Treatment of Male Albino Rats with 5-fluorouracil and/or Cyclophosphamide Caused Serious Alterations in Sexual Hormones, Histological Structure of the Testis, and Semen Quality
Authors: Azab Azab Elsayed , M Yahya Rabia A , El.M.Shkal Karema , M. Attia Ahmed , A. Yehia Mona 
Published: November 2022

Background: The therapeutic effect of Cyclophosphamide (CPA) is thus attributed to phosphoramide mustard and acrolein that leads to the formation of high level of reactive oxygen species (ROS), which results in decreased antioxidant activity. Excessive production of ROS could also culminate in oxidative stress.  Objectives: The aim of this study is to evaluate the effect of sub lethal dose of the cyclophosphamide, 5-FU combination of 5-FU and CPA on testicular function, and histopathological alterations in male albino rats. These functions were monitored through some selected biochemical parameters and confirmed by DNA, RNA concentration and histopathological examination.  Materials and Methods: Twenty-eight male adult rats were grouped randomly into four groups (n=7 each group), Five for biochemical studies and 2 for histological studies. Group I (control): Rats were injected with saline intraperitoneally and at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood and testes tissue samples were taken and prepared for biochemical and histological measurements. Biochemical parameters in rat serum and tissues were evaluated.  Results: Treatment of male rats with CPA, 5-FU and their combination caused a significant decrease in sperm count, motility while increased dead and abnormal sperms compared to those of control. Co-treatment of CPA and 5-FU caused a significant decrease in sperm count, sperm motility and increase in abnormal sperms compared to individual treatment of CPA and 5-FU. Levels of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were decreased in the CPA, 5-FU and their combination-treated group. Co-treatment of 5-FU and CPA synergistically reduced testicular hormones compared with individual chemotherapy. Cyclophosphamide, 5-FU and their combination decreased testis DNA and RNA concentrations compared to the control. The combination of CPA and 5-FU was more effective to DNA and RNA compared to individual administration of the chemotherapy. Epididymis of the control rats showed normal histological structure with normal sperm density. Large tubules lined by pseudostratified columnar epithelium with abundant stereocilia projection from their surface. Long and dense processes of sperm tails were observed within the Lumina. The epididymis tubules of CPA-exposed rats were smaller and the majorities of them were free from mature spermatozoa. Epithelium contained numerous numbers of sloughed cells with cell debris in Lumina. 5-FU treated rat showed atrophy as well as necrosis, the arrangement of germ cells was disordered. The number of cell layers of the seminiferous tubules was significantly reduced. Epididymis of CPA+5-FU-treared rats showed necrotic degeneration and atrophy of the germinal cells, decrease spermatid when compared to CPA.  Conclusion: It could be concluded that treatment of mammals with chemotherapy is associated with the production of free radicals that lead to hazardous alterations in sexual hormones, DNA, and RNA concentration, and histopathological structure in tistes and semin quality of male albino rats. However, 5-FU and CPA combination could produce a serious alteration in these parameters. Future work should consider combined chemotherapy regimens. Toxicological studies must be performed before using drugs as combination before application. Further research is required on toxicological impacts of drugs and pollutants mixtures.