|
Investigating the prenatal
exposure of hydro-alcoholic extract of ginger
on the function of Pituitary – Gonad axis
in male mature offspring rats
Nasim Zamani (1, 2)
Ebrahim Hosseini (3)
Mehrdad Modaresi (4)
Abdallah Ghasemi Pirbalouti (5)
(1) Department of Biology, College of Science,
Fars Science and Research, Branch, Islamic Azad
University, Fars, Iran
(2) Department of Biology, College of Science,
Shiraz Branch, Islamic Azad University, Shiraz,
Iran.
(3) Department of Biology, Shiraz Branch, Islamic
Azad University, Shiraz, Iran
(4) Department of animal science, Isfahan (Khorasgan)
Branch, Islamic Azad University, Isfahan, Iran
(5) Research Center for Medical Plants, Shahrekord
Branch, Islamic Azad University, Shahrekord,
Iran
Correspondence:
Ebrahim Hosseini
Department of Biology,
Shiraz Branch,
Islamic Azad University,
Shiraz, Iran
|
Abstract
Background and Objective: Ginger
has been used for a long time as a spice
in food as well as pharmaceutics in a
wide variety of diseases. Ginger has been
shown to prevent the nausea in pregnant
women. The aim of the present study was
to examine the effect of hydro-alcoholic
extract of ginger (HEG) on function of
pituitary – gonad axis in mature
male rats exposed to HEG in the prenatal
period.
Method:
In this experimental study, 40 pregnant
female rats were divided into four groups.
Groups contained control, placebo (daily
received 0.5 ml normal saline), and treatment
groups receiving 50 mg/kg and 100 mg/kg
of HEG in pregnancy period. At the end
of the infancy period, males of groups
were separated and 10 rats out of each
group were randomly chosen in maturity.
Upon the time of
maturity of chosen male rats, blood samples
were drawn for measurement of the levels
of sex hormones in male rats. Also the
number of Leydig, Sertoli, spermatogonia,
spermatocytes and spermatide cells were
counted.
Results:
Administration of HEG in groups received
50mg/kg and 100 mg/kg which resulted in
a significant increase in concentration
of testosterone, LH and FSH hormones in
male progenies. HEG administration also
significantly increased the number of
Leydig and Sertoli cells, spermatogonia,
spermatocytes and spermatid.
Conclusion:
With regard to the results of this research,
consumption of HEG in the perinatal period
results in increase in function of Pituitary
– Gonad axis in born male adult rats.
Key words: Ginger;
testosterone; Luteinizing Hormone; Follicle
Stimulator Hormone; Spermatocyte,
|
Despite many achievements in modern medicine,
the main problem is still the usage of synthetic
chemical drugs for the treatment of diseases
causing serious side effects in patients receiving
them (1). Nowadays traditional medicine has
been revisited as the use of herbal medicine
is markedly increasing due to it possessing
lower side effects (2). So the current approach
is to apply herbal medicine to obtain a high
standard of therapy for the treatment of myriad
diseases with minimum side/adverse effects.
Ginger (Zingiber officinale) belongs to the
Zingeber Aceae family. As spice, ginger has
been used in the diet and pharmaceutical components.
Historically medicine has shown that ginger
has been widely used in China, Japan and India
for the treatment of nausea and vomiting in
women during pregnancy (3).
The ingredients of ginger contain water, protein,
fat, minerals (including iron, calcium and phosphorus),
vitamins (such as thiamine, riboflavin, niacin
and vitamin C), fiber and carbohydrate. These
compounds may be different as a result of variation
in agricultural, drying and storage conditions.
In the rhizome of fresh ginger, gingerols are
the main components. Special aroma and the taste
of ginger come from the mixture of gingerols,
shogaol and zynjerun which are found in ginger
(4 and 5).
Until now, more than 50 types of antioxidants
have been isolated from the rhizome of ginger.
Gingerols are the most important components
of ginger that have significant antioxidant
properties. In addition, they have a high antioxidant
activity due to containing vitamins such as
A, B, C and E as well as flavonoids and glutathione
(6). Ginger has a wide variety of pharmaceutical
properties to treat many health problems over
the years, including stomach ache and intestinal
problems. Because of possessing cholinergic
and anti-histamine properties, ginger has desirable
effects on reducing the nausea and vomiting
in women during pregnancy (7). Ginger is able
to stimulate blood circulation, increase cell
activity and metabolism. It also can have anti-cancer
property because of antioxidant activity and
ability in inactivating the effective factors
on carcinogenesis (8). Regular intake of ginger
in the dietary regimen can improve the activity
of heart and circulation system (9). Ginger
causes a significant decrease in the physical
signs of initial dysmenorrhoea (10). Studies
indicate that the extract of ginger stimulates
menstruation, eliminates the irregularities
in the menstruation cycle, increases spermatogenesis
and enhances sperm fertility factors (11, 12).
Furthermore, ginger is used to treat fever,
rheumatism, neuronal diseases, gingivitis, tooth
pain, asthma and coughing (13).
There are many concerns about using chemical
drugs in women during pregnancy for the nausea
and vomiting owing to possible deformities in
fetus. Hence, using herbal components paves
the way for alternative treatment in pregnant
women. Based on the above evidence, having less
side effects for ginger usage has opened a new
horizon to treat such complications in women
during pregnancy (14).
Research has shown that ginger increases spermatogenesis
and effectiveness of sperm fertility parameters.
Regarding high prevalence of men’s infertility
in the world which is resulting from the production
of damaged sperm and malfunction of the cells
responsible for spermatogenesis, there is a
need for an alternative therapy for the treatment
of infertility due to the high cost of therapeutic
agents and severe side effects. Several lines
of evidence suggest ginger has a beneficial
role in spermatogenesis and sperm parameters
because of the antioxidant properties of ginger.
In light of the effectiveness of ginger on spermatogenesis,
the present study was established to examine
the effect of prenatal exposure to HEG on pituitary
– gonad axis hormones and spermatozoa of
young adult male rats.
In this study, 40 Wistar adult female rats
weighing between 200-220 gr were grouped into
4 groups (10 per group) including control, placebo
and two treatment groups. In addition, 8 Wistar
adult male rats were used for crossbreeding.
Rats were kept in Animal House of Azad Islamic
University of Falavarjan in a 12 hour light/12
hour dark cycle in 25 ° c and relative humidity
ranging from 40-60% in order to be acclimatized
in their new place. Also, water and food were
provided ad libitum.
To prepare the HEG, the rhizome of ginger was
obtained from the Agricultural Research Center
of Isfahan. For this purpose, fresh and intact
plants were used. Then herbarium no.128/3/001/001
was approved by the plant specialists of Islamic
Azad University of Falavarjan. After that, ginger
rhizome was dried and then ground and finally
the resulting powder was extracted by maceration.
Before crossbreeding the female rats with males,
in order to synchronize the menstrual cycles
of female rats, 100 mg estradiol valerate was
dissolved into 0.2 ml olive oil and then was
injected into the rat muscles using insulin
syringes. After 42 hours of the first injection
50 mg of progesterone was injected into the
muscles of rats. After 6 hours of the second
injection, a vaginal smear was obtained from
the rats. Marcondes’ method was used for
recognizing the steps of estrous cycle. In this
method, each step of the cycle is recognized
based on the proportion among three cell populations
including epithelial, horny and leukocytes observed
in the vaginal smear (15).
Microscopic observations showed that synchronizing
the cycle of rats had occurred in the estrous
s step. Then, for crossbreeding, 8 adult male
rats were co-caged with female rats (16). Upon
observing sperm in vaginal smears the day 0
of pregnancy was defined. During pregnancy for
two treatment groups 50 mg/kg and 100 mg /kg
HEG were intraperitoneally injected every day.
The control group received no treatment. The
placebo group daily
received 0.5ml normal saline. At the end of the
infancy period, male and female offspring were
separated and kept without any treatment for up
to 2 months. Then, 10 male rats of each four groups
were randomly selected for analysis of hormones.
To do that, blood was obtained from their hearts
after being anesthetized. Blood samples were centrifuged
at 300 rpm for 5 minutes and kept in -20°
C until usage.
The levels of FSH, and LH hormones were measured
by electro-chemiluminesence luminescence method
(ECL) and the levels of testosterone hormones
were measured by enzyme linked immunosorbent
assay (ELISA). Kits used for measuring FSH and
LH were purchased from (Cusabio, USA) and one
for testosterone with mark IBL, GmbH made in
Germany, respectively.
In order to count the number of sexual dynastic
cells, at first, right testicles of male rats
were removed and placed in a 10% solution of
formalin. Soon after, dehydration by ethanol,
clearing by xylenol alcohol and tissue embedding
were done. Next, using Rotary Microtome (LEIYZ
Australian model 1512) 5 micron thickness tissue
sections were provided. Then, the obtained sections
were stained by hematoxylin and eosin. The number
of Leydig, Sertoli, spermatogonia, spermatocytes
and spermatide cells were counted using light
microscopy. Finally, data were analyzed by SPSS
software by one-way analysis of variance (ANOVA)
and Tukey HSD test. Significance level was considered
if p value was less than 0.05.
Results
obtained
from
data
analysis
showed
that
there
wasn’t
any
significant
difference
between
serum
mean
of
LH,
FSH
and
testosterone
hormones
and
sex
lineage
cells,
while
HEG
in
both
used
doses
resulted
in
significant
increase
in
serum
mean
of
LH
and
testosterone
hormones
and
also
in
serum
mean
of
FSH
hormones
in
P0.01
in
the
groups
receiving
a
high
dose
of
HEG
(Table
1).
In
addition,
results
obtained
from
counting
lineage
cells
showed
that
administration
of
HEG
in
both
doses
resulted
in
significant
increase
in
the
number
of
Leydig,
spermatogonia,
Sertoli,
spermatocytes
and
spermatide
cells
in
these
groups
in
comparison
to
controls
in
P0.01
level
(Table
2
and
Figure
1).
Click
here
for
Table
1.
Comparison
of
the
mean
serum
level
of
LH,
FSH
hormones
and
testosterone
in
the
groups
treated
with
HEG
Clock
here
for
Table
2:
the
number
of
lineage
sex
cells
in
the
groups
treated
with
HEG
in
comparison
to
control
Click
here
for
Figure
1:
Light
photomicrograph
of
thyroid
tissue
in
group
1(control),
Placebo
group
(2)
(3)
group
received
the
extract
of
HEG
with
dose
50
mg/kg
(4)
group
received
HEG
with
dose
100
mg/kg
H
&
E
was
used
for
staining
the
tissues.
Results
of
this
study
showed
that
administration
of
HEG
in
both
doses
resulted
in
significant
increase
in
the
levels
of
testosterone,
LH
and
FSH
hormones.
HEG
also
increased
the
number
of
germ
cell
lineage.
In
view
of
increase
in
number
of
Leydig,
spermatogonia,
spermatocytes
and
spermatid
cells
along
with
increase
in
testosterone
hormone,
it
seems
that
testosterone
hormone
plays
an
important
role
in
division
of
Gametes,
nourishing
the
dividing
gametes.
HEG
could
have
a
beneficial
role
in
sperm
through
direct
effect
on
Sertoli
cells
and
excretion
of
tube
fluid
and
various
proteins
including
growth
factor
and
transferrin
(17).
Subsequently,
given
the
important
role
of
testosterone
in
spermatogenesis,
it
is
obvious
that
increasing
the
levels
of
this
hormone
could
increase
the
number
of
sperm.
Our
findings
show
a
significant
increase
in
the
count
of
sperm
after
treatment
with
ginger.
In
similar
studies,
the
concentration
of
testosterone
and
LH
in
groups
receiving
ginger
extract
was
significantly
increased
in
comparison
to
controls.
Since
the
testosterone
is
an
androgenic
hormone
produced
by
Leydig
cells
which
belong
to
testis
stimulated
by
the
excretion
LH
from
pituitary
gland,
it
would
be
plausible
that
the
mechanism
underlying
this
phenomenon
might
be
due
to
the
direct
effect
of
HEG
on
luteotropic
cells
of
anterior
pituitary
increased
levels
of
LH(
17).
Ginger
has
many
types
of
antioxidants.
Among
these
compounds,
gingerols
are
of
note.
Gingerols
possess
anti-oxidant,
anti-serotonergic
and
anti-inflammatory
properties.
(18)
In
line
with
the
results
of
this
study,
Khaki
et
al
in
an
experimental
study
have
shown
that
ginger
can
increase
the
number
of
sperm
and
their
motility
which
may
be
attributed
to
gingerols
and
shogaol.
They
stimulate
the
androgens
especially
the
testosterone
(19).
In
addition
to
the
above
properties,
ginger
has
a
high
anti-oxidant
activity
because
of
the
vitamins
including
vitamin
A,
B,
C
and
E
also
flavonoids
and
glutathione
(18).
Vitamin
E
is
considered
as
a
strong
non-enzyme
antioxidant
which
can
inhibit
the
peroxidation
lipids
of
the
cell
membrane
through
scavenging
the
free
radicals
(20).
In
the
male
genital
system,
the
antioxidant
activity
of
vitamins
has
been
reported
and
is
thought
to
be
a
result
of
inhibition
the
destructive
effects
of
free
radicals
in
the
testis
(21)
and
sperm
(22
and
23).
Moreover,
vitamin
E
can
strengthen
the
antioxidant
defense
system
of
testis
and
sperm
cells
(24).
Studies
have
shown
that
ROS
are
produced
by
two
different
sources
in
sperm
fluid
containing
damaged
spermatozoa
cells
and
active
white
blood
cells
whereby
a
high
amount
of
them
results
in
male
infertility
through
breakage
in
the
DNA
structure,
decrease
in
live
sperm
percentage
and
dissociation
of
sperm
from
ovule
surface
(25
and
26).
These
compounds
increase
the
amount
of
malone-di-aldehyde.
Malone-di-aldehyde
leads
to
distortion
in
distribution
of
lipid
in
cell
membrane
through
penetration
of
the
structure
of
cell
membrane.
Furthermore,
ROS
can
cause
chromosome
disintegration
by
intercalating
into
the
DNA.
Vitamin
E
can
make
a
breakage
between
two
peroxide
lipid
bonds
thereby
the
inhibition
producing
free
radical
(27).
Another
crucial
vitamin
in
ginger
is
vitamin
C
that
acts
as
a
neutralizing
antioxidant
scavenging
the
free
radicals
produced
by
ROS.
It
has
been
demonstrated
that
it
would
facilitate
the
entrance
of
other
antioxidants
such
as
vitamin
E
and
uric
acid
to
the
cycle
(28).
Glutathione
peroxidase
(GPx)
enzyme
plays
an
important
role
in
protecting
the
sperm
and
epididymis
in
which
the
reduction
of
GPx
results
in
infertility.
Extract
of
ginger
increases
the
activity
and
expression
of
GPx
enzyme
cells
of
liver,
kidney,
breast,
testis,
etc.
Studies
show
that
antioxidant
enzymes
including
GPx
and
superoxide
dismutase
protect
the
cell
through
hindrance
of
the
formation
of
the
peroxide
and
oxidative
reactions.
(29)
Therefore,
GPx
prevents
the
deleterious
effects
of
DNA
breakage
consequences
in
the
sperm
and
sperm-producing
cells.
It
also
protects
the
sperm
nuclei
and
epididyme
fluid
against
free
radicals,
resulting
in
correct
maturation
of
sperm.
Consistent
with
these
results,
Mohammadi
et
al
studied
the
effect
of
ginger
on
testicles
of
rats
by
treating
the
cells
with
Cyclophosphamide.
They
found
that
ginger
had
protective
effect
on
the
testis
of
rats
because
of
high
antioxidant
content
(30).
In
a
study
conducted
by
Hafez
in
Greece
on
the
effect
of
a
ginger
and
cinnamon
combination
on
infertile
diabetic
rats,
a
significant
increase
was
observed
in
sperm
parameters
and
reproductive
behavior
in
terms
of
sperm
parameters
including
count,
motility
and
viability
(31).
Another
study
was
conducted
by
Abo-Ghanema
et
al
using
the
combination
of
ginger
and
L-carnitine
to
treat
infertile
rats.
The
authors
showed
that
this
combination
increased
the
weight
of
testicles
and
seminal
vesicles,
improved
the
quality
and
quantity
of
semen
(32).
Selenium
is
another
antioxidant
found
in
ginger.
Selenium
is
a
quasi-metal
micro-nutrient
which
is
requisite
for
the
dietary
regimen
of
mammals
found
in
plant
and
animal
products.
Various
reports
of
research
implies
that
the
positive
effect
of
selenium
on
male
health
is
by
reducing
the
signs
and
symptoms
of
diseases
such
as
infertility,
viral
infections,
cancer
and
cardiovascular
diseases.
Selenium
is
an
essential
antioxidant
for
spermatogenesis
and
male
fertility
(33,
34).
Investigation
carried
out
in
this
regard
showed
that
selenium
stimulates
the
motility
of
sperm
(35).
Tantalizing
evidence
suggests
a
key
role
for
oxidative
stress
in
the
development
of
infertility
in
men
implying
that
further
studies
are
warranted
to
unravel
the
role
of
oxidative
stress
in
the
progression
of
male
infertility
(36).
Regarding
the
protective
role
of
ginger
on
sperm
through
antioxidant
properties
and
deleterious
effects
of
oxidative
agents
on
them,
it
is
suggested
that
antioxidants
found
in
ginger
could
be
used
as
a
potential
therapeutic
agent
for
the
treatment
and
alleviation
of
infertility
in
men.
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