EFFECTS OF PROGUANIL, DAPSONE AND ARTESUNATE ON MALE REPRODUCTIVE ACTIVITIES IN MAMMALS

Abstract

Many antimalarial drugs have been implicated in male infertility. Proguanil, dapsone and artesunate are among the antimalarial drugs whose effects on the reproductive system are yet to be well investigated. This study was therefore designed to investigate the effects of these drugs on male reproductive activities. Adult male rats in groups of six were used. Rats in group I were administered proguanil (2.9 mg kg⁻¹ body weight) orally for 5 days. Groups II and III were treated with proguanil for 6 weeks. Group Ill was allowed to recover for 6 weeks. This procedure was repeated in rats administered dapsone (1.4 mg kg⁻¹ body weight) or artesunate (2.9 mg kg⁻¹ body weight). Control rats received distilled water. Body and relative reproductive organ weights of the rats were determined. Histological analysis of the testis and epididymis was done. Serum levels of Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSU) and testosterone were measured by enzyme immuno-assay technique. Sperm was collected and analyzed for motility, viability, morphology and count. Fertility study was done by mating technique. Sertoli cells were cultured with test drugs for 5 days after which their viability and nuclei integrity were assessed using 3-[4,5- dimethylthiazol-2y1]-2, 5-diphenyltetrazolium bromide and 4-6-Diamidino-2- phenylindole stains respectively. The expressions of Glial cell line Derived Neurotropic Factor (GDNF) and transferrin genes were determined by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Extender study was carried out on sperm collected from normal West African Dwarf Buck and treated with the drugs. Human wertruaDzoa were [also collected and treitted livid the drugs and motility was assessed. Data were analysed using Student's-test and ANOVA. Proguanil, dapsone and artesunate significantly reduced (P<0.05) relative epididymal weight (proguanil; 0.17±0.01, dapsone; 0.19±0.01, artesunate; 0.24±0.01, control; 0.29±0.01), relative testicular weight (proguanil; 1.22±0.04, dapsone; 1.26±0.04, artesunate; 1.30±0.03, control. 1.49±0.03) of the treated rats. Sperm motility and viability of rats treated for 5 days were significantly decreased (P<0.05) with no change in sperm count and morphology. However, sperm motility (proguanil; 40.20±2.81%, dapsone, 49.60±1.44%, artesunate: 57.20±1.56%, control 81.40±1.86%), viability and count were significantly reduced (P<0.05) after treatment for 6 weeks with proguanil showing the greatest effect and artesunate the least. Testicular and epididymal histology showed duration-dependent tissue degeneration. There was no significant change in serum LH and FSH in treated rats while testosterone concentration was significantly reduced (P<0.05) compared with control. Proguanil and dapsone caused reduction in litter size. These changes were gradually restored in recovery experiments. There was a dose-duration dependent decrease in the viability of Sertoli cells and the integrity of their nuclei. RT-PCR showed normal expression for GDNF and transferrin genes in Sertoli cells. Extender study showed a dose-duration dependence decrease in sperm motility. There was also a dose-dependent decrease in human sperm motility with proguanil showing the greatest effect. Proguanil, dapsone and artesunate induced reversible male infertility. Proguanil showed the greatest toxic action while artesunate the least. Epididymis and testis appear to be the sites of action.