Sub chronic Evaluation of Ciprofloxacin and Perfloxacin on Sperm

Transcription

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
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.
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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*
Sperm
Primordial
Cell %
18.0 ± 1.5
35.0 ± 1.81*
37.0 ± 1.11*
39.0 ± 2.00*
45.0 ± 3.10*
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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
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]. Research showed that testosterone is
essential for growth and in association with follicle stimulating hormones acts on somniferous tubules to initiate and
maintain spermatogenesis [9, 26, 30].
CONCLUSION
Ciprofloxacin and Perfloxacin impaired spermatogenesis time dependently in these animals. Further evaluation could
be carried out in human model because some agents that impaired spermatogenesis in animal model have been shown
to be none toxic in human due to rapid biotransformation.
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Correspondence to Author: Dr. Elias Adikwu , Department of Pharmacology, Faculty of Basic
Medical Sciences ,College of Health Sciences ,University of Port Harcourt,Choba, Rivers State
,Nigeria.E-mail: adikwuelias@gmail.com
601

Sub chronic Evaluation of Ciprofloxacin and Perfloxacin on Sperm

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