on hepatic AR-knockout mice fed a HFD showed that male H-ARâ/y (not female H-ARâ/â) were overweight and were characterized by reduced sensitivity to insulin as a result of an increased expression of the protein-tyrosine phosphatase 1B (PTP1B), negative regulator of the insulin signaling pathway. So, the hepatic androgen receptor (as a positive factor), could also play an important role in avoiding insulin resistance development [31].
In our previous study on the same animal model, we showed that the offspring (F1:Fin) of rats exposed to finasteride had altered levels of serum androgens (T, DHT) and adverse changes in the morphology and physiology of testes and epididymides [32,33]. Given this trans-generational effect of finasteride on the male reproductive system and the aforementioned information on the role of androgens and AR in glucose metabolism, the aim of this study was to assess whether the androgen (T, DHT) imbalance in the F1:Fin generation of rats from males receiving finasteride can affect the accumulation of glycogen > in the liver (androgen-dependent organ), serum glucose concentration and the hepatic mRNAs and proteins, GLUT2, IR, and AR expression.
Androgens achieve the genomic effect via activation of nuclear receptors, followed by binding to a specific DNA region, known as the androgen response element (ARE) motif, localized in its target gene [41]. Testosterone replacement therapy restores GLUT-2 expression in castrated rat livers suggesting that testosterone may have a direct effect on GLUT-2 transcription and translation [20]. In the promoter region of the GLUT-2 gene, the presence of androgen response elements (ARE) has not been identified yetâthis is probably why we did not observe any correlation between androgen concentration and GLUT-2 mRNA expression. However, according to McEwan et al. [42], AR acts as an independent ligand-activated transcription factor or it may bind to some other coactivators [43,44] to increase GLUT-2 expression. Androgens could also achieve a biological effect via a receptor associated with the plasma membrane of the cell, a mechanism that has not been thoroughly researched [13]. Although in our study F1:Fin rats in each age group had increased concentrations of circulating testosterone, the level of AR transcript was decreased, and adult rats in this group (90 PND) also had cytoplasmic immunoexpression of AR in some hepatocytes. This is in line with the conclusion of Shen et al. [13], who stated that âthe integration of nongenomic effects via membrane receptor signaling and genomic effects via nuclear receptor signaling of sex hormones is critical to produce the final sex hormone cellular outcomesâ.
The conclusion is clear and important:
It can be concluded that finasteride has trans-generational consequences and probably epigenetic side effects that could lead to some metabolic syndromes such as hyperglycaemia, insulin resistance, type 2 diabetes or a fatty liver in males. Moreover, finasteride should become the focus of research in the relatively new field of pharmacologyâ pharmacoepigenomics.
Owing to strong evidence of DHT/AR-mediated regulation of many epididymal functions, this group previously investigated and reported important findings on the transgenerational negative effects of finasteride on fertility related androgenic parameters in rats â(Kolasa-Wolosiuk et al., 2015; Kolasa-WoĆosiuk et al., 2018, 2019)â. Reduced androgen levels in the offspring of finasteride-treated adult male rats were noted as similar to those reported in studies exploring the effects of prenatal exposure to the antiandrogenic endocrine disruptors flutamide and vinclozolin â(Kolasa-WoĆosiuk et al., 2019).
