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Guang
Jia, Lei Yan, Jian-Ling Wang, Department of Occupational and
Environmental Health Sciences, School of Public Health, Peking
University, Beijing 100083, China
Yi-Qun Gu, Department of Pathology, Hepingli Hospital,
Beijing 100013, China
Kung-Tung Chen, Department of General Education, Ming-hsin
University of Science and Technology, Taiwan, China
You-Yong Lu, School of Oncology, Peking University, Beijing
100034, China
Ya-Ping Su, J. C. Gaston Wu, Department of Chemistry,
National Taiwan Normal University, Taiwan, China
Correspondence to: Dr. Guang Jia, Department of Occupational
and Environmental Health Sciences, School of Public Health, Peking
University, 38 Xue Yuan Road, Beijing 100083, China.
jiaguangjia@yahoo.com.cn
Telephone: +86-10-82801523
Fax: +86-10-62015583
Received: 2003-07-04
Accepted: 2003-07-24
Abstract
AIM: To better clarify the main target organs of dimethylarsinic
acid toxicity and the role of metallothionein (MTs) in modifying
dimethylarsinic acid (DMAA) toxicity.
METHODS:
MT-I/II null (MT-/-) mice and the corresponding wild-type
mice (MT+/+), six in each group, were exposed to DMAA
(0-750 mg/kg body weight) by a single oral injection. Twenty four
hours later, the lungs, livers and kidneys were collected and
undergone pathological analysis, induction of apoptotic cells as
determined by TUNEL and MT concentration was detected by
radio-immunoassay.
RESULTS:
Remarkable pathological lesions were observed at the doses ranging
from 350 to 750 mg/kg body weight in the lungs, livers and kidneys
and MT+/+ mice exhibited a relatively slight destruction
when compared with that in dose matched MT-/- mice. The
number of apoptotic cells was increased in a dose dependent manner
in the lungs and livers in both types of mice. DMAA produced more
necrotic cells rather than apoptotic cells at the highest dose of
750 mg/kg, however, no significant increase was observed in the
kidney. Hepatic MT level in MT+/+ mice was significantly
increased by DMAA in a dose-dependent manner and there was no
detectable amount of hepatic MT in untreated MT-/- mice.
CONCLUSION:
DMAA treatment can lead to the induction of apoptosis and
pathological damage in both types of mice. MT exhibits a protective
effect against DMAA toxicity.
Jia
G, Gu YQ, Chen KT, Lu YY, Yan L, Wang JL, Su YP, Wu JCG. Protective
role of metallothionein (I/II) against pathological damage and
apoptosis induced by dimethylarsinic acid. World J Gastroenterol
2003; 10(1): 91-95
http://www.wjgnet.com/1007-9327/10/91.asp
INTRODUCTION
Arsenic is a metalloid that naturally occurs in soil, water, and
air. Arsenicals are also non-biodegradable by-products during
production of copper, lead, and other ores and coal consumption.
Exposure to arsenic by food, drinking water, soil and air containing
arsenic is widely existed in the world. Inorganic arsenicals are
well known human carcinogens, specifically for the lung, liver,
kidney, skin, bladder and other internal organs[1,2].
Dimethylarsinic acid (DMAA) is a major form of organic arsenic in
the environment and the main metabolite of ingested inorganic
arsenicals in most mammals, including humans[2-4]. DMAA
itself can be used as herbicide and pesticide and also naturally
exists in some seafood. Recent studies have revealed that DMAA is a
genotoxic, multi-site promoter of carcinogenesis as well as a
complete carcinogen in rodents[5-7], which provides a
novel clue to investigate the mechanism of arsenicals in
carcinogenesis.
Arsenicals, including DMAA, are moderately effective inducers
of MT in mice and rats[8,9]. MTs, thiol-rich metal
binding proteins, have been shown to be easily induced by oxidative
stress and heavy metals and play an important role in homeostasis of
essential metals, detoxication of heavy metals, scavenging reactive
oxygen intermediates and preventing carcinogenesis as an endogenous
defensive factor[10-15]. Especially to be mentioned, its
capacity of scavenging hydroxyl and superoxide radicals is much more
efficient than GSH, an established antioxidant[15]. Among
the four major isoforms of identified MTs, MT-I and MT-II existing
in all tissues examined, are the predominant forms in the livers.
Recently Liu et al[16] reported that MT-I/II null
mice were more sensitive than wild type mice to hepatotoxic and
nephrotoxic effects of oral or injected inorganic arsenicals.
Sakurai et al[17] reported that DMAA could induce
apoptosis by reducing glutathione(GSH) in vitro. However, the
effect of MT on induction of apoptosis and the main organic toxicity
by DMAA in vivo remain elusive.
MT-I/II null (MT-/-) mice have been proved to be a
good tool for studying MT’s normal function and the consequences
of its deficiency[18]. In the present study, MT-I/II null
(MT-/-) mice and the corresponding wild-type mice (MT+/+)
were exposed to DMAA by oral injection, we investigated the
pathological lesions and apoptosis in main target organs including
the liver, lung and kidney of the mice, to elucidate the toxicity of
DMAA and the ability of MT to modify DMAA toxicity.
MATERIALS
AND METHODS
Chemicals
Dimethylarsinic
acid (purity 100 %) was purchased from Wako Pure Chemical Co.
(Osaka, Japan). An in situ apoptosis detection kit (ApopTagTM) was
purchased from Intergen Co. NY, USA.
Animals
and treatment
MT null (MT-/-) mice whose MT-I and II genes had null
mutation and wild type (MT+/+) mice provided kindly by
Dr. A. Choo (Murdoch Institute for Research into Birth Defects,
Royal Children’s Hospital, Australia), were of a mixed genetic
background of 129 Ola and C57BL/6 strains. F1 hybrid mice were mated
with C57BL/6 mice, and their offsprings were back-crossed to C57BL/6
for six generations. MT-/- and MT+/+ mice were
obtained by mating of those heterozygous (MT-/+) mice.
MT-/- and MT+/+ mice were routinely
bred in the vivarium of the National Institute for Environmental
Studies (NIES, Japan). Microbiological and viral examinations were
performed with regular quarantine procedures for more than one year,
and we did not find either pathogenic infections or significant
phenotypical abnormalities. Both strains of mice were housed in
cages in ventilated animal rooms with a controlled temperature of 23±1 °C, a relative
humidity of 55±10%,
and a 12 h light/dark cycle. They were maintained on standard
laboratory chow and tap water ad lib, and received humane care
throughout the experiment according to the guidelines of the NIES.
Eight-week-old female MT-/- and MT+/+ mice
were assigned randomly in equal numbers to all groups (six mice for
each treatment group). Fresh DMAA solution was prepared by
dissolving it in sterilized water. The mice were administered DMAA
(0-750 mg/kg) by oral gavage.
Sample
collection
At 24 h after administration of DMAA, the lung, liver and
kidney were collected from each mouse under diethyl ether
anesthesia. Portions of tissues were fixed in 10% neutral formalin,
processed by the standard histological techniques, and stained with
hematoxylin and eosin for light microscopic examination. For TUNEL
staining, sections (5 mm)
were placed on poly-L-lysine precoated slides.
TUNEL
for apoptosis
Apoptotic cells were detected with an apoptosis detection
kit according to the manufacturer’s instructions. Briefly, the
samples were incubated with digoxigenin-labeled dNTP in the presence
of terminal deoxynucleotidyl transferase followed by peroxidase-conjugated
anti-digoxigenin antibody. Nuclear staining of apoptotic cells was
detected with 3', 3'-diaminobenzidine followed by counterstaining of
nuclei with methyl green. An apoptosis index (AI) was obtained by
dividing the number of positive cells in the area observed[19].
MT
Concentration
MT (MT-I and MT-II isoforms) concentration in the liver was
measured by radioimmunoassay using sheep anti-rat MT-I antiserum[20].
The detection limit of this method was 0.2 mg
MT/g of tissue.
Statistical analysis
ANOVA with subsequent post hoc’s test was used as
appropriate. All values were expressed as ±SD. Differences were considered
significant at P<0.05.
RESULTS
Histopathological observation
In untreated MT-/- mice and the corresponding MT+/+
mice, the lung, liver and kidney showed normal morphology.
Significant lesions were observed at doses of DMAA ranging from 375
to 750 mg/kg body weight in both types of mice. However, the
pathological lesions in MT-/-mice were more severely
widespread when compared to that in dose matched MT+/+
mice.
Changes including congestion, atelectasis and mild to
moderate hemorrhages in the alveoli of the lungs were observed in MT-/-
mice. Adequate air space in the alveoli was observed more frequent
in MT+/+ mice compared to that of MT-/- mice.
Pulmonary capillary congestion could affect alveolar space,
resulting in severe acute impairment of respiratory function.
Capillary rupture led to leakage of red blood cells into the
interstitium, as well as into the alveoli (Figure 1).
Figure
1 Typical HE
staining. The bar is 100 mm.
A, B:
the lungs from control of MT-/-and MT+/+ mice;
C, D:
the lungs from 750 mg/kg DMAA group of MT-/-and MT+/+
mice. Arrows indicate atelectasis and hemorrhage.
At 24 h after DMAA treatment, severe liver damages
characterized by cellular cloudy swelling, paleness of cell
cytoplasm, vacuolization of hepatocytes and a few areas of focal
necrosis were found in MT-/- mice while a limited degree
of changes was observed in dose matched MT+/+ mice livers
(Figure 2).
Figure
2 Typical HE
staining. The bar is 100 mm.
A, B:
the livers from control of MT-/-and MT+/+
mice; C, D:
the livers from 750 mg/kg DMAA group of MT-/-and MT+/+
mice. The arrows indicate necrosis.
Histological changes in the kidney are shown in Figure 3.
Treatment with DMAA produced swelling of glomerulus and its
surrounding tubular tissue and urinary space compression in both
types of mice.
Figure
3 Typical HE
staining. The bar is 100 mm.
A, B:
the kidneys from control of MT-/-and MT+/+
mice; C, D:
the kidneys from 750 mg/kg DMAA group of MT-/-and MT+/+
mice. The arrows indicate the swelling of glomerulus and the
surrounding tubular tissue and urinary space compression.
Figure 4(PDF)
Apoptosis in lungs of MT+/+ and MT-/-
mice detected by TUNEL twenty-four hours after oral DMAA treatment. A:
Typical apoptotic cells in alveolar area of MT-/- mice at
a dose of 188 mg/kg body weight. Brown staining indicates the
apoptotic cells. The bar is 20 mm.
B: Typical
apoptotic cells in bronchial area of MT-/- mice at a dose
of 188 mg/kg body weight. Brown staining indicates apoptotic cells.
The bar is 20 mm.
C: AI in alveolar area. D: AI in bronchial area. All the values were
expressed as ±SD. ANOVA with subsequent post hoc’s
test was performed for comparison of AI. a,bSignificant difference
at P<0.05, P<0.01 when compared with the
corresponding control group. c,dSignificant difference at P<0.05,
P<0.01 when compared with the dose-matched MT-/-
mice group.
Figure 5(PDF)
Apoptosis in livers of MT+/+ and MT-/-
mice detected by TUNEL twenty-four hours after oral DMAA treatment. A:
Typical apoptotic cells in the liver of MT-/- mice at a
dose of 188 mg/kg body weight. Brown staining indicates apoptotic
cells. The bar is 20 mm.
B. AI in the livers. All values were expressed as ±SD. ANOVA with subsequent post hoc’s
test was performed for comparison of AI. a, bSignificant
difference at P<0.05, P<0.01 when compared with
the corresponding control group. c,dSignificant difference at P<0.05,
P<0.01 when compared with the dose-matched MT-/-
mice group.
Induction of apoptotic cells detected in lungs, livers and
kidneys of MT-/- and MT+/+ mice
High induction of apoptotic cells in bronchial epithelial
cells was observed in MT-/- mice treated with DMAA at 375
mg/kg body weight, however, the same changes were not observed in
dose matched MT+/+ mice. At a high dose of 750 mg/kg body
weight, the coincident increase of apoptotic cells was observed in
both types of mice and no significant difference was observed
between them.
In control group, the incidence of apoptotic cells in
alveolar epithelial cells in MT+/+ mice was significantly
higher than that in MT-/- mice, implying that MT+/+
mice might have a stronger ability to induce apoptosis than MT-/-
mice. A significant increase of apoptotic cells occurred in MT-/-
mice treated by 188 mg/kg DMAA, a relative low dose when compared
with that in bronchial epithelial cells. However, no significant
increase was observed in MT+/+ mice at the same dose of
188 mg/kg DMAA. With the increase of dose, high induction of
apoptotic cells was observed in both types of mice (Figure 4).
Figure 5 shows that in control group, the incidence of
apoptotic cells in MT+/+ mice was 156.33±41.041/cm2, significantly
higher than that in MT-/- mice. The incidence of
apoptotic cells in the livers rose with the increase of dose in both
types of mice. However, at the highest dose of 750 mg/kg, DMAA
produced more necrotic cells rather than apoptotic cells observed by
HE staining (Figure 2).
DMAA failed to induce remarkable apoptotic cells in the
kidneys from both types of mice (data not shown).
MT
concentration in liver of MT+/+ mice
MT concentration was determined in the liver of MT+/+
mice and MT-/- mice treated with DMAA (Figure 6). Hepatic
MT level in MT+/+ mice was significantly increased by
DMAA in a dose-dependent manner. However, there was no detectable
amount of hepatic MT in untreated MT-/- mice, and it
could not be induced by DMAA.
Figure
6(PDF) MT
concentration in livers of MT+/+ mice detected by radio-immunoassay.
All the values were expressed as ±SD. ANOVA with subsequent post hoc’s
test was performed for comparison of AI. bSignificant
difference at P<0.01 when compared with the corresponding
control group.
DISCUSSION
The present study demonstrated that DMAA could produce
pathological lesions in the lungs, livers and kidneys, and
induce apoptosis in the lungs and livers. Most importantly,
it is the first report to show that inability to produce MT-I/II in
MT-/- mice caused an increased sensitivity to toxicity
induced by DMAA.
Treatment with DMAA caused severe and wide spread lesions in
MT-/- mice, whereas, these changes were much less severe
in MT+/+ mice. It indicates that MT-/- mice
were more sensitive to DMAA and MT played a protective role against
the toxicities to main organs. Yamanaka[7] reported that
DMAA in mice could be further metabolized and converted into
dimethylarsine radicals and dimethyl arsenic peroxy radicals. Marked
formation of 8-oxod G was observed in the lung and liver, which are
the target organs for arsenic carcinogenesis. No increase in 8-oxod
G levels was observed in the kidney. Meanwhile, MT was capable of
scavenging hydroxyl and superoxide radicals and its capability of
scavenging them was much more efficient[11,12,15]. In our
study, the expression of MT(I/II) was induced by DMAA in a dose
dependent manner in the livers of MT+/+ mice, no MT(I/II)
was observed in MT-/- mice. Thus the reduction of lesions
induced by DMAA in the main target organs of MT+/+ mice
could be explained at least partly by MT reduction induced by DMAA,
and the toxicity induced by DMAA could be explained partly by way of
oxidative stress participation.
After a lethal damaging stimulation, two main structural
routes of cell death might occur: apoptosis and necrosis. It has
become apparent that the magnitude and type of injurious stimuli
could determine whether a cell underwent death through apoptosis or
necrosis. Severe damaging stimuli tended to result in necrosis, and
lower grade damaged stimuli tended to cause apoptosis[21-30].
Recently, Sakurai et al reported that DMAA could
induce apoptosis by reducing glutathione (GSH) in vitro[17].
However, the effect of MT on the induction of apoptosis by DMAA in
vivo remains elusive. Furthermore, the perturbation of apoptosis
has been thought to contribute to carcinogenesis either through
enhanced initiation or progression[29-38]. In this study,
the induction of apoptosis was detected by TUNEL in the lungs,
livers and kidneys from both types of mice. In the lungs, a
significant increase of apoptosis was observed in alveolar cells of
MT-/- mice at a relative low level compared with that in
bronchial cells, suggesting that alveolar cells were more sensitive
than bronchial cells and MT had some protective role against the
induction of apoptosis induced by DMAA at a relative low level. With
the increase of dose, DMAA induced high levels of apoptosis in both
types of mice and at the highest dose of 750 mg/kg, necrotic cells
predominated over apoptosis in the livers, revealing the serious
toxicity of DMAA at this dose. Since the kidney is the major organ
for arsenic elimination and most of arsenicals could be rapidly
eliminated through the kidney[1-3], renal cells are thus
exposed to a major portion of the absorbed arsenical dose. However,
the induction of apoptosis was not affected by DMAA, the underlying
mechanism needs further investigations.
In conclusion, the present studies demonstrate that oral
administration of DMAA can produce toxic response of the respiratory
system, liver and kidney in both MT-/- and MT+/+
mice. The pathological effects are clearly pronounced in MT-/- mice.
Intracellular MT appears to play an important role in preventing the
toxic effects of DMAA.
ACKNOWLEDGEMENT
We thank Dr. Sone Hideko and Masahiko Satoh (National Institute
for Environmental Studies, Japan) for kindly providing the
experiment materials. This work was supported in part by a
Grant-in-aid for Scientific Research from the Ministry of Education,
China and a grant from the Japan Science and Technology Agency,
Japan.
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