ASIAN J. EXP. BIOL. SCI. VOL 3(3) 2012: 595-601 © Society of Applied Sciences ORIGINAL ARTICLE Sub chronic Evaluation of Ciprofloxacin and Perfloxacin on Sperm Parameters of Male Guinea Pigs Adikwu Elias and Brambaifa Nelson Department of Pharmacology ,Faculty of Basic Medical Sciences ,College of Health Sciences University of Port Harcourt Choba, Rivers State Nigeria. ABSTRACT Ciprofloxacin and Perfloxacin are fluorinated quinolone antibiotics. They are among the drugs of choice for the long term treatment of bacterial prostatitis and epididymitis infection in humans. They are known to have high concentration in semen, prostate, epididymis, vesicle gland, and tissues of testis in human. Studies showed that they are safe for therapeutic use but there are reports that the impaired spermatogenesis in animals. This study was designed to investigate the time dependent toxicological effect of these drugs on spermatogenesis. Forty five (45) adult male guinea pigs which were divided into two (2) experimental sections of nine (9) groups with each group containing five (5) animals were used in this study. 42.87mg/kg/day of Ciprofloxacin and 34.29mg/kg/day of Perfloxacin were orally administered to these animals for 7, 14, 21 and 28 days respectively while the control group received oral sterile water. Perfloxacin and Ciprofloxacin produced significant decrease (p<0.05) in testicular weight, sperm count, sperm motility and serum testosterone level. Perfloxacin produced significant decrease (p<0.05) in the body weight of these animals. Significant increase (p<0.05) in sperm morphology, sperm debris and sperm primordial cell was observed in these animals. It is therefore concluded that these doses of Ciprofloxacin and Perfloxacin which are higher than therapeutic doses may be detrimental to spermatogenesis in a time dependent manner. Keywords: Ciprofloxacin, Perfloxacin, Spermatogenesis, Guinea Pig INTRODUCTION In the past three decades a marked decrease in the quality of semen in men has been reported [4, 11, 18]. Antibiotics are among the classes of drugs causing decrease in semen quality [6, 24, 32]. Antibiotics are used in the treatment of bacterial infections. Ciprofloxacin and other fluoroquinolones are employed in the long term treatment of bacterial prostatitis. However, antimicrobial therapy has been shown to significantly affect semen parameters inhuman and animal models [32]. Studies in animals and humans have shown that antibiotics from all the major classes have significant adverse effects on spermatogenesis and sperm transport through the reproductive tract as well as affecting sperm function [32]. Patients on antibiotics often demonstrate below-average semen parameters while in some instances this may be caused by the infection itself. It is likely that antibiotics have a direct effect on sperm function [6]. It is very imperative that the effects of antibiotics on sperm function are known [6]. Ciprofloxacin and Perfloxacin which are Fluorinated Quinolones are among antibiotics that may impair spermatogenesis as reported [44, 45]. It was reported that 12.5mg/g of Ciprofloxacin administered to male rats for 60 days decreased testicular weight and sperm count [19]. Sperm count and sperm motility were decreased in male rats when 135mg/kg of Ciprofloxacin was administered for 15 days [1]. This is in agreement with the report of Demir et al [12] who showed that Ciprofloxacin caused recognizable histological damage associated with a mild decrease in testicular volume and sperm concentration. King et al [42] also observed that Ciprofloxacin altered membrane properties and also adversely affected sperm motility with decreased rapid progression. Mostafa et al [25] stated that ciprofloxacin at a dose level of 4.5 and 9.0 mg/100g body weight administered to rats for 7 and 65 days significantly decreased sperm cell motility and concentration. Significant increase in sperm cell abnormality was also observed. There was also decrease in testicular weight, seminal vesicle and prostate glands of treated rats. In my previous work on toxicological effect of ciprofloxacin on testicular function in male guinea pigs, it was observed that ciprofloxacin ASIAN J. EXP. BIOL. SCI. 3 (3) 2012 595 Subchronic Evaluation of Ciprofloxacin and Perfloxacin on Sperm Parameters of Male Guinea Pigs Adikwu Elias and Brambaifa Nelson decreased testicular weight, sperm count, sperm motility and serum testosterone levels. Sperm primordial cell, sperm morphology, and sperm debris were significantly increased [40]. Similar observations were noted when Perfloxacin was administered to male guinea pigs [41]. Nashwa et al [45] reported that 12.50mg/kg of ciprofloxacin administered to rats induced adverse effects on reproductive organ weight, sperm count, sperm motility and viability. Testosterone, follicle stimulating hormone and luteinizing hormone levels were also affected. In assessing the genotoxic potential of Ciprofloxacin using mouse micronucleus and sperm morphology assays, 320μg/ml, 160μg/ml, 80μg/ml, 32μg/ml and 16μg/ml of ciprofloxacin were daily administered intraperitoneally for 5 days to mice. It was observed that Ciprofloxacin produced a statistically significant concentration-dependent induction of micronucleus and abnormal sperm morphology in the exposed mice. Administration of 65, 130 and 260mg/kg of Ciprofloxacin to rats for 35 days induced chromosomal aberrations in spermatocytes and morphological sperm abnormalities [44] Furthermore, Perfloxacin at a dose level of 11.43mg/kg/day administered to male rats decreased testicular weight and serum testosterone level [13]. Study showed that 135mg/kg of Perfloxacin decreased sperm motility, sperm count and daily sperm production in rats [1]. 500mg/kg/day of Perfloxacin administered for 26 weeks to dogs impaired spermatogenesis and caused testicular damage [43]. Perfloxacin also caused reduction in the accessory organ weight (Seminal and Prostatic glands) and testicular atrophy in rats [43]. Mostafa et al [25] reported that sperm count and sperm motility were significantly decreased by 3.6 and 7.2mg/100g bw of Perfloxacin administered to rats for 7 and 65 days. In the light of these reports this research work was designed to evaluate the time dependent effect of Ciprofloxacin and Perfloxacin in male Guinea Pigs. MATERIALS AND METHODS Experimental Animals Male guinea pigs obtained from University of Port Harcourt animal house Nigeria and weighing 480±5g were acclimatized to housing condition for one (1) week prior to commencement of experiment. They were housed in large wire mesh cages under standard housing conditions of temperature 22±30C and provided with water and feed adlibitum. The animals were allowed free access to food and water. All animals used in the study were handled in accordance with the international and institutional guidelines for care and use of laboratory Animals in Biomedical Research as promulgated by the Canadian Council of Animal Care. Drugs The Ciprofloxacin and Perfloxacin used in this study were obtained from the University of Port Harcourt Teaching Hospital (UPTH) Port Harcourt. The stock solution of Ciprofloxacin was produced by the dissolution of its tablet form in sterile water obtained from the Department of Chemistry, Faculty of Sciences University of Port Harcourt. The stock solution of Perfloxacin was prepared by the dissolution of its injection form in normal saline [13, 34]. Dose Selection The doses used in the present study are high in comparison to the therapeutic dose levels in human because small laboratory animals eliminate drugs faster than humans [21]. Therefore higher doses were used in order to achieve simulated toxic concentrations of these drugs in the system of the animals [29]. Experimental Design This study was divided into two experimental sections experiment 1and experiment 2. Experiment 1 – Twenty five (25) adult male guinea pigs were divided into five (5) groups of (5) animals each. Each group was treated with 42.87mg/kg/day of oral Ciprofloxacin for 7, 14, 21 and 28 days respectively while the control group received sterile water. Experiment 2 – Twenty (20) male guinea pigs were divided into four (4) groups of five (5) animals each. Each group was treated with 34.29mg/kg/day of Perfloxacin for 7, 14, 21 and 28 days respectively. At the end of each treatment course the animals were sacrificed using diethylether anesthesia. Hormonal Assay Blood was collected into lithium heparinize bottle via cardiac puncture. It was centrifuged for 15min at 3000rpm and serum was separated and assayed for testosterone using enzyme immunoassay (EIA) technique [3]. Testosterone Enzyme Immuno Assay This was carried out in three stages namely: Reaction of antibody with serum testosterone and testosterone label, Magnetic solid phase separation step and Colour development step. 596 ASIAN J. EXP. BIOL. SCI. 3 (3) 2012 Subchronic Evaluation of Ciprofloxacin and Perfloxacin on Sperm Parameters of Male Guinea Pigs Adikwu Elias and Brambaifa Nelson In the reaction of antiserum with serum testosterone and testosterone label, 50ul of test blood sample was pippetted into different tubes. The testosterone blocking reagent, diluted testosterone label and testosterone antiserum (100ul) were added to the test tube, covered and vortex mixed. Magnetic Separation Reagent; Reaction 100ul of testosterone separation reagent was added to different test tubes, covered and vortex mixed. The tubes were C incubated in water bath at 370 for30minutes. The assay tubes were removed from water bath and placed on a magnetic base. The rack of tubes was kept upright in magnetic separation for 5minutes after which the supernatant liquid from all the tubes were decanted. Then the tubes were changed from upright position and remove from the magnetic base. Washing Step 50ul of dilute testosterone enzyme immune assay (EIA) wash buffer was added to different tubes and vortex mixed. The rack of tubes was placed on a magnetic base. The tubes were kept upright in the magnetic separation for 5minutes. The supernatant liquid were decanted from all the tubes and the separator was returned to an upright position. The rack of tubes was removed from the magnetic base. The whole process was repeated. This process is essential to remove all unbound components. Colour Development Step 500ul of substrate solution was added to different test tubes, covered and votex mixed. The tubes were transferred to 370C water bath and incubated for 6 minutes. The tubes were removed from the bath and1ml of EIA stop buffer was added to the magnetic base and the tubes were kept upright in different tubes and mixed. The rack of tubes was placed onto a magnetic separation for 10 minutes. The absorbance of the test sample and standard were recorded spectrophotometrically and compared with the blank. Measurement of Semen Parameters The testes were carefully removed and weighed. The caudal epididymis was dissected. An incision (about 1mm) was made on the caudal epididymis and drops of sperm were squeezed onto the microscope slide and two drops of normal saline were added to mobilize the sperm cells. Epididymal sperm motility was then assessed by calculating motile spermatozoa per unit area and was expressed in percentage. Epididymal sperm count was done using the counting chamber in the haemocytometer [2]. Sperm morphology was assessed and expressed as percentage sperm morphology. Sperm debris was equally evaluated and expressed as percentage sperm debris using standard laboratory technique [36] Statistical Analysis Data were expressed as mean ± standard error of mean (SEM). Results were subjected to statistical analysis using one way analysis of variance (ANOVA). The 0.05 level of probability was used as the criterion for significance. RESULTS Ciprofloxacin produced an insignificant change in the weight of the animals with respect to the control while Perfloxacin produced significant decrease (p<0.05) in the weight of the animals with respect to the control (Table 1and 3) Table1. Effect of Ciprofloxacin on body weight, testicular weight, sperm primordial cells and testosterone in male guinea pigs Dose (mg/kg) Testis Weight (g) Change in Body Weight (g) Testosterone (ng/ml) CONTROL 34.29 ( 7days) 34.29 (14 days) 34.29 (21days) 34.29 (28 days ) 2.30 ± 0.03 2.10 ± 0.02 1.25 ± 0.02* 1.18 ± 0.01* 1.08 ± 0.02* 50.0 ± 1.5 49.1 ± 1.3 48.2 ± 1.2 45.0 ± 1.71 41..5 ± 1.61 3.00 ± 0.66 1.30 ± 0.13* 1.20 ± 1.40* 1.23 ± 1.70* 0.92 ± 1.15* ASIAN J. EXP. BIOL. SCI. 3 (3) 2012 Sperm Primordial Cell % 18.0 ± 1.5 35.0 ± 1.81* 37.0 ± 1.11* 39.0 ± 2.00* 45.0 ± 3.10* 597 Subchronic Evaluation of Ciprofloxacin and Perfloxacin on Sperm Parameters of Male Guinea Pigs Adikwu Elias and Brambaifa Nelson Table 3.Effect of Perfloxacin on body weight, testicular weight, sperm primordial cells and testosterone in male guinea pigs Dose (mg/kg) Testis Weight (g) Change in Body Weight (g) Testosterone (ng/ml) CONTROL 34.29 ( 7days) 34.29 (14 days) 34.29 (21days) 34.29 (28 days) 2.30 ± 0.03 2.10 ± 0.02 1.10 ± 0.02* 1.28 ± 0.01* 0.90 ± 0.02* 50.0 ± 1.05 49.1 ± 1.31 47.2 ± 1.22 24.1 ± 1.71* 18.6 ± 1.61* 3.00 ± 0.66 1.30 ± 0.13* 1.20 ± 1.40* 1.23 ± 1.70* 0.92 ± 1.15* Sperm Primordial Cell % 18.0 ± 1.50 30.5 ± 1.90* 38.0 ± 1.62* 40.0 ± 1.81* 45.5 ± 3.10* Ciprofloxacin and Perfloxacin produced significant decrease (p<0.05) in the testicular weight of these animals with respect to the basal testicular weight. The decrease was observed to be prominent with increase in length of exposure to these drugs (Table I and 3). There was significant decrease (p<0.05) in sperm count in these animals after treatment with Perfloxacin and Ciprofloxacin for 7, 14, 21 and 28 weeks (Table 2 and 4). Exposure of these animals to these drugs produced significant time dependent decrease (p<0.05) in sperm motility with respect to the control (Table 2 and 4). Table 2:Effect of Ciprofloxacin on sperm motility, sperm count, sperm morphology and sperm Dose (mg/kg/day) Sperm Motility (%) Sperm Count 106/ml CONTROL 42.87 ( 7days) 42.87 (14 days) 42.87 (21days) 42.87 (28days) 65.00 ± 1.70 34.00 ± 1.75* 30.00 ± 2.34* 32.00 ± 2.60* 26.00 ± 1.95* 65.00 ± 3.00 35.00 ± 2.25* 33.00 ± 1.60* 30.00 ± 1.50* 27.00 ± 2.40* Sperm Morphology % 15.00 ± 1.00 33.00 ± 1.60* 34.00 ± 1.30* 39.00 ± 1.22* 42.00 ± 2.32* Sperm Debris % 15.00 ±1.22 34.00 ± 3.12* 38.00 ± 1.13* 40.00 ± 1.70* 42.00 ± 1.60* Table 4: Effect of Perfloxacin on sperm motility, sperm count, sperm morphology and sperm debris. Dose (mg/kg) Sperm Motility (%) Sperm Count 106/ml Sperm Morphology% Sperm Debris % CONTROL 34.29 ( 7ays) 34.29 (14days) 34.29 (21days) 34.29 (28days) 65.00 ± 1.70 39.00 ± 1.05* 30.00 ± 1.58* 25.00 ± 2.11* 15.00 ± 1.58* 65.00 ± 3.00 34.00 ± 2.43* 30.00 ± 2.11* 28.00 ± 1.70* 25.00 ± 2.24* 15.00 ± 1.00 32.00 ± 1.22* 35.00 ± 2.23* 40.00 ± 1.72* 45.00 ± 2.52* 15.00 ±1.12 31.00 ± 1.93* 38.30 ± 1.26* 40.00 ± 1.80* 44.50 ± 1.13* Morphology and sperm debris were increased significantly (p<0.05). Effects are more pronounced with increase duration of exposure to these drugs (Table 2 and 4). Ciprofloxacin and Perfloxacin produced significant increase at (p<0.05) ANOVA in sperm primordial cells of these treated animals. This increase was observed to be proportional to the time of exposure of these animals to the drugs. The decrease in serum testosterone level observed in these animals after treatment with those drug was significant at (p<0.05) ANOVA when compared with the control value. This decrease is proportional to the length of exposure to these drugs. DISCUSSION In-vivo and in-vitro genotoxicity study suggested that these drugs are safe for therapeutic use [15]. However reports have shown that the impair spermatogenesis in animal models [1, 25]. In this study these drugs produced significant decreased in the testicular weight of the animals with respect to the basal testicular weight. This was also reported 598 ASIAN J. EXP. BIOL. SCI. 3 (3) 2012 Subchronic Evaluation of Ciprofloxacin and Perfloxacin on Sperm Parameters of Male Guinea Pigs Adikwu Elias and Brambaifa Nelson when these drugs were administered to other animal species [13, 25]. The insignificant change in weight of Ciprofloxacin treated animals with respect to the control agrees with the observation of Nowinska et al [17] who administered 210mg/kg of ciprofloxacin to young and matured rats for four weeks. The ability of Perfloxacin to produced significant decrease in weight of the animals with respect to the control was also reported by some researchers [13]. Decrease in testicular weight observed in these animals after treatment with Ciprofloxacin and Perfloxacin could be due to increased peroxide radical generation in the testis after exposure to these drugs [37, 23, 38].This might have led to histopathological changes in the testis , DNA damage and chromosomal aberrations [12, 16, 19, 31]. Capase -3 which plays important role in apoptosis might have been activated by these agents [28, 39]. It was reported that decrease or increase in the weight of an organ after exposure to a chemical substance or drug is an indicator of the toxic effect of that chemical [33]. Mostafa et al. [25] also reported decreased in sperm cell motility when these agents were administered to rats. Decreased in sperm motility observed in these animals could have been initiated through the inhibition of energy production process required for sperm vitality and sperm motility [14]. Research showed that decreased in sperm motility is often used as a criterion of chemical –induced testicular toxicity [5] Decrease in sperm count and motility are valid indices of male infertility in laboratory animals [38]. Decreased in sperm count as observed in this study was also reported by some researchers who used other animal species [10, 25, 43]. This observed decreased could be due to damage to somniferous tubules which are responsible for sperm production [1, 19, 20] It is known that alterations in epididymal sperm count provide a direct measure of fertility in animals [22]. Mostafa et al [25] who administered these drugs to rats also reported increased in sperm cell abnormalities as observed in this study. Increase in sperm morphology and sperm debris by Ciprofloxacin and Perfloxacin could be due to inhibition of meiosis of primary spermatocytes into secondary spermatocytes and haploids spermatids (meiotic cell division phase of spermatogenesis) and increase in mitotic activity thus resulting in the production of many premature spermatozoa [27]. Chia et al [7] reported that sperm morphology is a useful tool for diagnosing male infertility. It is also a semen parameter that differentiates between fertile and infertile men [8]. Decrease in serum testosterone as observed in this study was also reported when these drugs were administered to male rats [13, 35]. Leydig cells are responsible for testosterone production and release hence decrease in testosterone level in these animals could be due to direct damage to the leydig cells[1, 19]. 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