背景:越来越多的数据表明,肝脏的生理是性激素依赖性的,某些类型的肝功能衰竭在男性中更常见,还有一些女性。在男性中,在生理条件下,睾酮通过雄激素受体(AR)增加胰岛素受体(IR)表达和糖原合成,并减少由肝脏特异性葡萄糖转运蛋白2(GLUT-2)控制的葡萄糖摄取。我们先前的研究表明非那雄胺可能损害了这种机制,一种常用于泌尿科和皮肤科的药物,抑制5α-还原酶2,将睾酮(T)转化为双氢睾酮(DHT)。我们的研究还表明,暴露于非那雄胺的大鼠的后代的T-DHT比率发生了变化,并显示出睾丸和附睾的变化。因此,这项研究的目的是评估非那雄胺的给药是否对(i)GLUT-2依赖性糖原在肝脏中的积累有跨代作用,(ii)雄性大鼠后代肝细胞中的IR和AR表达,(iii)血清T和DHT水平与GLUT2,IR表达之间的关系,和ARmRNA,(iv)血清葡萄糖水平及其与GLUT-2mRNA的相关性。
方法:对7、14、21、28和90天大的Wistar雄性大鼠(F1:Fin)的肝脏(雄激素依赖性器官)进行了研究。对照组是未处理的Wistar父母的后代(F1:对照)。在肝脏的组织学切片中,高碘酸希夫(PAS)染色(可视化糖原)和IHC(检测GLUT-2,IR,和AR)进行。肝脏匀浆用于qRT-PCR评估GLUT2,IR,和ARmRNA表达。PAS阳性糖原面积百分比与GLUT-2的免疫表达相关,血清T和DHT水平与GLUT-2、IR相关,和AR转录水平,血清葡萄糖浓度与动物年龄和GLUT-2mRNA相关,采用Spearman的等级相关系数。
结果:在F1:Fin大鼠的每个年龄组中,糖原的积累升高,但与GLUT-2表达的变化无关。GLUT-2,IR,在F1:Fin动物中,AR转录物及其免疫反应性在统计学上显着降低。在F1:Fin大鼠中,T和DHT的血清水平与雄激素受体mRNA呈负相关。来自F1:Fin组的动物具有统计学上升高的葡萄糖水平。此外,在成年F1中:鳍大鼠,在肝脏中观察到脂肪变性(见附录A).
结论:似乎用非那雄胺治疗成年雄性大鼠会导致其后代肝脏中碳水化合物代谢的变化。这可能导致不适当的肝能量稳态或甚至高血糖,胰岛素抵抗,以及代谢综合征和肝脏脂肪变性的一些症状。
BACKGROUND: A growing body of data indicates that the physiology of the liver is sex-hormone dependent, with some types of liver failure occurring more frequently in males, and some in females. In males, in physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). Our previous study indicated that this mechanism may be impaired by finasteride, a popular drug used in urology and dermatology, inhibiting 5α-reductase 2, which converts testosterone (T) into dihydrotestosterone (DHT). Our research has also shown that the offspring of rats exposed to finasteride have an altered T-DHT ratio and show changes in their testes and epididymides. Therefore, the goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA.
METHODS: The study was conducted on the liver (an androgen-dependent organ) from 7, 14, 21, 28, and 90-day old Wistar male rats (F1:Fin) born by females fertilized by finasteride-treated rats. The control group was the offspring (F1:Control) of untreated Wistar parents. In the histological sections of liver the Periodic Acid Schiff (PAS) staining (to visualize glycogen) and IHC (to detect GLUT-2, IR, and AR) were performed. The liver homogenates were used in qRT-PCR to assess GLUT2, IR, and AR mRNA expression. The percentage of PAS-positive glycogen areas were correlated with the immunoexpression of GLUT-2, serum levels of T and DHT were correlated with GLUT-2, IR, and AR transcript levels, and serum glucose concentration was correlated with the age of animals and with the GLUT-2 mRNA by Spearman\'s rank correlation coefficients.
RESULTS: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. The levels of GLUT-2, IR, and AR transcripts and their immunoreactivity statistically significantly decreased in F1:Fin animals. In F1:Fin rats the serum levels of T and DHT negatively correlated with androgen receptor mRNA. The animals from F1:Fin group have statistically elevated level of glucose. Additionally, in adult F1:Fin rats, steatosis was observed in the liver (see Appendix A).
CONCLUSIONS: It seems that treating male adult rats with finasteride causes changes in the carbohydrate metabolism in the liver of their offspring. This can lead to improper hepatic energy homeostasis or even hyperglycaemia, insulin resistance, as well as some symptoms of metabolic syndrome and liver steatosis.