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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Journal DOI :
The Korean Society of Toxicology
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Volume 20, Issue 4 - Sep 2004
Volume 20, Issue 3 - Sep 2004
Volume 20, Issue 2 - Jun 2004
Volume 20, Issue 1 - Mar 2004
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Overview on Molecular Toxicological Aspects of Helicobacter pylori Virulence Factor, Cytotoxin-associated Antigen A (CagA)
Kim Byung J. ; Jung Hwa Jin ; Hwang Jee Na ; Kang Seok Ha ; Oh Se-Jin ; Seo Young Rok ;
Toxicological Research, volume 20, issue 3, 2004, Pages 179~185
Helicobacter pylori (H. pylori) infects more than half of the people in the world as a major microbe to cause most of gastric diseases. Recently, cytotoxin associated-antigen A (CagA) is believed as one of the most important virulence factors of H. pylori. Molecular toxicological pathway of CagA is necessary to investigate for understanding the pathological and toxicological aspects of H. pylori, since this virulence protein harasses intercellular processes of host cells to get profit for the survival of H. pylori. CagA is coded from cag pathogenicity island (cag PAI) and translocated into host cells by Type 4 secretion system (TFSS). Tyrosine phosphorylation of CagA targets Src homology 2-containing phosphotyrosine phosphatase (SHP-2) to form a CagA-SHP-2 complex. This complex depends on the similarity of sequence between EPIYA motif and Src homology 2 domain (SH2 domain) of CagA. The generation of growth factors is an essential role of CagA in protecting and healing gastric mucosa for the survival of H. pylori. On the other hand, the activation of IL-8 by CagA induces neutrophils generating inflammation and free radicals. Indeed, free radicals are well known carcinogen to induce DNA damage. In addition, the transduction of mitogen-activation signal by CagA is one of the interesting features to understand how to cause cancer. The relationship between cancer and inflammation with CagA was mainly discussed in this review.
Myeloperoxidase Polymorphism and Vitamin C Levels during Pregnancy Affect Maternal Oxidative Stress and Their Neonatal Birth Weights
Park Bohyun ; Kim Young-Ju ; Park Eun Ae ; Lee Hwayoung ; Ha Eun-Hee ; Park Jongsoon ; Kim Jeongyoun ; Hong Yun-Chul ; Park Hyesook ;
Toxicological Research, volume 20, issue 3, 2004, Pages 187~193
This study aimed to determine the association of maternal oxidative stress and adverse pregnancy outcome with serum vitamin C concentration and a myeloperoxidase (MPO) genetic polymorphism during pregnancy. We investigated 450 pregnant women who visited Ewha Womans University Hospital for prenatal care during gestational weeks 24～28. During the second trimester, we measured serum vitamin C levels and urinary 8-hydroxyde-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) as an oxidative stress biomarker. We determined the presence of a maternal MPO polymorphism (G-to-A substitution at nucleotide 463) using a PCR-RFLP assay. We compared the level of oxidative stress and birth weight with the vitamin C concentration and the presence of the MPO polymorphism. The mean level of maternal oxidative stress tended to be higher and the birth weight lower for MPO type A/A than for types A/G and G/G. Vitamin C levels above the 75 percentiles were associated with reduced concentrations of urinary MDA and 8-OHdG but increased birth weight. Our data demonstrate that oxidative stress and neonatal birth weight are associated with the MPO genetic polymorphism, with the association modified by the maternal vita-min C levels.
Tissue Distribution and Toxicokinetics of 4-Tert-Octylphenol in Rats
Kang Mi Kyung ; Ahn Mee Ryung ; Chung Hye Joo ; Choi Sun Ok ; Choi Hong Serk ; Yang Ji Sun ; Lee Yong Bok ; Yoo Tae Moo ; Sohn Soo Jung ;
Toxicological Research, volume 20, issue 3, 2004, Pages 195~203
4-Tert-Octylphenol (OP) is a surfactant additive widely used in the manufacture of a variety of detergents and plastic products. OP can disrupt endocrine function in humans and animals. This study was carried out to obtain toxicokinetic parameters of OP in male Sprague-Dawley (SD) rats. Male rats were administered with OP by single oral application of 200 mg/kg body weight. Blood, urine and tissues samples were taken at several time intervals after administration. Analysis of samples for OP was performed by column-switching high performance liquid chromatography (HPLC). In addition, we exam-ined tissue distribution and accumulation of OP after single oral application of 50, 100, and 200 mg/kg, single intravenous injection of 1, 5 and 10 mg/kg or daily application of 50 mg/kg for 14 consecutive days. After single oral administration of 200 mg/kg, Cmax of 213
123 ng/ml was reached within the first 1.3 hr (Tmax) in the plasma. AUC was calculated for 1,333
484 ngㆍhr/ml. The final elimination half-life of plasma was longer than that of urine, but urinary clearance was lower than oral. A very small fraction of OP (Fe < 0.0017%) was excreted in urine within 24 hr. These results indicated that the major excretion route of OP was not urine. The mean maximal tissue distribution of OP was obserbed at 6 hr after treatment and slowly decreased time-dependently. High OP concentrations were detected in fat at 24 hr. The OP in fat was slowly released with longer elimination half-life and lower clearance than that of other tissues. OP was not accumulated in the liver following single oral application but 14-day oral treatments resulted in two-fold accumulation. It was probably due to the saturation of detoxification pathways. On the other hand, the mRNA expression of cytochrome P450 isoforms except CYP2C11 was not affected by OP at any dose. The expression of CYP2C11 mRNA decreased in a dose-dependent manner. This result suggests that OP changes expression of the male-specific cytochrome P450 isoforms in rat liver, and these changes are closely related to the toxic and estrogenic effect of OP.
Endocrinic Effects of Toxaphene and Chlordane in Human Hepatoma Cell (HepG2 Cell) Transfected with Estrogen Receptor and Luciferase Reporter Gene
Kim Kyeong-Bae ; Jung Ji-Won ; Yang Se-Ran ; Kang Kyung-Sun ; Lee Yong-Soon ;
Toxicological Research, volume 20, issue 3, 2004, Pages 205~211
Concern that some chemicals in our environment may affect human health by disrupt-ing normal endocrine function has prompted a research on interactions of environmental contaminants with steroid hormone receptor. Toxaphene and chlordane are among the 12 persistent organic pollutants identified by the United Nations Environment Programme as requiring urgent attention. We compared the estrogenic activity of two organochlorine pesticides, toxaphene and chlordane, at estrogen receptor a (ER
) and estrogen receptor
). Human hepatoma cells (HepG2) were transiently transfected with rat ER
plus an estrogen-responsive complement C3-luciferase (C3-Luc) reporter gene. After transfection, cells were treated with various concentrations of toxaphene and chlordane to investigate agonism or antagonism of these chemicals. Both toxaphene and chlordane were potent agonists in HepG2 cells for ER
. In contrast, these chemicals had a minimal agonist activity with ER
and almost abolished 17
-mediated activity. Therefore, toxaphene and chlordane behaved as an ER
agonist and an ER
antagonist with estrogen-responsive reporter plasmid C3-Luc, and exposure to these organochlorine pesticides could have a crictical effect on normal endocrine function.
The Effects of Oxidative Stress Induced by Aluminum on Cellular Macromolecules in the Hippocampus and Cerebral Cortex of Rats
Moon Chul-Jin ; Koh Hyun-Chul ; Shin In-Chul ; Lee Eun-Hee ; Moon Hae-Ran ;
Toxicological Research, volume 20, issue 3, 2004, Pages 213~223
This work aimed to study the effectiveness of cellular oxidative parameter (malondial-dehyde, protein carbonyl, and 8-hydroxy-2'deoxyguanosine). The experimental groups were aluminum treated rats and control rats. Aluminum treatd rats were given intraperitoneally aluminum nitrate nonahydrate (
, 0.2 mmol/kg) daily for 30 days except Sunday. Control rats were injected 1 ml of saline. After the dose, rats were decapitated and hippocampus and cerebral cortex were removed. The measured parameters were tissue malondialdehyde (MDA, index of lipid peroxidation), protein carbonyl (index of protein oxidation), 8-hydroxy-2'-deoxy-guanosine (8-OHdG, index of DNA oxidation), reduced glutathione (GSH) levels as well as glutathione reductase (GR) and catalase. AI concentrations in the tissues were also measured. All results were corrected by tissue protein levels. The results were as followed; 1. The concentrations of AI in the cortex and hippocampus were significantly higher in the AI-treated rats than in the control rats. 2. Antioxidative enzyme's activity, catalase and GR, were significantly higher in the AI-treated rats than the control rats. GSH levels were also higher in the AI-treated rats. 3. MDA, protein carbonyl, and 8-OHdG concentration of AI-treated rats were significantly higher than those of control rats. 4. The concentrations of antioxidants, and oxidative stress parameter were correlated with the concentrations of AI in hippocampus and cerebral cortex. Catalase and GR activity were also correlated with the concentration of AI. Based on these results, it can be suggested that intraperitoneally injected AI was accumulated in the brain and induced the increase of antioxidant levels and antioxidative enzyme activity. Also, the oxidative products of cellular macromolecules are significantly related to tissue AI concentration. Therefore MDA, protein carbonyl, and 8-OHdG are useful markers for oxidative stress on cellular macromolecules.
Use of the In Vivo Single-cell Gel Electrophoresis Assay for Evaluating Genotoxicity in Clam
Kim Il-Yang ; Hyun Chang-Kee ;
Toxicological Research, volume 20, issue 3, 2004, Pages 225~232
The suitability of the single cell gel electrophoresis (SCGE) assay as a test for the monitoring of genotoxicity of aquatic environment was evaluated. The SCGE assay was employed to detect DNA damage induced in clam (Spisula sachalinensis) exposed to a direct mutagen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or an indirect mutagen, benzo[a]pyrene (B[a]P). The cells of gill and digestive glands were isolated from clam by homogenization, which was the optimized cell dissociation method, and the level of DNA damage was assessed and expressed as mean tail length. In the gill cells, significant dose- and time-dependent increase was observed in the mean tail length at the concentration from 0.01 to 0.5 ppm MNNG for 96 h. The linear correlation between relative dam-age index (RDI) values was suggested to provide criteria of genotoxicity monitoring for direct acting mutagen. The dose- and time-dependent responses of the digestive glands cells were less sensitive than those of the gill cells. In contrast, the genotoxic response resulting from the exposure of 0.01～1.0 ppm B[a]P to clam revealed a higher sensitivity in the digestive glands cells than the gill cells. The comparison between the time profiles of genotoxic responses in clam and carp, the latter had been obtained in our previous study, indicated that the metabolism of genotoxic compounds in the two aquatic organisms were quite different each other. We conclude that the SCGE assay has the potential as a screening test for routine genotoxicity monitoring of aquatic organisms because of its higher sensitivity and simplicity.
Differential Alterations of Endotoxin-induced Cytokine Expression and Mitogen-activated Protein Kinase Activation by Mercury in Mouse Kidney
Kim, Sang-Hyun ; Kim, Dae-Keun ; Shin, Tae-Yong ; Choi, Cheol-Hee ;
Toxicological Research, volume 20, issue 3, 2004, Pages 233~239
The present study was designed to determine the impact of mercury on endotoxin-induced inflammatory cytokine expression and corresponding signal transduction in mouse kidney. Male BALB/c mice were exposed continuously to 0, 0.3, 1.5, 7.5, or 37.5 ppm of mercury in drink-ing water for 14 days and at the end of the treatment period, lipopolysaccharide (LPS, 0.5 mg/kg) was injected intraperitoneally 2 h prior to euthanasia. The doses of mercury and LPS did not cause hepatotoxicity or renal toxicity as indicated by unaltered plasma alanine aminotransferase and aspartate aminotransferase levels, and terminal UTP nucleotide end-labeling assay from kidney, respectively. Mercury decreased kidney glutathione (GSH) and with LPS, it additively decreased GSH. Mercury activated p38 mitogen-activated protein kinase (MAPK) and additively increased LPS-induced p38 MAPK phosphorylation. In contrast, mercury inhibited LPS-induced activation of extra-cellular signal-regulated kinase (ERK) but had no effect alone. Mercury increased the gene expression of tumor necrosis factor
) and potentiated LPS-induced TNF
expression. Mercury did not affect LPS-induced interleukin-1
) expression but decreased LPS-induced IL-6 expression. These results suggest that low levels of mercury might augment LPS-induced TNF
expression by altering GSH and p38 MAPK. Mercury modulates LPS-induced p38 and ERK activation, and downstream TNF
and IL-6 expression in kidney, respectively.
Bisphenol A Disturbs Intracellular Calcium Homeostasis and its Relationship with Cytotoxicity
Lee Yoot Mo ; Lee Sang Min ; Son Dong Ju ; Lee Sun Young ; ; Nam Sang Yun ; Kim Dae Joong ; Yun Young Won ; Yoo Hwan Soo ; Oh Ki Wan ; Kim Tae Seong ; Han Soon Young ; Hong Jin Tae ;
Toxicological Research, volume 20, issue 3, 2004, Pages 241~250
We previously found that bisphenol A (BPA) caused neurotoxic behavioral alteration. Since disturbance of calcium homeostasis is an implicated contributor in the neurotoxic mechanism of environmental toxicants, we investigated whether BPA alters calcium homeostasis. Unlike other neurotoxic agents which cause increase of intracellular calcium level, BPA decreased
dose-dependently in PC12 cells and cortical neuronal cells regardless of the calcium existence in buffer. BPA at greater concentrations than 100
reduced cell viability significantly in both types of cells. BPA also suppressed L-glutamate (L-type channel activator, 30 mM) and trifluoperazine (calmodulin antagonist, 30
)-induced increase of
. BPA further lowered caffeine (RYR activator, 100
, but did not alter dantrolene (RYR inhibitor, 100
), heparin (IP3 inhibitor, 200 units/ml) and xestospongin C (IP3 inhibitor, 5
. Cell viability was not directly related to intracellular calcium change by bisphenol A that alternation of intracellular calcium may not be a direct causal factor of BPA-induced neuronal cell death.
Behavior Alterations and Expression of Estrogen Receptors in Mice Exposed to Bisphenol A
Seoung Min Jae ; Shin Im Cheol ; Lee Yoot Mo ; Son Dong Ju ; Song Youn Sook ; Jeon Kei Hyun ; Kim Yun Bae ; Lee Beum Jun ; Kim Dae Joong ; Yun Young Won ; Kim Tae Seong ; Han Soon Young ; Song Suk Gil ;
Toxicological Research, volume 20, issue 3, 2004, Pages 251~261
A large number of chemical pollutants including phthalates, alkylphenolic compounds and organochlorine pesticides have the ability to disrupt endocrine function in animals, and alter cog-nitive function. Because hormone mediated events play an important role in central nervous system development and function, the changes in cognitive function seem to be mediated by the endocrine-like action of these chemicals. The present study therefore was designed to investigate effect of bisphenol A (BPA), an endocrine disrupting chemical on neuro-behavial patterns, and expression of estrogen receptors and tyrosine hydroxylase, a limiting enzyme of dopamine synthesis pathway. BPA was treated orally for 3 weeks into 3 week old mice, and then the neuro-behavial patterns (stereo-type behaviors such as jumping rearing and forepaw tremor, climbing behavior, tail flick, rotarod and locomotor activity), and the expression of estrogen receptors and tyrosine hydroxylase were deter-mined every 3 week for 9 weeks. During the treatment of BPA, the food uptake and body weight increase were not significantly changed. BPA resulted in the increased stereotype behaviors (jump-ing, rearing and forepaw tremor) 6 or 9 weeks after treatment. The time response to tail flick and locomotor activity were decreased by the treatment of BPA, whereas the time for rotarod was increased by the treatment of BPA. The expression of estrogen receptor alpha and beta was increased in the brain and pituitary gland. Maximum expression was found in the brain after 9 week of 100 mg/kg BPA treatment and in the pituitary gland after 6 week of 100 mg/kg BPA treatment. Tyrosine hydroxylase was increased in dose and time dependent manners in the brain but no change was found in the pituitary gland. The present data show that exposure of BPA in the young mice could alter expression of estrogen receptors and dopamine synthesis pathway, thereby modulate neuro-behavial patterns (increase of stereotype behaviors but decrease locomotor activity).
Single and Four-Week Oral Toxicity Studies of Difructose Dianhydrides (DFA IV) in Sprague-Dawley Rats
Lee Chang-Woo ; Lee Myong-Lyoll ; Kim Hwan-Mook ; Yoon Won-Kee ; Kim Seung-Hwan ; Son Hwa-Young ; Kim Hyoung-Chin ;
Toxicological Research, volume 20, issue 3, 2004, Pages 263~272
This study was to investigate single and repeated-dose toxicities of DFA IV, a new candidate of nutraceutical which has preventive effect on anemia and osteoporosis. In single-dose oral toxicity study, the test article were administered once by gavage to rats at dose level of 0, 2,000 and 5,000 mg/kg. No dead animal, abnormal sign and abnormal necropsy finding was found in control and treated groups. Thus the approximate lethal dose of DFA IV was considered to be higher than 5,000 mg/kg in rats. In four week repeated dose oral toxicity study, the test article was administered once daily by gavage to rats at dose levels of 0, 500, 1,000 and 2,000 mg/kg. No abnormality was observed in mortality, clinical findings, body weight changes, food and water consumptions, opthalmoscopic findings, hematological findings, necropsy findings, organ weights and histopathological findings. In urinalysis, specific gravity was increased in 2,000 mg/kg groups of male rats. In serum biochemical analysis, creatine phosphokinase was increased in all treatment groups of male rats. These increases in urine specific gravity and serum creatine phosphokinase activity were not accompanied with related signs such as histopathological changes or clinical findings. In conclusion, four week repeated oral dose of DFA IV to rats did not cause apparent toxicological change at the dose of 500, 1,000 or 2000 mg/kg body weight. Thus it is suggested that no-observed-adverse-effect level (NOAEL) of DFA IV in rats would be 2,000 mg/kg/day body weight.
Two-Week Repeated Inhalation Toxicity Study of Dimethyl Disulfide in Rats
Kim Jong-Choon ; Shin Jin-Young ; Shin Dong-Ho ; Kim Sung-Ho ; Lee Sung-Bae ; Han Jung-Hee ; Chung Yong-Hyun ; Kim Hyeon-Yeung ; Park Seung-Chun ;
Toxicological Research, volume 20, issue 3, 2004, Pages 273~280
The present study was carried out to investigate the potential toxicity of dimethyl disulfide by a 2-week inhalation in F344 rats. The test article, dimethyl disulfide, was exposed by inhalation to male and female rats at dose levels of 0, 33, 100, or 300 ppm/6 hrs/day for 2 weeks. At the end of treatment period, all males and females were sacrificed. During the test period, clinical signs, mortality, body weights, food consumption, hematology, serum biochemistry, and gross findings were examined. The mean body weights of the male 300 ppm group and the female 33 ppm or higher dose groups were significantly lower than those of the control group, respectively. The mean food consumption at male 300 ppm and female 100 and 300 ppm were significantly decreased compared with the controls. Some treatment-related serum biochemical changes, including decreased alkaline phosphatase at male 300 ppm and female 100 and 300 ppm, reduced total bilirubin at male 300 ppm, and decreased alanine aminotransferase at female 300 ppm, were observed in a dose-dependent manner, but these findings were considered to be of no toxicological significance. There were no adverse effects on mortality, clinical signs, hematology, and necropsy findings in any treatment group. Based on these results, it was concluded that the 2-week repeated dose of dimethyl disulfide by inhalation resulted in suppressed body weight gain and decreased food consumption at the dose of male 300 ppm and suppressed or reduced body weight gain and decreased food consumption at the dose of female 33 ppm or higher. In the present experimental conditions, the no-observed-adverse-effect level (NOAEL) was considered to be 100 ppm/6 hrs/day for male rats and below 33 ppm/6 hrs/day for female rats.
Single and Five-Week Oral Dose Toxicity Studies of Calcitriol and Alendronate Mixtures in Rats
Moon, Sung Won ; Jin, Ji Yun ; Lee, Jin Hee ; Sim, Sang Soo ; Kim, Chang Jong ;
Toxicological Research, volume 20, issue 3, 2004, Pages 281~292
The purpose of this study was to assess the single and 5 week oral dose toxicity of calcitriol and alendronate combination (1 : 10,000) treatment for osteoporosis or Paget's disease in male and female rats. In single dose oral toxicity study, the values of
of calcitriol and alendronate mixture were 750.075 mg/kg in male rats and 775.0775 mg/kg in female rats, respectively. Body weight and food consumption were continuously increased after adminstration of calcitriol and alendronate mixtures, and there was no significant changes in body weight and food consumption in all groups. In five-week oral toxicity study of calcitriol and alendronate mixture at a dose of 0.2
+ 2 mg, 1
+ 10 mg, 5
+ 50 mg and 25
+ 250 mg, respectively, there was no mortality, abnormal behavior and appearance in all groups throughout the administration period (5 weeks) and recovery period (2 weeks). Dose-dependent changes in parameters of urinalysis and hematological analysis were not observed in male and female rats treated with calcitriol and alendronate mixtures. All the values of the parameters appeared to be in the normal range. These data indicate that both calcitriol and alendronate are drugs having low toxicity in rats. NOAEL of calcitriol and alendronate mixtures were 50.005 mg/kg in 5-week oral toxicity.