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APPENDIX II-AK:
Shushila Patel, et al, Cypermethrin-Induced DNA Damage in Organs and Tissues of
the Mouse: Evidence from the Comet Assay, Mutation Research/Genetic Toxicology
and Environmental Mutagenesis, Volume 607, Issue 2, 5 September 2006,
Pages 176-183
This information was copied from:
doi:10.1016/j.mrgentox.2006.04.010
Copyright © 2006 Elsevier B.V. All rights reserved.
Cypermethrin-induced DNA damage in organs and tissues of the
mouse: Evidence from the comet assay
Sushila Patela, Alok K. Pandeya, Mahima Bajpayeea, Devendra Parmara and Alok Dhawan, a, ,
aDevelopmental
Toxicology Section, Predictive Toxicology Group, Industrial Toxicology Research
Centre, PO Box 80, M.G. Marg, Lucknow
226001, Uttar Pradesh, India
Received 25 October 2005; revised 13 February 2006; accepted 10
April 2006. Available online
Abstract
Cypermethrin is the most widely used Type II pyrethroid pesticide because of its high effectiveness
against target species and its low mammalian toxicity reported so far. It is a
fast-acting neurotoxin and is known to cause free radical-mediated tissue
damage.
The present study investigates the genotoxic effects of cypermethrin
in multiple organs (brain, kidney, liver, spleen) and tissues (bone marrow,
lymphocytes) of the mouse, using the alkaline comet assay. Male Swiss albino
mice were given 12.5, 25, 50, 100, 200 mg/kg BW of cypermethrin
intraperitoneally, daily for 5 consecutive days. A
statistically significant (p < 0.05) dose-dependent
increase in DNA damage was observed in all the organs assessed, as evident from
the comet-assay parameters, viz., Olive tail moment (OTM; arbitrary unit), tail
DNA (%) and tail length (μm). Brain showed
maximum DNA damage followed by spleen > kidney > bone
marrow > liver > lymphocytes, as evident by the OTM.
Our data demonstrate that cypermethrin
induces systemic genotoxicity in mammals as it causes
DNA damage in vital organs like brain, liver, kidney, apart from that in the hematopoietic system.
Keywords: Multiple-organ genotoxicity;
Swiss mice; Cypermethrin; DNA damage; Comet assay
Article Outline
1. Introduction
2.1. Materials
2.3. Single-cell
preparation from tissues
2.4. Single-cell
preparation from organs
2.5. Cell
count and viability assay
2.6. Single-cell
gel electrophoresis/comet assay
2.6.1. Preparation
of slides and lysis
2.6.2. Electrophoresis
and staining of slides
2.7. Scoring
of slides
2.8. Statistics
3. Results
4. Discussion
An increase in global food demand has resulted
in a significant increase in the use of pesticides in agriculture. This has
caused great concern among health and environmental scientists, since some of
these chemicals induce mutations (somatic as well as germ-line) in experimental
systems [1]. In humans, exposure to pesticides has been
associated with cancer [2].
Synthetic pyrethroid
pesticides account for over 30% of the global pesticide use [3]. Two distinct classes of pyrethroids
have been identified, based on different behavioral, neuropsychological and
biochemical profiles. Type I pyrethroids mainly cause hyper-excitation and fine tremors, while Type II pyrethroids possess a cyano-group
and produce a more complex syndrome, including clonic
seizures [4]. These compounds have gained popularity over organochlorine and organophosphate pesticides due to their
high effectiveness against target species [5], their relatively low mammalian toxicity [6] and rapid biodegradability [7]. Cypermethrin, the
alpha-cyano-3-phenoxybenzyl ester of 2,2-dimethyl-3-(2,2-dichlorovinyl)
cyclopropane carboxylic acid, is the most widely used
Type II pyrethroid pesticide. It is a composite
synthetic pyrethroid, a broad spectrum,
bio-degradable insecticide, and a fast-acting neurotoxin with good contact and
stomach action. It is used to control many pests, including moths, pests of
cotton, fruit, and vegetable crops. Consistent with its lipophilic
nature, cypermethrin has been found to accumulate in
body fat, skin, liver, kidneys, adrenal glands, ovaries, and brain [8].
Cypermethrin exerts its neurotoxic
effect through voltage-dependent sodium channel [9] and
integral protein ATPase in the neuronal membrane [10]. In
vitro and in vivo studies have also shown that it causes free
radical-mediated tissue damage in brain, liver [11] and erythrocytes [12].
Cypermethrin has been classified by the US Environmental
Protection Agency [13] (EPA, 1989) as a possible carcinogen. The
pesticide has been shown to induce chromosomal aberrations and micronucleus
formation in mouse bone marrow as well as in spleen [14] and [15]. It
also increases the frequency of sister chromatid
exchange in bone marrow cells of mice [16]. DNA
damage was observed in lymphocytes of workers occupationally exposed to
pesticides such as cypermethrin [17].
Conventional cytogenetic
techniques like the micronucleus assay, the chromosomal aberration test and the
sister chromatid exchange assay, assess genotoxicity in cells exhibiting mitotic activity, such as
those in the hematopoietic system. In spite of the
blood–organ barriers, several chemicals reach these organs and elicit their
toxic response including genotoxicity. However, the genotoxicity in organs cannot be assessed using
conventional cytogenetic techniques. Therefore, Tsuda et al. [18] devised a method to assess multi-organ genotoxicity in the mouse using alkaline comet assay. This
is a rapid and sensitive procedure to measure DNA lesions in any organ
regardless of its mitotic activity.
An attempt was, therefore, made in the present
study to examine the genotoxic effect of cypermethrin in major organs and tissues of mouse.
2.1. Materials
Technical grade cypermethrin
(purity 98.5%, CAS no.: 52315-07-8) was a gift from Aimco
Pesticides Ltd.,
2.2. Animals and treatment
Male Swiss albino mice (6-week-old,
20 ± 2 g) were obtained from the Industrial Toxicology Research
Centre (
The study design included seven groups of four
mice each caged separately, which were treated intraperitoneally,
daily for five consecutive days with 12.5, 25, 50, 100, 200 mg/kg BW dose
of cypermethrin as follows:
Group 1 (vehicle control)—corn oil
(10 ml/kg BW, 5 consecutive days).
Group 2 (positive control)—ethylmethane
sulfonate (100 mg/kg BW, 24 h before
sacrifice).
Groups 3–7 were given cypermethrin,
intraperitoneally and daily for 5 consecutive days
with an interval of 24 h between treatments. The last dose was given
6 h before sacrifice, as follows: Group 3, 12.5 mg/kg BW; Group 4,
25 mg/kg BW; Group 5, 50 mg/kg BW; Group 6, 100 mg/kg BW; Group
7, 200 mg/kg BW.
Animals were sacrificed by cervical dislocation
after withdrawing blood from the orbital sinus. Organs were taken out
immediately for isolation of single cells.
2.3. Single-cell preparation from tissues
Lymphocytes were isolated from whole blood using
Histopaque-1077 by the method of Boyum [20] with slight modifications. Briefly, 20 μl of blood was added to 1 ml RPMI-1640 (
Both the femurs were dissected out and cleaned
thoroughly to remove muscles and other tissue. Bone marrow cells were flushed
in 1 ml FBS using a syringe.
2.4. Single-cell preparation from organs
Preparation of a single-cell suspension from
organs was done according to the method of Tice et al. [21]. Briefly, 0.2 g
of each organ was placed in 1 ml chilled mincing solution (Hank's balanced
salt solution, with 20 mM EDTA and 10% DMSO) in
a petridish and chopped into pieces with a pair of
scissors. The pieces were allowed to settle and the supernatant containing the
single cells was taken.
2.5. Cell count and viability assay
Cells from organs and tissues were counted using
a hemocytometer and diluted with PBS to achieve a
concentration of 0.2 × 106 cells/ml. The viability of
cells isolated from liver, spleen, kidney and brain was checked by
5,6-carboxyflourescein dye [22], while trypan blue
was used for lymphocytes and bone marrow cells [23].
2.6. Single-cell gel electrophoresis/comet assay
2.6.1. Preparation of slides and lysis
Conventional slides (size
75 mm × 25 mm, Blue Label Scientifics Pvt. Ltd.,
2.6.2. Electrophoresis and staining of slides
Electrophoresis was carried out according to the
method of Singh et al. [24]. The slides were placed in a horizontal gel
electrophoresis tank (Life Technologies,
Each slide was stained with 75 μl EtBr (20 μg/ml) for 5 min and dipped in chilled distilled
water to wash off excess EtBr, and cover slip placed
over it. Slides were placed in a dark humidified chamber to prevent drying of
the gel. The slides were scored within 24 h.
2.7. Scoring of slides
Slides were scored using an image-analysis system
(Kinetic Imaging, Liverpool, UK) attached to a fluorescence microscope (Leica, Germany) equipped with appropriate filters (N2.1,
excitation wavelength of 515–560 nm and emission wavelength of
590 nm). The microscope was connected to a computer through a charge-coupled
device (CCD) camera to transport images to software (Komet
3.1) for analysis. The final magnification was 400×. The comet parameters
recorded were Olive tail moment (OTM, arbitrary units), tail DNA (%) and tail
length (migration of the DNA from the nucleus, μm).
Images from 50 cells (25 from each replicate slide) were analyzed.
2.8. Statistics
The data of comet parameters were tested for
homogeneity of variance and normality, and were found normally distributed. The
data were, therefore, analyzed by use of one-way analysis of variance (ANOVA).
In all cases p < 0.05 was considered significant compared
with the respective controls.
3. Results
Cell viability for all the samples was found to
be more than 90% in every experiment (data not shown).
A statistically significant (p < 0.05)
dose-dependent increase in DNA damage was observed in all organs and tissues of
mice exposed to cypermethrin, as was evident from an
increase in the Olive tail moment (arbitrary units; Table 1). A
similar pattern was observed for tail DNA (%) and tail length (μm) (Table 2 and Table 3).
However, no significant DNA damage was observed in the mice administered the
lowest dose of cypermethrin, i.e., 12.5 mg/kg BW
(Group-3) as was evident from the OTM values (Table 1).
Effect
of cypermethrin on nuclear DNA of various organs and
tissues in mice with respect to Olive tail moment (arbitrary units)
Groups |
Bone marrow |
Brain |
Kidney |
Liver |
Lymphocytes |
Spleen |
Controla |
3.28 ± 0.38 |
3.91 ± 0.38 |
3.20 ± 0.16 |
2.90 ± 0.18 |
3.23 ± 0.21 |
3.10 ± 0.15 |
|
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CYPb—12.5 mg/kg
BW |
3.93 ± 0.33ns |
9.41 ± 0.28ns |
3.58 ± 0.21ns |
3.05 ± 0.14ns |
3.66 ± 0.08ns |
3.86 ± 0.35 ns |
CYP—25 mg/kg
BW |
5.40 ± 0.09*** |
9.84 ± 1.64* |
6.45 ± 0.32*** |
4.25 ± 0.63* |
4.40 ± 0.16** |
6.15 ± 0.55*** |
CYP—50 mg/kg
BW |
6.13 ± 0.27*** |
11.24 ± 1.89* |
6.92 ± 0.43*** |
5.97 ± 0.29*** |
5.64 ± 0.10*** |
7.24 ± 0.21*** |
CYP—100 mg/kg
BW |
6.59 ± 0.22*** |
12.63 ± 1.21** |
7.32 ± 0.53*** |
7.18 ± 0.42*** |
5.84 ± 0.39*** |
9.20 ± 0.43*** |
CYP—200 mg/kg
BW |
7.52 ± 0.38*** |
23.45 ± 3.87*** |
13.65 ± 1.18*** |
11.21 ± .52*** |
8.62 ± 0.23*** |
11.31 ± 0.40*** |
|
||||||
|
22.08 ± 1.95*** |
29.75 ± 1.85*** |
24.09 ± 3.31*** |
23.76 ± 3.11*** |
19.15 ± 2.19*** |
27.20 ± 2.93*** |
Values
represent mean ± S.E. of four animals in each group. ns: not significant, *p < 0.05,
**p < 0.01, ***p < 0.001
when compared with control.
a Corn oil-vehicle
control (10 ml/kg BW).
b CYP—cypermethrin.
c
Effect
of cypermethrin on nuclear DNA of various organs and
tissues in mice with respect to tail DNA (%)
Groups |
Bone marrow |
Brain |
Kidney |
Liver |
Lymphocytes |
Spleen |
Controla |
9.97 ± 0.77 |
11.12 ± 0.47 |
10.16 ± 0.29 |
9.25 ± 0.68 |
10.44 ± 0.64 |
10.07 ± 0.40 |
|
||||||
CYPb—12.5 mg/kg
BW |
11.64 ± 0.76ns |
19.81 ± 0.33** |
11.26 ± 0.56ns |
9.86 ± 0.52ns |
11.45 ± 0.26ns |
12.01 ± 1.09ns |
CYP—25 mg/kg
BW |
14.55 ± 0.34*** |
21.61 ± 2.80** |
17.78 ± 0.57*** |
12.73 ± 2.14* |
14.51 ± 0.29*** |
17.42 ± 0.93*** |
CYP—50 mg/kg
BW |
16.25 ± 0.68*** |
22.01 ± 2.20** |
18.74 ± 1.64*** |
16.17 ± 0.59*** |
15.27 ± 1.27*** |
17.59 ± 1.39*** |
CYP—100 mg/kg
BW |
16.40 ± 0.69*** |
23.96 ± 1.74** |
18.86 ± 0.89*** |
17.25 ± 0.70*** |
17.26 ± 0.29*** |
19.32 ± 0.22*** |
CYP—200 mg/kg
BW |
19.37 ± 0.83*** |
34.53 ± 3.27*** |
27.08 ± 2.15*** |
20.98 ± 0.58*** |
21.68 ± 0.75*** |
23.22 ± 0.75*** |
|
||||||
|
33.65 ± 1.20*** |
42.95 ± 0.89*** |
37.33 ± 2.38*** |
37.51 ± 2.38*** |
36.63 ± 2.71*** |
37.40 ± 0.85*** |
Values
represent mean ± S.E. of four animals in each group. ns: not significant, *p < 0.05,
**p < 0.01, ***p < 0.001
when compared with control.
a Corn oil-vehicle
control (10 ml/kg BW).
b CYP—cypermethrin.
c
Effect
of cypermethrin on nuclear DNA of various organs and
tissues in mice with respect to tail length (μm)
Groups |
Bone marrow |
Brain |
Kidney |
Liver |
Lymphocytes |
Spleen |
Controla |
61.73 ± 7.70 |
72.06 ± 10.15 |
70.24 ± 9.53 |
67.33 ± 7.94 |
58.60 ± 5.14 |
63.01 ± 6.98 |
|
||||||
CYPb—12.5 mg/kg
BW |
97.28 ± 5.57** |
135.61 ± 16.23** |
83.96 ± 3.28ns |
92.67 ± 2.07** |
87.58 ± 0.46*** |
82.58 ± 4.16* |
CYP—25 mg/kg
BW |
109.71 ± 1.28*** |
138.67 ± 6.97*** |
111.52 ± 1.51*** |
104.80 ± 2.39*** |
90.37 ± 2.08*** |
109.53 ± 3.32*** |
CYP—50 mg/kg
BW |
113.50 ± 7.26*** |
164.43 ± 12.17*** |
124.95 ± 4.10*** |
137.46 ± 6.10*** |
97.94 ± 4.50*** |
107.44 ± 5.44*** |
CYP—100 mg/kg
BW |
122.45 ± 7.85*** |
175.25 ± 14.05*** |
140.92 ± 11.33*** |
147.05 ± 10.00*** |
121.72 ± 3.71*** |
146.95 ± 9.28*** |
CYP—200 mg/kg
BW |
123.03 ± 6.69*** |
182.15 ± 5.43*** |
145.22 ± 3.38*** |
191.72 ± 5.31*** |
145.05 ± 14.84*** |
141.66 ± 4.42*** |
|
||||||
|
186.12 ± 11.55*** |
195.93 ± 7.53*** |
183.92 ± 11.14*** |
191.72 ± 5.31*** |
85.05 ± 1.25*** |
205.85 ± 13.98*** |
Values
represent mean ± S.E. of four animals in each group. ns = not significant, *p < 0.05,
**p < 0.01, ***p < 0.001
when compared with control.
a Corn oil-vehicle
control (10 ml/kg BW).
b CYP—cypermethrin.
c
When OTM
values were compared at different doses, brain was found to exhibit the highest
level of DNA damage followed by
spleen > kidney > bone
marrow > liver > lymphocytes (Table 1 and Fig. 1). An almost similar pattern was observed for
tail DNA (%) and tail length (μm) (Table 2 and Table 3).
Fig. 1. Effect of cypermethrin
on percentage distribution of cells with respect to Olive tail moment in: (A)
Lymphocytes, (B) Bone marrow, (C) Brain, (D) Liver, (E) Spleen, and (F) Kidney.
The OTM data were further analyzed in terms of
percentage distribution of cells. With increasing dose of cypermethrin
a shift from less damaged cells in control (OTM category <2) to highly
damaged cells (OTM category >10) in all the organs was observed (Fig.
1).
4. Discussion
The molecular mechanisms of the genotoxicity of cypermethrin are
not yet elucidated and require further studies. Due to the hydrophobic nature
and small molecular size, cypermethrin passes through
the cell membrane and reaches the nucleus. It is suggested that within the
nucleus cypermethrin binds to DNA through the
reactive groups of its acid moiety, leading to destabilization as well as
unwinding of the DNA, which could be a possible mechanism for its genotoxicity [25]. Cypermethrin has
been shown to induce oxidative stress and generation of reactive oxygen species
(ROS) in experimental systems [11] and [26]. It has
been demonstrated that ROS may cause DNA damage, which could lead to
single-strand breaks and mutation [27].
Our data
clearly show that cypermethrin induces DNA strand
breaks in different organs and tissues of mice, with the brain showing the
highest level of damage. The results are consistent with our previous findings
where the insecticide caused DNA damage in brain ganglia of Drosophila melanogaster [28]. Cypermethrin induces free radical-mediated lipid peroxidation in rat brain [11]. This provides evidence that DNA damage
observed after cypermethrin exposure could be a
consequence of free radical attack to DNA.
Brain is one of the target organs of cypermethrin as it acts on the sodium channels and induces neurotoxicity [9]. It is
known that after absorption, pyrethroids rapidly
distribute through the body [29] and
readily enter the brain because of their high lipophilicity
and lack of exclusion by the multi-drug transporter glycoprotein [30] at the
blood–brain barrier. Previous studies from our laboratory have shown that deltamethrin, a Type II pyrethroid
belonging to the same group as cypermethrin, is
metabolized by cytochrome P450s in rat brain and has
a greater neurotoxic potential than the parent
compound [31], [32] and [33] and
probably does not get cleared from the brain due to the blood–brain barrier [34]. The
fact that metabolites of cypermethrin are generally
hydrophilic, which hampers their clearance from the brain due to the
blood–brain barrier, and the high metabolic activity and low DNA-repair
capacity in the brain [35] could
be the reason that the highest level of genotoxicity
was observed in the brain.
Cypermethrin-induced
DNA damage in other vital organs like liver and kidney. This
could be attributed to the fact that cypermethrin
exposure induces free radical-mediated tissue damage in rat liver and kidney [26].
An induction of DNA damage in the hematopoietic system, viz., spleen, bone marrow and
lymphocytes was observed in the present study, which is consistent with the
study of Bhunya and Pati [36] showing that cypermethrin
induces chromosomal aberrations and micronucleus formation in mouse bone
marrow. Amer et al. [15] have reported
an increased incidence of sister chromatid exchange
and chromosomal aberrations in mouse spleen cells after in vitro
exposure to cypermethrin. Their data were supported
by an epidemiological study showing DNA damage in human lymphocytes by use of the
comet assay [17]. These studies support the findings of the
present study where we have observed DNA damage in different tissues using the
comet assay.
The differences in DNA damage observed among the
organs in the present study could be explained by the fact that there is a
differential expression of basal levels of DNA repair genes in various tissues
of the mouse as shown by Tomascik-Cheeseman et al. [37] using DNA microarrays.
Moreover, the variation in constitutive expression of cytochrome
P450 across the various organs in mice has been demonstrated [38]. For example, CYP1A1 is shown to be maximally
expressed in spleen followed by liver and kidney. Thus, the fact that tissues
differ considerably in their capacity to biotransform
xenobiotics has important toxicological implications,
e.g., with respect to DNA damage formation.
The fact that cypermethrin
induces DNA damage in various organs and tissues of mice bears significance, as
cypermethrin exposure can lead to adverse effect on
humans via systemic genotoxicity. Differential DNA
damage as well as repair in various organs could lead to an increase in the
susceptibility towards disease and disorders.
Financial assistance from Council of Scientific
and Industrial Research,
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Corresponding author. Tel.: +91 522 2613786x320; fax: +91 522
2628227/2611547.
Mutation Research/Genetic Toxicology and
Environmental Mutagenesis |
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