Journal of Trace Elements in Medicine and Biology 25 (2011) 5966

Contents lists available at ScienceDirect

Journal of Trace Elements in Medicine and Biology

journal homepage: www.elsevier.de/jtemb

Toxicology

Effect of selenium on carbimazole-induced testicular damage and oxidative

stress in albino rats
Saber Abdul Ruhman Sakr , Hoda Abdel-hafez Mahran, Amany Ebrahem Nofal
Zoology Department, Faculty of Science, Menoua University, Shebin El-kom, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Carbimazole is an antithyroid drug used in treatment of hyperthyroidism. The present investigation
Received 7 January 2010 studied the effect of carbimazole on testicular activity in albino rats and the ameliorative role of sele-
Accepted 23 July 2010 nium. Treating rats with carbimazole (1.35 mg/kg b.w) daily for 8 weeks caused reduction in the body
and testes weight. Moreover, the diameters of the seminiferous tubules and heights of their germi-
Keywords: nal epithelium were signicantly reduced. Testes of treated rats showed many histological alterations
Carbimazole
included congestion of blood vessels, hemorrhage, degeneration of interstitial tissue and degeneration of
Selenium
spermatogenic cells with apoptosis and necrosis. Histochemical results revealed reduction in polysaccha-
Testis
Rat
rides, total proteins and nucleic acids contents in testicular tissue. In addition, the level of testosterone,
Antioxidant luteinizing hormone (LH), T3 , T4 and thyroid stimulating hormone (TSH) was signicantly decreased in
sera of treated animals. Moreover, a high lipid peroxidation with a decrease in the enzymatic antioxi-
dant status, superoxide dismutase (SOD) and catalase (CAT) was recorded in testes homogenate. Treating
animals with carbimazole and selenium showed an improvement in the histological structure as well as
histochemical components of the testis with an increase in the number of spermatogenic cells. There
was an increase in testosterone, LH, T3 , T4 and TSH levels. Moreover, administration of selenium led to
decrease in malondialdehyde and increase in catalase and superoxide dismutase activities. It is suggested
that the curative effect of selenium against testicular damage induced by carbimazole may be due to its
antioxidant properties.
2010 Elsevier GmbH. All rights reserved.

Introduction time and appears to be considerable higher than after radioiodine

Carbimazole is a thionamide drug used in treatment of hyper-
thyroidism and reduce thyroid function before surgery. On the
other hand, many authors reported that the use of carbimazole
was accompanied by deleterious effects. Vilchez et al. [1] reported
that within 15 days following the start of carbimazole therapy,
both minor (e.g., pruritus, rash, urticaria, fever and arthralgias)
and potentially life-threatening (e.g., agranulocytosis, hepatotox-
icity with severe cholestatic jaundice) were developed. Marazuela
et al. [2] mentioned that carbimazole was capable of inducing acute
pancreatitis and cholestatic hepatitis in a 33-year-old female. Zaidi
et al. [3] reported that carbimazole administration even in thera-
peutic dose during pregnancy and lactation resulted into alteration
of the thyroid microstructure of newborn. Calanas-Continente et
al. [4] reported a necrotizing glomerulonephritis and pulmonary
hemorrhage associated with carbimazole therapy. After carbima-
zole treatment, the risk of thyroid carcinoma increases with the
Corresponding author. Tel.: +20 482316262.
E-mail address: sabsak@yahoo.com (S.A.R. Sakr).
treatment [5].
Selenium is an essential element involved in various biological
processes in nearly all tissues of animals and human [6]. It is impor-
tant in many biochemical and physiological processes including the
biosynthesis of coenzyme Q (a component of mitochondrial elec-
tron transport systems), regulation of ion uxes across membranes,
maintenance of the integrity of keratins, stimulation of antibody
synthesis, and activation of glutathione peroxidase [7]. Grtner [8]
reported that the plasma selenium levels indicate the amount of cir-
culating selenoproteins and selenoenzymes. These are important
for modulating the immune system and also for thyroid hormone
metabolism. Moreover, sodium selenite is commonly used as a
direct supplement for the treatment of selenium deciency. Sele-
nium has a long history in chemoprevention of mammary and colon
cancers in rodent models and has shown promise in prevention of
prostate and other human cancers [9]. Liao et al. [10] reported that
selenium played a benecial role for prevention of cisplatin hepa-
totoxicity in mice. Jihen et al. [11] mentioned that selenium has
a cooperative effect in the protection against cadmium-induced
structural damage in the liver of rat. El-Shenawy and Hassan [12]
reported that selenium has a protective effect against liver and

0946-672X/$ see front matter 2010 Elsevier GmbH. All rights reserved.
doi:10.1016/j.jtemb.2010.07.002
60 S.A.R. Sakr et al. / Journal of Trace Elements in Medicine and Biology 25 (2011) 5966
kidney damage induced by mercury chloride in rats. The present
work was undertaken to study the effect of selenium on testicular
damage induced by carbimazole in albino rats.
Materials and methods
Animals
Sexually mature male albino rats (Rattus norvegicus) weighing
115 5 g and aged 15 weeks were purchased from the breed-
ing center of experimental animals at Helwan University, Helwan,
Egypt. The animals were kept in the laboratory under constant tem-
perature (22 1 C) for at least 1 week before and along the period
of the experimental work. They were maintained on a standard
rodent diet composed of 55% corn starch, 20% casein, 15% corn oil,
5% salt mixture and 5% vitaminized starch (Egyptian Company of
Oils and Soap Kafr-Elzayat, Egypt). Water available ad libitum.
Experimental design
The animals were divided into 4 groups. Group 1: animals of this
group (20 rats) were served as normal control. Group 2: animals
of this group (30 rats) were orally given carbimazole (1.35 mg/kg
b.w) (equivalent to the therapeutic dose for human [13]) dissolved
in water, daily for 8 weeks. Group 3: animals of this group (30
rats) were orally given sodium selenite (10 g/kg b.w) dissolved
in water, daily for 8 weeks. Group 4: animals of this group (30 rats)
were orally administered carbimazole (1.35 mg/kg b.w) and sodium
selenite (10 g/kg b.w) [14] daily for 8 weeks. All the experiments
were done in compliance with the Guide for the Care and Use of
Laboratory animals. The treated animals were sacriced by cervical
decapitation after 4 and 8 weeks of treatment.
Histological and histochemical examination
Ten rats were weighted and sacriced from treated and con-
trol groups after 4 and 8 weeks. Their testes were excised and
weighted. For histological study, testes were xed in alcoholic
Bouins uid, dehydrated in ethyl alcohol, cleared in xylol and
embedded in parafn wax. Sections of 5 m thickness were cut and
stained with haematoxylin and eosin for histological examination.
For histochemical study, specimens were xed in Carnoys uid.
Periodic acid Schiffs reaction [15] was used for demonstration of
polysaccharides. Total proteins were detected using the mercury
bromophenol blue method [16]. Nucleic acids (DNA & RNA) were
determined using Schiff-methylene blue method [17]. The mean
diameter of the seminiferous tubules and the height of the germinal
epithelia were determined using an ocular micrometer.
Biochemical analysis
Hormonal assays
The blood samples were obtained from the animals by heart
puncture. The serum level of testosterone was determined accord-
ing to Abraham [18], luteinizing hormone was detected according
to Jaffe and Behrman [19]. Total T3 and T4 were determined accord-
ing to Evered et al. [20] while TSH was detected according to
Ronnov-Jessen et al. [21] using radioimmunoassay kits produced
from Immunotech (Marseille, France) by Immulite analyzer.
Oxidative stress and antioxidant enzymes assays
For determination of oxidative stress and antioxidant enzymes
in the testes, supernatant obtained after centrifugation of testicular
tissue homogenates was used. Malondialdehyde was assayed as
described by Ohkawa et al. [22], superoxide dismutase activity was
determined according to the method of Rest and Spitznagel [23]
and catalase activity was determined using Aebi et al. [24] method.
Statistical analysis
The results were expressed as mean SD of different groups.
The differences between the mean value were evaluated by ANOVA
followed by Students t test using Minitab 12 computer program
(Minitab Inc., State Collage, PA).
Results
Change in body and testes weight
Data exist in Fig. 1 showed that daily treatment with carbima-
zole for 8 weeks caused signicant decrease in body and testes
weight of rats in comparison with control group. The daily adminis-
tration of carbimazole and selenium for 8 weeks caused signicant
increase in body and testes weight of rats in comparison with car-
bimazole group. When selenium was given to animals, insignicant
change in body and testes weight was recorded.
Morphometric results
Fig. 2 showed the morphometric changes in the diameter of the
seminiferous tubules and their epithelial heights. Treating rats with
selenium for 8 weeks caused insignicant increase in the diame-
ters of the seminiferous tubules compared with control group. Rats
daily treated with carbimazole for 4 and 8 weeks showed signif-
icant decrease (P < 0.05) in tubules diameters and their epithelial
heights. On the other hand, animals daily treated with carbima-
zole and selenium for 4 and 8 weeks showed highly signicant
increase (P < 0.001) in the diameter of seminiferous tubules and
their epithelial heights in comparison with carbimazole group.
Hormonal results
Testosterone hormone and luteinizing hormone
Treating animals with carbimazole for 4 and 8 weeks showed
signicant reduction (P < 0.05) in serum testosterone hormone and
luteinizing hormone in comparison with control group (Fig. 3).
Treatment with carbimazole and selenium for 4 and 8 weeks caused
signicant increase (P < 0.001) in serum testosterone and LH in
comparison with rats treated with carbimazole. There was insignif-
icant increase in levels of these hormones in sera of animals treated
with selenium for 4 and 8 weeks in comparison with control group.
Total T3 , T4 and TSH
Fig. 4 revealed that animals treated with carbimazole showed
signicant reduction (P < 0.05) in serum T3 , T4 and TSH hormones
after 8 weeks of treatment in comparison with control group. There
was insignicant change in T3 , T4 and TSH hormones in sera of ani-
mals daily treated with selenium for 8 weeks in comparison with
control group. On the other hand, treating animals with carbima-
zole and selenium for 8 weeks caused signicant increase in serum
T3 , T4 and TSH hormones in comparison with rats treated with
carbimazole.
Oxidative and antioxidant enzymes
Malondialdehyde
Data exist in Fig. 5 revealed that there was signicant (P < 0.05)
increase in the level of malondialdehyde in the testes homogenates
of animals daily treated with carbimazole for 4 and 8 weeks com-
pared with control group. Animals treated daily with carbimazole
and selenium showed decrease of the MDA level compared with
 S.A.R. Sakr et al. / Journal of Trace Elements in Medicine and Biology 25 (2011) 5966 61

Fig. 1. Effect of different treatments on (a) body weight and (b) testes weight. * Signicant at P < 0.05 in comparison with control group. ** Highly signicant at P < 0.001 in
comparison with carbimazole group.

Fig. 2. Effect of different treatments on (a) the diameter of seminiferous tubules and (b) the epithelial heights of seminiferous tubules.

Fig. 3. Effect of different treatments in serum level of (a) testosterone hormone (ng/ml) and (b) luteinizing hormone (mI/ml).

Fig. 4. Change in serum level of (a) total T3 hormone (ng/ml), (b) total T4 hormone (ng/ml) and (c) total TSH (LU/ml) in different treatments.
62 S.A.R. Sakr et al. / Journal of Trace Elements in Medicine and Biology 25 (2011) 5966
Fig. 5. Effect of different treatments on (a) testicular MDA (nmol/ml), (b) testicular catalase (mol/s/ml) and testicular SOD (/ml).
carbimazole group. No signicant change was recorded between
control and selenium-treated group.
The antioxidant enzymes (superoxide dismutase and catalase)
Animals treated with carbimazole for 4 and 8 weeks showed
decrease in the level of testes superoxide dismutase and catalase
enzymes compared with control group. Animals given carbima-
zole and selenium showed signicant increase in the level of SOD
and CAT compared with carbimazole group. No signicant change
was obtained in SOD and CAT levels in testes homogenates of rats
treated with selenium for 4 and 8 weeks (Fig. 5).
Histopathological results
Fig. 6 showed testis of control rat. Testes of rats administered
with carbimazole for 4 weeks showed many histopathologi-
cal changes. These changes included rupture of the intertubular
connective tissue, intertubular hemorrhage, degeneration of the
germinal epithelium and the presence of large spaces between
the spermatogenic cells (Fig. 7a). Some spermatogenic cells exhib-
ited apoptosis (Fig. 7b). These histopathological alterations were
increased in rats treated for 8 weeks with carbimazole. In these
specimens, the seminiferous tubules were reduced in their diame-
ters and appeared with wide lumens with few sperms. Moreover,
spermatogenic cells were degenerated and reduced in the num-
ber. The persist cells appeared with pyknotic nuclei (Fig. 8a). In
the same specimens, the Leydig cells were degenerated and blood
hemorrhage was common in the intertubular connective tissue.
Examination of testes of rats daily treated with carbimazole
and selenium for 8 weeks revealed less prominent histopathologi-
cal changes when compared with the same period of carbimazole
group. In these specimens, the seminiferous tubules restored their
Fig. 6. Section in the testis of a control rat showing seminiferous tubules. (A): type
A spermatogonia, (SP): primary spermatocytes, (SZ): spermatozoa, (IT): interstitial
tissue (H&E, 400).
normal-like shape and the number of spermatogenic cells increased
(Fig. 8b).
Histochemical results
Polysaccharides
Testis of control rat showed a strong PAS-positive material in
tunica albuginea as well as in the intertubular connective tissue.
The spermatogenic cells exhibited weak reaction while the sperms
showed strong reaction (Fig. 9a). Testes of carbimazole-treated
animals revealed gradual decrease of PAS-positive materials. This
decrease started after 4 weeks of treatment and reached its max-
imum after 8 weeks. In these specimens, tunica albuginea, the
boundaries of the seminiferous tubules as well as the intertubu-
lar connective tissue had a weak PAS-positive material (Fig. 9b).
Examination of testis of rats treated with carbimazole and selenium
showed a gradual increase of the polysaccharide content (Fig. 9c).
Total proteins
The total proteins appeared in the testicular tissues of control
rats as deeply stained granules inside the nuclei and cytoplasm
of all spermatogenic cells. The tunica albuginea, intertubular con-
nective tissue as well as the boundaries of seminiferous tubules
showed strong reaction (Fig. 10a). Animals treated with car-
bimazole showed a noticeable decrease in the protein content
of all the spermatogenic cells in both the nucleus and the cyto-
plasm (Fig. 10b). Treating animals with carbimazole and selenium
revealed that spermatogenic cells contained a somewhat normal
content of total protein (Fig. 10c).
Nucleic acids (DNA, RNA)
DNA present in the testis of control rat as granules of magenta
colour in the nuclei of all the spermatogenic cells. In addition, a
strong reaction was seen in the nuclei of Sertoli cells and the inter-
stitial cells. RNA was shown as blue ne granules in the cytoplasm
of all these cells (Fig. 11a). Marked loss of both RNA- and DNA-
containing particles was appeared after 8 weeks of the treatment
with carbimazole (Fig. 11b). Animals treated with carbimazole and
selenium showed an increase in RNA content in the cytoplasm
and the nuclei appeared with marked DNA-stainability and symp-
toms of regaining of a normal-like picture of nuclear structure was
observed (Fig. 11c).
Discussion
Our results indicated that carbimazole affected testis structure
and function in albino rats. Sera of rats treated with carbimazole
revealed a signicant decrease in T3 , T4 , TSH, testosterone and LH
level. Similarly, Upadhyaya et al. [25] noticed considerable reduc-
tion in T3 and T4 with trend towards the rise in plasma levels
of monoamine oxidase and histaminase in carbimazole-treated
 S.A.R. Sakr et al. / Journal of Trace Elements in Medicine and Biology 25 (2011) 5966 63

Fig. 7. Seminiferous tubules obtained from a rat treated with carbimazole for 4 weeks showing (a) rupture in the spermatogenic layer (arrow) and intertubular hemorrhage
(He) and (b) apoptotic cells (arrows), (H&E, 400).

Fig. 8. Seminiferous tubules of a rat (a) treated with carbimazole for 8 weeks showing marked degeneration of spermatogenic cells, intertubular hemorrhage (He) and
pyknotic nucleus (arrow) and (b) treated with carbimazole and selenium showing normal spermatogenic cells, (H&E, 400).

Fig. 9. Seminiferous tubules of (a) a control rat showing strong PAS-positive reaction, seminiferous tubules and boundaries tissue, (b) a rat treated with carbimazole for 8
weeks showing marked decrease of PAS-positive materials (arrow) and a rat daily treated with carbimazole and selenium for 8 weeks showing nearly normal content of
PAS-positive materials, (PAS, 400).

Fig. 10. Seminiferous tubules of (a) a control rat showing strong protein contents in all layers of spermatogenic cells, Leydig cells, and sperms head, (b) a rat treated with
carbimazole for 8 weeks showing marked decrease of total proteins and (c) a rat treated with carbimazole and selenium for 8 weeks showing improvement of protein
materials (bromophenol blue, 400)..
64 S.A.R. Sakr et al. / Journal of Trace Elements in Medicine and Biology 25 (2011) 5966
Fig. 11. Seminiferous tubules showing (a) normal content of RNA and DNA-containing particles in spermatogenic cells of a control rat, (b) reduction of RNA-containing particles
in cytoplasm of spermatogenic cells of an animal treated with carbimazole for 8 weeks, DNA particles are also reduced and (c) an increase of RNA and DNA-containing particles
in all spermatogenic cells of an animal treated with carbimazole and selenium for 8 weeks (Schiff-methylene reaction, 1000).
rats. Abbassy et al. [26] found that serum thyroxine, TSH and
thyrotropin-binding inhibitory immunoglobulins are decreased
after 2, 4 and 6 weeks of carbimazole treatment. Frenais et al. [27]
reported that carbimazole converts to the active agent methima-
zole which act on the thyroid to reduce production of the thyroid
hormones, T3 and T4 . Methimazole is rapidly absorbed from the
gastrointestinal tract and reaches a peak plasma level about an hour
after administration.
Treating rats with carbimazole caused reduction in body and
testes weight, and induced many histological alterations. The testis
showed reduction in the diameter of seminiferous tubules as well
as the germinal epithelial heights. The histological alterations
included congestion of blood vessels, hemorrhage, degeneration
of interstitial tissue and degeneration of spermatogenic cells with
apoptosis and necrosis. The effect of antithyroid drugs including
carbimazole on male reproductive system was studied in different
animals. Marty et al. [28] found that absolute testes, epididy-
mal, prostate and seminal vesicle weights were decreased by
6-propylthiouracil. Also, it signicantly decreased serum T4 level.
Maran and Aruldhas [29] reported that daily administration of
0.05% methimazole to the nursing mothers induced many changes
in newborn male rats; signicantly reduced seminiferous tubules
diameter, the proliferation and differentiation of germ cells were
arrested and their number were decreased. Also, the absolute
weight of testes, plasma testosterone, estradiol and sex hormone
binding globulin levels were signicantly decreased. Vijayakumar
and Nalini [30] reported that carbimazole administration of rat sig-
nicantly reduced T3 , T4 and testosterone levels. Hamouli-Said et
al. [31] reported that treatment of lactating mothers rats with 6-
propyl-2-thiouracil during 21 days was associated with reduction
in testes weight, diameter of seminiferous tubules, hormonal levels
and delay in maturation of germ cells of pups. Lee et al. [32] con-
cluded that hypothyroidism induced in prepubertal male rats by
interperitoneal injection of 10 mg/kg/day propylthiouracil for 30
days caused reduction in the total triiodothyronine and thyroxine
serum level.
Results obtained in the present work revealed that treating rat
with carbimazole caused reduction in polysaccharides, total pro-
teins and nucleic acids contents in tissue of testes. These results
are in agreement with that obtained by some investigators. Palmero
et al. [33] reported that oral administration of methimazole from
the day of birth of rats was characterized by a severe retardation
of body and testis growth and a net inhibition of the increase in
Sertoli cell gamma-glutamyl transpeptidase activity as well as in
androgen-binding protein and lactate production. These results are
consistent with the impairment of protein synthesis in Sertoli cells
from hypothyroid rats compared with control. Ram and Waxman
[34] concluded that treatment with the antithyroid drug methima-
zole led to a 7585% depletion of hepatic microsomal p450 reductase
activity and protein in both male and female rats. Szanto et al. [35]
concluded that propylthiouracil decreased both hepatic receptor-
related protein and low-density lipoprotein receptor expression in
rats. Meisami et al. [36] reported that testicular weight and DNA
content were markedly reduced in rat pups administered by propy-
lthiouracil. Mori [37] reported that carbimazole caused a signicant
decrease of the proliferation, nucleic acids and protein synthe-
sis of the thyroid follicular and adrenocortical cells. Krasilnikova
et al. [38] reported that hypothyroidism induced by mercazolil
decreased protein kinase C activity in both membrane and cytosol
as well as phospholipid and triacylglycerol synthesis in rat liver.
Examination of testes homogenates of animals treated with
carbimazole in the present study indicated a signicant reduc-
tion in the activities of the antioxidant enzymes (SOD and CAT)
and increase in malondialdehyde. In agreement with these results,
Vijayakumar and Nalini [30] indicated that superoxide dismutase,
catalase and glutathione peroxidase were reduced in erythrocytes
of rats treated with carbimazole compared with control animals.
Choudhury et al. [39] concluded that activities of superoxide dis-
mutase and catalase decreased in the post-mitochondrial fraction
of testes of hypothyroid rats. Sahoo et al. [40] found that feeding
lactating mothers and adult rats with 0.05% 6-n-propylthiouracil in
drinking water for 30 days or for 90 days from birth reduced tes-
ticular superoxide dismutase, catalase, and glutathione reductase
and glutathione peroxidase activities.
Excess levels of reactive oxygen and nitrogen species can attack
biological molecules such as DNA, protein and phospholipids which
led to increase of lipid peroxidation and depletion of the antiox-
idant enzymes (superoxide dismutase, catalase and glutathione
peroxidase) [41]. In the present work, a high lipid peroxidation
with a concomitant decrease in the enzymatic antioxidant status,
superoxide dismutase and catalase were recorded. Superoxide dis-
mutase and catalase are closely related to the direct elimination of
reactive oxygen. Therefore, the reduction in the activities of these
enzymes may result in a number of deleterious effects due to the
accumulation of superoxide radicals and hydrogen peroxide. Thus,
it is suggested that carbimazole-induced oxidative stress which
resulted in the testicular alterations observed in the present work.
Concerning the effect of selenium, the present study indicated
that selenium had a time dependant ameliorative effect against
the toxicity of carbimazole. Treating rats with carbimazole and
selenium revealed a histological, histochemical and biochemi-
cal improvement. Moreover, administration of selenium led to
decrease in malondialdehyde and increase in catalase and super-
oxide dismutase activities. This is in agreement with Joanta et al.
[42] who concluded that selenium and carbimazole had opposite
effects: selenium decreased blood lipid peroxides while carbima-
zole increased lipid peroxides from both thyroid gland and serum.
Also, catalase and superoxide dismutase activities in the thy-
roid gland increased in selenium-treated animals and decreased
under carbimazole administration. The protective effect of sele-
nium against toxicity of different drugs and chemicals was studied
by several investigators. Seema et al. [43] investigated the effect
 S.A.R. Sakr et al. / Journal of Trace Elements in Medicine and Biology 25 (2011) 5966
of exogenous selenium on the testicular toxicity induced by nico-
tine in rats. Administration of nicotine caused reduction in sperm
count and sperm motility. Activities of testicular enzymes 3beta
hydroxysteroid dehyrogenase and 17beta hydroxysteroid dehyro-
genase were decreased. Levels of testosterone in the serum were
also reduced. However, the extent of these alterations was lesser
in the group administered with nicotine along with selenium. In
the present work, selenium co-administration induced an increase
in LH and testosterone. The secretion of testosterone in the Ley-
dig cells is regulated by LH released from the pituitary gland. It is
suggested that selenium had a stimulating effect on LH or on the
biosynthesis of testosterone [44].
It was reported that selenium as a constituent of seleno-
proteins has structural and enzymatic role in male fertility.
Its biological function is expressed through biologically active
compounds including glutathione peroxidase (GSH-Px) and glu-
tathione S-transferase (GST) [45]. Moreover, selenium was found
to up-regulate the expression of Catsperm genes, a family of
sperm cation channels which play a major role in sperm motil-
ity and male fertility [46]. Jana et al. [47] reported that sodium
selenite supplementation signicantly protected against exercise-
induced testicular gametogenic and spermatogenic disorders,
prevented testicular oxidative stress and increased antioxidant
status. Grotto et al. [48] examined the possible antigenotoxic
effect of selenium in rats chronically exposed to low levels of
methylmercury. Selenium co-administration showed a signicant
reduction in methylmercury-induced genotoxicity, re-established
glutathione peroxidase activity and reduced DNA damage. Kara
et al. [49] reported that selenium protected rat testes against
cadmium-induced oxidative damage. On the contrary, Adesiyan
et al. [50] reported that selenium attenuated the toxic effects of
atrazine-induced liver change but had no protective effects against
biochemical alterations in testis and epididymis except testicular
lactate dehydrogenase.
Santos and Takahashi [51] concluded that selenium is effec-
tive in reducing the genetic damage induced by the antitumor
agent doxorubicin in vitro in human lymphocyte. The authors
added that the mechanism of chemoprotection of selenium may
be related to its antioxidant properties as well as its ability
to interfere with DNA repair pathways. Guttenplan et al. [52]
showed that the organoselenium compound, 1,4-phenylenebis
(methylene) selenocyanate inhibited 4-nitroquinoline-N-oxide (4-
NQO)-induced tongue tumorigenesis and DNA damage in the
tongue of Fisher rats.
Yu et al. [53] concluded that selenium (0.1 mg/kg Na2 SeO3 )
inhibited oxidative stress, apoptosis and cell cycle changes induced
by excess uoride in kidney of rats. Othman and El Missiry [54]
recorded that selenium administration before lead intoxication
produced pronounced prophylactic action against lead effects and
enhanced the endogenous antioxidant capacity of the cells by
increasing the activities of the superoxide dismutase, glutathione
reductase and the glutathione content. Also, lipid peroxidation was
decreased in both liver and kidney of male albino rats. Kashanian
et al. [55] reported that selenium diminished DNA damage induced
by incubation of calf thymus DNA with diazinon.
In conclusion, selenium treatment was observed to amelio-
rate the toxicity induced by carbimazole in testes of rats. This
effect of selenium may be attributed to its antioxidative effect,
hence it enhanced activities of the antioxidant enzymes (catalase
and superoxide dismutase) and reduced level of lipid peroxidation
(malondialdehyde).
References
[1] Vilchez FJ, Torres I, Garcia-Valero A, Lpez-Tinoco C, de Los Santos
A, Aguilar-Diosdado M. Concomitant a granulocytosis and hepatotoxic-
65
ity after treatment with carbimazole. Ann Pharmacother 2006;40(11):
205963.
[2] Marazuela M, De Paco GS, Jlmenez I, Carraro R, Fernandez-Herrera J, Pajares
JM, Gomez-Pan A. Acute pancreatitis, hepatic cholestasis and erythema
nodosum induced by carbimazole treatment for Graves disease. Endocrinol
J 2002;49(3):3158.
[3] Zaidi TM, Khan AA, Hasan BM, Faruqi AN. Carbimazole induced thyroid histopa-
thy in albino rats during development. J Anat Soc Ind 2004;53(2):147.
[4] Calanas-Continente A, Espinosa M, Manzano-Garca G, Santamara R, Lopez-
Rubio F, Aljama P. Necrotizing glomerulonephritis and pulmonary hemorrhage
associated with carbimazole therapy. Thyroid 2005;15(3):2868.
[5] Dotsch J, Rascher W, Dorr HG. Graves disease in child hood: a review of the
options for diagnosis and treatment. Paediatr Drugs 2003;5(2):95102.
[6] Bartel J, Bartz T, Wolf C, Charkiewicz E, Kuhbacher M, Pohl T, Kyriakopoulos
A. Activity of the glutathione peroxidase-2. Differences in the selenium-
dependant expression between colon and small intestine. Cancer Genomics
Proteomics 2007;4(5):36972.
[7] El-Tayeb A, liu A, Ganl Q, Liu H, Xu H. Antagonistic effect of scutellarin on the
toxicit of selenium in Rat liver. Biol Trace Elem Res 2004;98(3):2538.
[8] Grtner R. Selenium and thyroid hormone axis in critical ill states: an overview
of conicting view points. J Trace Elem Med Biol 2009;23(2):714.
[9] Thirunavukkarasu C, Sakthisekaran D. Sodium selenite, dietary micronutrient,
prevents the lymphocyte DNA damage induced by N-nitrosodiethylamine and
phenobarbital promoted experimental hepatocarcinogenesis. J Cell Biochem
2003;88(3):57888.
[10] Liao Y, Lu X, Lu C, Li G, Jin Y, Tang H. Selection of agents for prevention of
cisplatin-induced hepatotoxicity. Pharmacol Res 2008;57(2):12531.
[11] Jihen el H, Imed M, Fatima H, Abdelhamid K. Protective effects of selenium
(Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver and kidney of the rat:
histology and Cd accumulation. Food Chem Toxicol 2008;46(11):35227.
[12] El-Shenawy SM, Hassan NS. Comparative evaluation of the protective effect
of selenium and garlic against liver and kidney damage induced by mercury
chloride in the rats. Pharmacol Rep 2008;60(2):199208.
[13] Paget GE, Barnes JM. In: Laurence DR, Bacharach AL, editors. Toxicity tests
in evaluation of drug activities pharmacometries, 1. London and New York:
Academic press; 1964. p. 135.
[14] Swathy SS, Panicker S, Indira M. Effect of exogenous selenium on the testicular
toxicity induced by ethanol in rats. Ind J Physiol Pharmacol 2006;50(3):21524.
[15] Kiernan JA. Histological and histochemical methods, theory and practice. NY,
USA: Pergamon Press; 1981.
[16] Pearse AGE. Histochemistry, theoretical and applied, 2, 3rd ed. London:
Churchill Livingstone; 1972.
[17] Garvin AJ, Hall BJ, Brissie RM, Spicer SS. Cytochemical differentiation of
nucleic acids with Schiff-methylene blue sequence. J Histochem Cytochem
1976;24:58790.
[18] Abraham GE. Handbook of radioimmunoassay. New York: Marcel Dekker, Inc.;
1977.
[19] Jaffe BM, Behrman NR. Methods of hormone radio-immunoassay. New York:
Academic Press; 1974.
[20] Evered DC, Osrmton BC, Smith PA, Hail R, Bird T. Grades of hypothyroidism. Br
Med J 1973;1:65762.
[21] Ronnov-Jessen D, Skov L, Faber J. Sensitive serum thyrotrophin assay assessed
for efciency of screening hospital patients. Clin Chem 1988;34(4):7978.
[22] Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by
thiobaubituric acid reaction. Anal Biochem 1979;95:3518.
[23] Rest RF, Spitznagel JK. Subcellular distribution of superoxide dismutase in
human neutrophils. Inuence of myeoperoxide on the measurement of super-
oxide dismutase activity. Biochem J 1977;166(2):14553.
[24] Aebi H, Wyss SR, Scherze B, Skvaril F. Heterogenecity of erythrocyte catalase II.
Isolation and characterization of normal and variant erythrocyte catalase and
their subunit. Enzyme 1974;17(5):30718.
[25] Upadhyaya L, Agrawal JK, Dubey GP. Effect of l-thyroxine and carbimazole on
blood levels of biogenic amines in rat. Exp Clin Endocrinol 1993;101(5):30710.
[26] Abbassy AA, Kamel SS, Assaad SN, Eid WE. Ultrasonographic and doppler study
of the thyroid gland in Graves disease before and after treatment with antithy-
roid drugs. Endocrinol Pract 1997;3(4):22530.
[27] Frenais R, Burgaud S, Horspool LJ. Pharmacokinetics of controlled-release car-
bimazole tablets support once daily dosing in cats. J Vet Pharmacol Ther
2008;31(3):2139.
[28] Marty MS, Crissman JW, Carney EW. Evaluation of the male pubertal assays
ability to detect thyroid inhibitors and dopaminergic agents. Toxicol Sci
2001;60(1):6376.
[29] Maran RR, Aruldhas MM. Adverse effects of neonatal hypothyroidism on Wistar
rat spermatogenesis. Endocrinol Res 2002;28(3):14154.
[30] Vijayakumar RS, Nalini N. Efcacy of piperine, an alkaloidal constituent from
piper nigrum on erythrocyte antioxidant status in high fat diet and antithyroid
drug induced hyperlipidemic rats. Cell Biochem Funct 2006;24(6):4918.
[31] Hamouli-Said Z, Tahari F, Hamoudi F, Hadj-Bekkouche F. Comparative study of
the effects of pre and post natal administration of a thyroid drug on testicular
activity in adult rat. Folia Histochem Cytobiol 2007;45(Suppl. 1):S517.
[32] Lee E, Kim HJ, Im JY, Kim J, Park H, Ryu JY, Lee J, Shim KA, Jung KK, Han
SY, Lee BM, Kim SH, Kim HS. Hypothyroidism protects di(n-butyl) phthalate-
induced reproductive organs damage in Sprague-Dawley male rats. J Toxicol
Sci 2008;33(3):299306.
[33] Palmero S, de Marchis M, Gallo G, Fugassa E. Thyroid hormone affects the devel-
opment of Sertoli cell function in the rat. J Endocrinol 1989;123(1):10511.
66 S.A.R. Sakr et al. / Journal of Trace Elements in Medicine and Biology 25 (2011) 5966
[34] Ram PA, Waxman DJ. Thyroid hormone stimulation of NADPH P450 reductase
expression in liver and extrahepatic tissue. Regulation by multiple mecha-
nisms. J Biol Chem 1992;267(5):3294301.
[35] Szanto A, Balasubramaniam S, Roach PD, Nestel PJ. Modulation of the low
density lipoprotein receptor related protein and its relevance to chylomicron-
remnant metabolism. Biochem J 1992;288(Pt3):7914.
[36] Meisami E, Naja A, Timiras PS. Enhancement of seminiferous tubular growth
and spermatogenesis in testes of rats recovering from early hypothyroidism: a
quantitative study. Cell Tissue Res 1994;275(3):50311.
[37] Mori FI. Autoradiographic and karyometry studies on the effect of carbima-
zole on the thyroid and adrenal glands in male albino rat. Horm Metab Res
2000;14:203.
[38] Krasilnikova OA, Kavok NS, Babenko NA. Drug-induced and postnatal hypothy-
roidism impairs the accumulation of diacylglycerol in liver and liver cell plasma
membranes. BMC Physiol 2002;16:212.
[39] Choudhury S, Chainy GB, Mishro MM. Experimentally induced hypo- and
hyper-thyroidism inuence on the antioxidant defence system in adult rat
testis. Andrologia 2003;35(3):13140.
[40] Sahoo DK, Roy A, Bhanja S, Chainy GB. Hypothyroidism impairs antioxidant
defence system and testicular physiology during development and maturation.
Gen Comp Endocrinol 2008;156(1):6370.
[41] Sies H. Oxidative stress introductory remark. In: Siers H, editor. Oxidative stress.
London: Academic Press; 1985.
[42] Joanta AE, Clichici S, Filip A, Daicoviciu D. Iodide excess induces oxidative stress
in blood and in thyroid gland. In: Proc Physiol Soc. 2010.
[43] Seema P, Swathy SS, Indira M. Protective effect of selenium on nicotine-induced
testicular toxicity in rats. Biol Trace Elem Res 2007;120(13):2128.
[44] Behne D, Weiler H, Kyriakopoulos A. Effects of selenium deciency on testicular
morphology and function in rats. J Reprod Fertil 1996;106:2917.
[45] Sidhu M, Sharma M, Bhatia M, Awasthi YC, Nath R. Effect of chronic cadmium
exposure on glutathione S-transferase and glutathione peroxidase activities in
rhesus monkey: the role of selenium. Toxicology 1993;83:20313.
[46] Mohammadi S, Movahedin M, Mowla SJ. Up-regulation of CatSper genes family
by selenium. Reprod Biol Endocrinol 2009;7:12631.
[47] Jana K, Samanta PK, Manna I, Ghosh P, Singh N, Khetan RP, Ray BR. Protec-
tive effect of sodium selenite and zinc sulfate on intensive swimming-induced
testicular gamatogenic and steroidogenic disorders in mature male rats. Appl
Physiol Nutr Metab 2008;33(5):90314.
[48] Grotto D, Barcelos GR, Valentini J, Antunes LM, Angeli JP, Garcia SC, Barbosa Jr
F. Low levels of methylmercury induce DNA damage in rats: protective effects
of selenium. Arch Toxicol 2009;83(3):24954.
[49] Kara H, Cevik A, Konar V, Dayangac A, Yilmaz M. Protective effects of antioxi-
dants against cadmium-induced oxidative damage in rat testes. Biol Trace Elem
Res 2007;120(13):20511.
[50] Adesiyan AC, Oyejola TO, Abarikwu SO, Oyeyemi MO, Farombi EO. Selenium
provides protection to the liver but not the reproductive organs in an atrazine-
model of experimental toxicity Exp Toxicol Pathol, 2010. Jan 16 [Epub ahead
of print].
[51] Santos RA, Takahashi CS. Anticlastogenic and antigenotoxic effects of
selenomethionine on doxorubicin-induced damage in vitro in human lympho-
cytes. Food chem Toxicol 2008;46(2):6717.
[52] Guttenplan J, Chen KM, Khmelnitsky M, Kosinska W, Hennessy J, Bruggeman R,
Desai D, Amin S, Sun YW, Spratt TE, El-Bayoumy K. Effects of 1,4-phenylenebis
(methylene) selenocyanate on mutagenesis and p53 protein expression in
the tongue of lacI rats treated with 4-nitroquinoline-N-oxide. Mutat Res
2007;634(12):14655.
[53] Yu RA, Xia T, Wang AG, Chen XM. Effects of selenium and zinc on renal
oxidative stress and apoptosis induced by uoride in rats. Biomed Environ Sci
2006;19(6):43944.
[54] Othman AI, El Missiry MA. Role of selenium against lead toxicity in male rats. J
Biochem Mol Toxicol 1998;12(6):3459.
[55] Kashanian S, Gholivand MB, Ahmadi F, Ravan H. Interaction of diazinon with
DNA and the protective role of selenium in DNA damage. DNA Cell Biol
2008;27(6):325532.