Basrah Journal of Veterinary Research,Vol.17, No.3,2018
Proceeding of 6th International Scientific Conference,College of Veterinary Medicine
University of Basrah,Iraq
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AMELIORATIVE EFFECT OF COQ10, DHEA AND THEIR
COMBINATION ON EMBRYOTOXICITY AND TERATOGENICITY
INDUCED BY NORFLOXACIN IN PREGNANT FEMALE RATS
Bassim K. Kuoti Al-Rekabi *; Mohammed A. Al-Diwan ** ; Alaa A. Sawad ***
* Department of Animal Production, College of Agriculture, University of Sumer, Thi-Qar,
Iraq.
** Department of Physiology, Pharmacology and Chemistry, College of Veterinary Medicine,
University of Basrah, Basrah, Iraq.
*** Department of Anatomy, Histology and Embryology, College of Veterinary Medicine,
University of Basrah, Basrah, Iraq.
Key words: CoQ10, DHEA, Maternal Toxicity, FGR, Norfloxacin
Corresponding authors E. Mail: [email protected]
ABSTRACT
This study was designed to evaluate the ameliorating role of CoQ10 and DHEA and their
combination on norfloxacin induced maternal toxicity and fetal growth retardation in pregnant
female rats and their fetuses. Twenty pregnant rats were divided equally into 5 groups, 4 animals
per each group as following: Control group (G1): 4 normal pregnant female received
0.5ml/animal/day DMSO by using gastric gavages from 5th - 19th day of gestation. First treated
group (T1): 4 normal pregnant female received 400 mg/kg norfloxacin daily by gastric gavages
as a single dose. Second treated group (T2): 4 normal pregnant female received orally 400 mg/kg
norfloxacin once daily and after 1hour later injected daily with CoQ10 200 mg/kg IP. Third
treated group (T3): 4 normal pregnant female received orally 400 mg/kg norfloxacin once daily
and after 1hour later injected daily with DHEA 25 mg/kg IP. Fourth treated group (T4): 4 normal
pregnant female received orally 400 mg/kg norfloxacin once daily and after 1hour later injected
daily with combination of CoQ10 200 mg/kg and DHEA 25 mg/kg IP for the same period. All
dams were sacrificed at 20th day of gestation and their fetuses were collected and subjected to the
morphological examinations. The obtained results showed that exposure to norfloxacin in
pregnant female rats during gestational period from 5th -19th day demonstrate clearly increased in
resorbed and stillbirth fetuses (dead fetuses at birth), and caused a significant decreased in fetal
body weight, fetal body length, fetal tail length, maternal weight gain and placental weight. It has
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330
been concluded that CoQ10 and DHEA prevented and treated morphological anomalies in rat
fetuses. Therefore, CoQ10 and DHEA are potential therapeutic antioxidant agents against
fetotoxicity induced by oxidative stress generated by norfloxacin intoxication.
INTRODUCTION
Exposure of developing embryo or fetus to definite chemical agents and drugs is known to
produce congenital anomalies leading to death in uterine or structural birth defects usually
known as teratogenesis [1]. Different forms of embryonic malformation have been attributed to
oxidative stress [2]. It has been a forceful evidence involving teratogens like norfloxacin to
reactive oxygen species generation [3]. Norfloxacin (NFX) is an active semi-synthetic
chemotherapeutic antibacterial agent and has a broad spectrum of antibacterial activity against
gram negative and gram-positive aerobic bacteria [4]. It is a therapeutic agent that is able to cross
placental barrier and enter fetal circulation. It acts by inhibition of bacterial DNA replication by
inhibition of bacterial DNA gyrase and topoisomerase II enzyme [5]. Therefore, every agent
given during pregnancy has a tendency to produce some sort of structural abnormality in neonate
at birth until proved otherwise [6]. However, period of organogenesis is mainly serious stage for
malformation to occur. Agents given during this period are more likely to cause birth defects.
This critical time of fetal development in rat and mice is from 6-15 days of their gestation [7]. A
birth defect or congenital abnormalities is a structural malformation of any type current at birth,
which may be macroscopic or microscopic, on surface or within body [8]. The fetal risks of these
substances occur during pregnancy by impaired cartilage formation in animal studies [9].
Coenzyme Q10 (CoQ10) is an endogenous substance act as a vital antioxidant proposed for
cellular membrane integrity either by direct reaction with free radicals or by regeneration other
antioxidant [10]. It is a lipid soluble, vitamin like substance required for proper functioning of
many organs and chemical reactions in body [11]. It has many beneficial effects in human and
animals health including cardiovascular disease, neurodegenerative disorders, age related
disorders, autoimmune disorder, DNA damage, thyroid disorders, male infertility, cancers,
diabetes, fibrosis, apoptosis, and obesity. It is a crucial redox and proton translocations
constituent of mitochondrial respiratory chain, and plays an essential role in mitochondrial
energy production through redox activity in the electron transport chain, transporting
electrons between enzymes. Thus, it plays an essential role in cellular bioenergetics and
membrane stabilizer and production of ATP in oxidative respiration process [12]. CoQ10 has
anti-inflammatory properties decreasing production of pro-inflammatory cytokines such as
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Proceeding of 6th International Scientific Conference,College of Veterinary Medicine
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interleukin (IL) and tumor necrosis factor (TNF-α) [13]. Dehydroepiandrosterone (DHEA) is one
of the most abundant endogenous circulating steroid hormones with multi-functional
properties; it is produced in adrenal glands, gonads, and brain, where it functions as a metabolic
intermediate in biosynthesis of androgen and estrogen sex steroids [14]. It plays a critical
endogenous antioxidant and pro-oxidant activity. It can also protect against lipid peroxidation
(LPO) induced by oxidative damage [15]. DHEA also has anti-inflammatory properties through
reduced pro-inflammatory cytokines secretion like IL and TNF-α and regulation of body immune
response [16]. DHEA and DHEAS are products of cholesterol metabolism with first enzymatic
reaction occur in mitochondria and are resulting from the action of cytochrome P450 [17]. This
study aimed to evaluate the ameliorating role of CoQ10 and DHEA and their combination on
maternal toxicity and fetal growth retardation in pregnant female rats exposed to norfloxacin.
MATERIALS AND METHODS
Drugs and chemical reagents
Norfloxacin was obtained as an tablets from Ajanta Pharma limited, India, 400 mg tablets) under
a trade name (Norexin) and administered by oral gavages after dissolving as a single dose, and
CoQ10 200 mg/kg and DHEA 25mg/kg obtained from (Sigma, St. Louis, MO, USA) was
administered intraperitoneally. Dimethylsulphoxide (DMSO) was purchased from Merck,
Darmstadt, Germany.
Experimental animals
Thirty male and female healthy rats (Rattus norvegicus) weighing 225-250 grams, 12-14 weeks
old (10 male vs. 20 female) were randomly divided into five equal groups, each group consisted
of 6 rats (2 male vs. 4 female). Each 6 animal was housed in an individual cage measured as15 x
35 x 50 cm and kept under normal temperature 22 - 28 °C and the daily light period was 12
hours by use of two fluorescent lamps, and humidity rate was about 50 %. Animals were
provided with water and diet ad libitum. The sexually mature female rats were acclimatized in
laboratory for 2 weeks, followed with daily vaginal smear examination for 4 pre-treatment
estrous cycles as described by [18] to establish their normal pattern of cyclical activity. The
female rats with proestrus stage were caged overnight and mated with fertile normal healthy
males of same strain, allowing one male for two females in one cage [19]. On next morning, the
female rats were examined for signs of mating such as sperms in vaginal smears or a vaginal
plug of mucoid greenish white material. Presence of both or any of these signs was considered as
day-1 of pregnancy [20].
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Experimental design and study strategy
After detection the first day of gestation for all females, 20 animals had been divided randomly
and equally into 5 groups as following: Control group (G1): 4 normal pregnant female received
0.5ml/animal/day DMSO by using gastric gavages from 5th - 19th day of gestation. First treated
group (T1): 4 normal pregnant female received orally 400 mg/kg norfloxacin once daily. Second
treated group (T2): 4 normal pregnant female received orally 400 mg/kg norfloxacin once daily
and after 1hour injected daily with CoQ10 200 mg/kg IP. Third treated group (T3): 4 normal
pregnant female received orally 400 mg/kg norfloxacin once daily and after 1hour injected daily
with DHEA 25 mg/kg IP. Fourth treated group (T4): 4 normal pregnant female received orally
400 mg/kg norfloxacin once daily and after 1hours injected daily with a combination of CoQ10
200 mg/kg and DHEA 25 mg/kg IP for same period of treatment.
Developmental observations
The rats before sacrifice were first weighed and then anaesthetized by placing them in a closed
beaker containing cotton sucked with chloroform for anesthesia. The abdominal cavity was
opened up through a midline abdominal incision to take the fetuses at 20th day of gestation. After
abdominal incision, the uterus was observed and location and number of fetuses and resorption
sites were observed. Fetal growth retardation represented by fetal body weight, fetal body length
or crown rump length (CRL), and fetal tail length were then evaluated. On 20th day of gestation,
all pregnant female rats of groups were sacrificed and fetuses were removed from the uterus and
evaluated for fetal mortality rate (resorbed or dead fetuses), maternal weight gain, placental
weight, living fetuses were evaluated.
Statistical Analysis
In this study, one way ANOVA analysis and LSD tests are used according to Statistical Package
for Social Sciences (SPSS, version 13) program. The data were expressed as Mean ± standard
deviation (Mean ± SD). Least significant difference test (LSD) was used to test the difference
between means (groups); P≤ 0.05 was considered significant (SPSS, 2001).
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RESULTS
Maternal rats toxicity
Maternal weight gain and placental weight changes
The exposure of pregnant female rats to norfloxacin dose (400 mg/kg) during gestational period
from 5th -19th day revealed a significant decrease (P≤0.05) in maternal weight gain and placental
weight changes compared to control group (Table 2). Whereas, groups that treated with CoQ10,
DHEA and their combination revealed significant increase (P≤0.05) in maternal weight gain and
placental weight changes compared to groups treated with norfloxacin, but they were still less
significantly (P≤0.05) compared with control value. It is also observed from table (2) that the
combination of CoQ10 and DHEA caused a highly significant increased (P≤0.05) in maternal
weight gain and placental weight changes and almost return to its normal levels compared with
control value.
Effect of norfloxacin (NFX) on developing fetuses
Growth retardation rate
The results on table (2) and figure (1) also pointed out that the pregnant female rats received
norfloxacin showed significant decrease (P≤ 0.05) in the fetal body weight, fetal body length and
fetal tail length compared to control group. Whereas, groups treated with CoQ10, DHEA and
combination of CoQ10 and DHEA showed a significant increase (P≤ 0.05) in fetal body weight,
fetal body length and fetal tail length compared to groups treated with norfloxacin, but they were
still less significantly (P≤0.05) compared to control value. It was indicated from table (2) and
figure (1) that combination of CoQ10 and DHEA caused a highly significant increased in growth
retardation rate represented by fetal body weight, fetal body length and fetal tail length, and
almost return to its normal levels compared with control value.
Total prenatal mortality rate
The results in table (1) illustrate a clearly increased in resorbed and dead fetuses of pregnant
female rats at 20th day of gestation that received norfloxacin compared to control group.
Whereas, the groups treated with CoQ10, DHEA and combination of CoQ10 and DHEA showed
a clearly reduced in resorbed and dead fetuses on day 20th of gestation compared to groups
treated with norfloxacin, but they still less compared to the control value. It is also observed
from table (1) that combination of CoQ10 and DHEA caused a highly decreased in resorbed and
stillbirth and almost returns to its normal levels compared with control value.
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Table (1): The effect of CoQ10 and DHEA and their combination on fetal mortality rate represented
by resorped fetus and stillbirth fetus of norfloxacin treated pregnant female rats from 5th-19th days of
gestation.
Parameters
Groups
Total No.
of sacrifice/
pregnant
rats
Total No. of
fetuses and
Implantation site
No. of lives
fetus
No. of
resorbed fetus
No. of dead
fetus
Control 0.5 ml DMSO 4
39 (8-12)
9.750 ± 1.137
39 100% 0 0% 0 0%
NFX 400mg/kg 4
28 (8-9)
7. 000 ± 2.403
15 53.57% 10 35.71% 3 10.72%
NFX 400mg/kg +
CoQ10 200 mg/kg 4
37 (8-12)
9.250 ± 1.157
37 100% 0 0% 0 0%
NFX 400mg/kg +
DHEA 25 mg/kg 4
36 (8-12)
9. 000 ±1.146
36 100% 0 0% 0 0%
NFX 400mg/kg +
Combination CoQ10
200 mg/kg+ DHEA 25
mg/kg
4
38 (8-12)
9.500 ±1.153
38 100% 0 0% 0 0%
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Table (2): The effect of CoQ10 and DHEA and their combination on growth retardation rate
represented by fetal body weight, fetal body length, fetal tail length, and placental weight,
maternal weight gain of norfloxacin treated pregnant female rats from 5th - 19th day of
gestation.
Parameters
Groups
Fetal body
weight
(F.WT) gm
Fetal body
length
(CRL) cm
Fetal tail
length
(F.TL) cm
Maternal
weight gain
(M.WT) gm
Placental
weight
(P.WT) gm
Control 0.5 ml DMSO 4.875± 0.11
a
5.19± 0.032
a
1.662± 0.043
a
28.50±2.320
a
0.605± 0.011
a
NFX 400mg/kg 2.466± 0.07
b
3.50± 0.123
b
1.283±0.060
c
12.00±2.065
b
0.490± 0.013
d
NFX 400mg/kg +
CoQ10 200 mg/kg
4.453± 0.03
a
5.17± 0.041
a
1.542±0.040
b
24.50±2.210
b
0.509± 0.507
bc
NFX 400mg/kg +
DHEA 25 mg/kg
4.431± 0.02
a
5.13± 0.053
a
1.533±0.050
b
23.30±2.320
b
0.505± 0.015
c
NFX 400mg/kg +
Combination CoQ10
200 mg/kg+ DHEA 25
mg/kg
4.400± 0.06
a
5.10± 0.072
a
1.552± 0.042
b
26.42±2.232
a
0.603± 0.020
b
Small letters means significant differences between treatment at (P≤0.05)
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Figure (1): Different size of fetuses of different treated groups showing growth retardation (fetal
body weight, fetal body length, and fetal tail length) from pregnant female rats at 20th day of
gestation. (A): Control group treated with DMSO, (B): First treated group (NFX), (C): Second
treated group (CoQ10), (D): Third treated group (DHEA), (E): Fourth treated group
(CoQ10+DHEA).
A (DMSO) B (NFX) C (CoQ10) D (DHEA) E(CoQ10+ DHEA)
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DISCUSSION
In seems from the results of the present study that norfloxacin treated pregnant female rats
during period of organogenesis from 5th -19th day of gestation caused significantly increased in
resorped and death fetuses either early or late, and significantly decreased in number of viable
fetuses compared to control group. These findings may be attributed to fluoroquinolones
inhibitory effect on DNA gyrase, which is an enzyme necessary for negative super coiling
twisting into double stranded DNA [21]. The inhibition of DNA synthesis induced by
fluoroquinolones may be attributed to its ability to releasing oxygen free radicals [22]. It has
been known that oxygen free radicals attack DNA causing mutations [23]. These results are
agreed with those obtained by many researchers such as: [24] and [25], who studied
embryotoxicity and teratogenicity of norfloxacin on pregnant female rats and their fetuses [26],
who confirmed that fetotoxicity induced by norfloxacin may be attributed to interfering of used
drug with placental transmission of amino acid leucin and magnesium from the dams to the
fetus due to deficiency of these amino acid produced high incidence of fetal resorption rate,
according to the negative relationship between parathyroid hormone secretion and magnesium
deficiency due to relation hypoparathyroidism with the insufficiently low PTH levels. As well
as, it may be recognized to discontinue creation of placental progesterone when production of
hormone switched from luteal to placental phase [27]. These results also may be attributed to
inhibition of DNA transcription at late stage of rapidly divided fetal cells [28]. [29], mentioned
that use of fluoroquinolone during first trimester of pregnancy caused failure in embryonic
fixation which occurs after fertilization which led to early fetal death and increase fetal
resorption. However, this study also showed decline in number of viable fetuses per pregnant
dams. This result was reliable with the data reported by [30]. The decrease in the numbers of
viable fetuses may be clarified on base of incomplete formation of placenta and degeneration of
trophoblast and decidual cell, which play an important role in transmission of nutrients from
the mother to the embryo [31].
It is also seems from the results that norfloxacin caused significantly decreased in fetal body
weight, fetal body length (crown-rump length) and fetal tail length compared to control group.
These result may be attributed to insufficiency of nutritional supply from the dam to the fetuses
because female rats receiving drugs shows signs of soft stool or diarrhea due to imbalance in
intestinal microflora, or may be due to trouble and drug interference in placental transmission
in some minerals metabolism from the dams to the fetus such as magnesium and zinc which
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deficiency causes decreased in fetal growth retardation and increase in fetal resorption and
early embryonic death [32].The critical role of zinc in fetal skeletal system development may
be attributed to stimulation of insulin like growth factor (IGF) which has essential function in
fetal growth [33]. Also, zinc stimulate bone formation and mineralization, and increase bone
alkaline phosphatase activity and DNA content [34]. [35], demonstrated that fetal body weight,
fetal body length and fetal tail length significantly decreased after ciprofloxacin administration
in pregnant female rats. Many earlier studies mentioned by [36] demonstrated decreased in fetal
body weight, fetal crown-rump length and fetal tail length after orally administration of
ofloxacin or levofloxacin to pregnant female rats. [37] showed that difloxacin decreased
significantly fetal growth retardation after oral administration of 20 and 40 mg/kg of drug to
pregnant female rats during period of organogenesis from 6th- 15th of gestation. However, other
study stated that fluoride accumulation with repeated exposure to fluoroquinolone is related to
the bone and cartilage damage [38]. The fluoroquinolone delayed developmental phase of
epiphyseal growth with growth inhibition [39]. In addition, significantly decreased in maternal
weight gain and placental weight compared to control group. These result may be attributed to
decrease in diet intake and water consumption [40]. Many earlier studies reported that
fluoroquinolones induced liver injury and hepatotoxicity through oxidative stress and
generation of oxygen free radicals in the microsomal system with depression in endogenous
antioxidant activity due to fluoride accumulation with repeated fluoroquinolone administration
[41], due to drugs metabolism by cytochrome P450 and/or redox reaction. In addition to
induced liver damage, drug also showed nephrotoxicity [42], cardiotoxicity [43], neurotoxicity
[44], and placental toxicity. [45] showed that fluoroquinolone toxicity is associated with
GABA-A receptor antagonism, resulting in decrease in the conductance of chloride ions. It has
also been known that fluoroquinolone act as GABA antagonist in organism which blocks K
channels connected to ATP [46]. As well as, it's related to NMDA receptor activation by
eliminating Mg2+ block in ion channel. In contrast, lomefloxacin and norfloxacin blocked ATP
sensitive K+ channels in pancreatic beta cells and increased insulin secretion [47].
In contrast, supplementation with CoQ10, DHEA and combination of CoQ10 and DHEA
during period of organogenesis from 5th-19th days of gestation caused prevention and improved
fetal skeletal malformation compared to norfloxacin treated group. These results may be
attributed to a powerful anti-oxidant and anti-inflammatory properties against norfloxacin
induced embryotoxicity and teratogenicity [48]. The present results are in agreement with
results obtained by [49] who they showed that CoQ10 administration to pregnant female rats
Basrah Journal of Veterinary Research,Vol.17, No.3,2018
Proceeding of 6th International Scientific Conference,College of Veterinary Medicine
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caused prevent morphological and skeletal abnormalities induced by antidepressant drug. Also,
it is confirmed that antioxidant properties of CoQ10 might play a vital role in inhibiting bone
resorption, cells differentiation, and protect osteoblast from oxidative damage induced by
generated free radicals led to improved bone mineral density and stability. [50] stated that
CoQ10 increased calcium absorption from gut, reduced urinary excretion of calcium, increased
calcium deposition in bone, improved bone strength, and enhanced synthesis of bone collagen.
[51] reported that a positive correlation between maternal CoQ10 and embryo development, in
addition to balanced lipid metabolic alterations. [52] demonstrate the protective role of CoQ10
against oxidative stress, generation of ROS, and fetal cell death during pregnancy. For another
explanation, [53] demonstrate that stimulation of maternal immune system by administration of
anti-oxidant and anti-inflammatory to the pregnant female rats can prevented and reduced fetal
malformation of the drugs. However, many studies reported beneficial influences of maternal
immune system on pregnancy outcome associated which reduced fetal teratogenicity through
contribution of cytokines produced by immune cells [54], decrease of expression of TNF-α in
fetal brain, modulation of fetal gene expression, inhibits pro-inflammatory cytokines synthesis,
and enhances apoptosis by alteration cellular processes such as proliferation and differentiation
[55]. [56] mentioned antioxidant and antimutagenic effect of vitamin C and β-carotene against
oxidative stress and mutagenesis induced by Quinolones.
On the other hand, [57] showed that DHEA prevented loss in bone mineral density (BMD),
decrease bone resorption, increase bone formation, increase production of bone cytokine and
insulin like growth factor-1(IGF-1). However, [58] shows that IGF-1 or testosterone increased
bone formation, while estrogen suppressed bone resorption. [59] showed a strong positive
correlation between supplementation of DHEA and improved BMD, BMI, and IGF-1 levels,
who explained that IGF-1 are growth promoting polypeptides play an important role in
regulating osteoblastic and osteoclastic functions and maintaining bone mass, and are
modulated by a groups of proteins like insulin-like growth factor binding proteins (IGFBPs)
which is carried in a complex with IGFBP-3, which play a significant role in regulation of bone
remodeling process in humans by enhancing anabolic effects of IGF-1 on bone. DHEA has
anabolic effects and promotes APL activity and collagen I synthesis [60]. Furthermore, DHEA
has a role in inhibition of interleukin 6 (IL-6) in skeletal muscle catabolism and stimulation of
IGF-I-mediated mechanisms that underlie osteoanabolic events [61]. Many studies reported a
helpful role of DHEA-S in bone strength. In another study, [62] reported that increased serum
levels of DHEA-S is highly associated with reduced bone loss at femur neck and the lumbar
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spine. Furthermore, [63] reported that circulating DHEA have a direct effect on bone through a
recognized DHEA receptor, or by conversion to androgens or estrogens within bone cells [64].
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