Abstract
BackgroundThe male reproductive system is a sensitive and intricate process that can be distressed following exposure to various toxicants. Therapeutic drugs, especially chemotherapeutics, can also adversely affect male fertility by instigating hormonal changes leading to testicular cells injury. Azathioprine (AZA) is an effective anticancer drug, but some cases of testicular toxicity have been reported. The aim of this work was to investigate the protective effects of taurine chloramine (TAU-Cl), a reported antioxidant and antiinflammtory peptide, against AZA-induced testicular dysfunction in male rats and ascertain the contributing mechanisms.MethodsForty male rats were allocated into four equal groups; (i) normal control rats, (ii) TAU-Cl group (100 mg/kg b.w/day for 10 weeks, (iii) AZA group (5 mg/day for 4 weeks); (iv) TAU-Cl/AZA group.ResultsAZA caused increased DNA damage in the testes, and alterations in sex hormones and sperm quality, including sperm count, viability, and motility. Moreover, testicular tissue from the AZA-treated group had increased levels of oxidative stress indicator, MDA, and decreased activity of the antioxidant enzymes as superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) levels. These deleterious events were accompanied by upregulated levels of the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), and protein expression of iNOS and NFκB-p65, interleukin-1beta (IL-1β), and proapoptotic marker; caspase-9, together with decreased Bcl-2, NrF2 and hemeoxygenase (HO-1) expression. In contrast, TAU-Cl pretreatment significantly abrogated these toxic effects which were confirmed histologically.ConclusionPretreatment with TAU-Cl exerts a protective effect against AZA-induced male reproductive testicular atrophy. This finding could open new avenues for the use of TAU-Cl as a complementary approach to chemotherapy supportive care.
Highlights
The male reproductive system is a sensitive and intricate process that can be distressed following exposure to various toxicants
Effect of AZA and taurine chloramine (TAU-Cl) on rat body and testis weights, and on levels of serum testosterone, Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) Since there was no significant difference across any parameters examined between the control and TAU-Cl groups, the comparison was referred to the control group
taurine chloramine (TAU-CL) pre-treatment successfully normalized the body and testis weight compared to the AZA-treated group
Summary
The male reproductive system is a sensitive and intricate process that can be distressed following exposure to various toxicants. Azathioprine (AZA) is an immunomodulatory and cytotoxic drug often used to treat inflammatory bowel disease, autoimmune disorders, organ transplant rejection, and cancer [1] It functions via multifaceted pathways; it inhibits purine metabolism, which leads to DNA damage [2], and at high chemotherapeutic doses inhibits DNA. Its active metabolite 6-mercaptopurine (6-MP) damages rapidly dividing cells, such as those in the bone marrow, intestinal epithelium, and reproductive organs of adults [7, 8] One of these major drug–related disorders is testicular atrophy and infertility, with genetic polymorphisms of the thiopurine methyltransferase enzyme, which is responsible for thiopurine metabolism, possibly contributing to its mechanism. Population studies have shown that patients with low enzymatic activity have a high risk for severe, potentially fatal toxicities [9]
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