Korea Institute of Toxicology

Chinju, South Korea

Korea Institute of Toxicology

Chinju, South Korea
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Tian Y.-H.,Sungkyunkwan University | Baek J.-H.,Korea Institute of Toxicology | Lee S.-Y.,Sungkyunkwan University | Jang C.-G.,Sungkyunkwan University
Synapse | Year: 2010

Bisphenol A (BPA), an environmental endocrine-disrupting chemical, has been extensively evaluated for reproductive toxicity and carcinogenicity. However, little is known about the behavioral and neurochemical effects of BPA exposure. This study examined whether chronic daily exposure to an environmental endocrine-disrupting chemical, bisphenol A [(BPA); 100 μg/kg/day or 500 lg/kg/day, p.o.], from prenatal Day 7 to postnatal Day 36 would lead to changes in anxiety and memory in mice. First, we observed the behavioral alterations of BPA-treated mice using two anxiety-related models, the open field test and elevated plus maze (EPM) test. In the open field test, BPA treatment (100 μg/kg/day) increased movement in the central zone. BPA treatment (500 μg/kg/day) also increased the time spent in the open arms in the EPM test. Second, we measured cognitive ability in the Y-maze test and novel object test. BPA-treated mice showed decreased alternation behavior in the Y-maze at both of doses, indicating working memory impairment. BPA-treated mice (100 μg/kg/day) also showed decreased novel object recognition as expressed by central locomotion and frequency in the central zone, showing recognition memory impairment. Finally, to measure changes in the dopaminergic and NMDAergic systems in the brain, we performed autoradiographic receptor binding assays for dopamine D1 and D2 receptors, the NMDA receptor, and the dopamine transporter. BPA treatment increased D2 receptor binding in the caudate putamen (CPu) but decreased DAT binding. BPA treatment also decreased NMDA receptor binding in the frontal cortex and CA1, CA3, and DG of the hippocampus. Taken together, our results suggest that long-term BPA exposure in mice can induce anxiolytic behaviors, cognitive deficits and changes in the dopaminergic and NMDAergic systems. © 2010 Wiley-Liss, Inc.


Choi J.S.,Korea Institute of Toxicology | Kim R.-O.,Korea Institute of Toxicology | Yoon S.,Korea Institute of Toxicology | Kim W.-K.,Korea Institute of Toxicology
PloS one | Year: 2016

Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway. Zebrafish embryos were exposed to 0.01, 0.1, 1, and 10 mg/L ZnO NPs for 96 h post-fertilization. The toxicity of ZnO NPs, based on their Zn concentration, was quite similar to that in embryonic/larval zebrafish exposed to corresponding ZnSO4 concentrations. Pericardial edema and yolk-sac edema were the principal malformations induced by ZnO NPs. Gene-expression profiling using microarrays demonstrated 689 genes that were differentially regulated (fold change >1.5) following exposure to ZnO NPs (498 upregulated, 191 downregulated). Several genes that were differentially regulated following ZnO NP exposure shared similar biological pathways with those observed with ZnSO4 exposure, but six genes (aicda, cyb5d1, edar, intl2, ogfrl2 and tnfsf13b) associated with inflammation and the immune system responded specifically to ZnO NPs (either in the opposite direction or were unchanged in ZnSO4 exposure). Real-time reverse-transcription quantitative polymerase chain reaction confirmed that the responses of these genes to ZnO NPs were significantly different from their response to ZnSO4 exposure. ZnO NPs may affect genes related to inflammation and the immune system, resulting in yolk-sac edema and pericardia edema in embryonic/larval developmental stages. These results will assist in elucidating the mechanisms of toxicity of ZnO NPs during development of zebrafish.


Tian Y.-H.,Sungkyunkwan University | Lee S.-Y.,Sungkyunkwan University | Kim H.-C.,Korea Institute of Toxicology | Jang C.-G.,Sungkyunkwan University
Neuroscience Letters | Year: 2010

The transient receptor potential vanilloid type 1 (TRPV1) is a non-selective ligand-gated cationic channel. The distribution of TRPV1 mRNA in various regions of the brain has been successfully established. Methamphetamine (MAP) is a psychostimulant and a major drug of abuse in many parts of the world. The powerful rewarding properties of MAP are attributed to multiple pharmacological actions, but the mechanistic association between TRPV1 expression and MAP-induced drug addiction has not established. In the present study, we conducted a time-course analysis of TRPV1 mRNA levels in the frontal cortex, striatum, and hippocampus of mouse brain following repeated MAP (2 mg/kg, i.p.) treatment. Our results demonstrate that expression of TRPV1 mRNA is significantly increased 1, 2, 6, 24, 48 h, and 1 week after the last MAP treatment in the frontal cortex but not in the striatum or hippocampus. These data support a potential role for TRPV1 in the treatment of MAP-induced drug addiction. © 2010 Elsevier Ireland Ltd. All rights reserved.


Kim H.J.,Kyungpook National University | Lim J.-S.,Kyungpook National University | Kim W.-K.,Korea Institute of Toxicology | Kim J.-S.,Kyungpook National University
Proceedings of the Nutrition Society | Year: 2012

Glyceollins, one family of phytoalexins, are de novo synthesised from daidzein in the soyabean upon exposure to some types of fungus. The efficiency of glyceollin production appears to be influenced by soyabean variety, fungal species, and the degree of physical damage to the soyabean. The compounds have been shown to have strong antioxidant and anti-inflammatory activities, and to inhibit the proliferation and migration of human aortic smooth muscle cells, suggesting their potential to prevent atherosclerosis. It has also been reported that glyceollins have inhibited the growth of prostate and breast cancer cells in xenograft animal models, which is probably due to their anti-oestrogenic activity. In essence, glyceollins deserve further animal and clinical studies to confirm their health benefits. © 2011 The Authors.


Hwang Y.S.,Korea Institute of Toxicology | Qu X.,Rice University | Li Q.,Rice University
Carbon | Year: 2013

The photochemical transformation of carboxylated multiwall carbon nanotubes (COOH-MWCNTs) in water and the subsequent impact on their aggregation and deposition behaviors were examined. The photochemical transformation of COOH-MWCNTs was investigated under UVA (300-400 nm) irradiation, the main component of UV light in solar irradiation. Time-resolved dynamic light scattering measurement and quartz crystal microbalance with dissipation monitoring were used to study the initial aggregation and deposition kinetics. Characterization of the physicochemical properties of the COOH-MWCNTs before and after irradiation revealed a loss in surface oxygen after UV irradiation, most likely a result of decarboxylation of the nanotube surface. These changes in surface chemistry greatly reduced the colloidal stability of COOH-MWCNTs in NaCl solutions. No noticeable changes in particle surface zeta potential and stability were observed in CaCl2 solutions after irradiation. Consistent with the decreased colloidal stability in NaCl solutions, the irradiated COOH-MWCNTs had a notably higher deposition than the initial COOH-MWCNTs in NaCl solutions when aggregation did not occur. Our results suggest that the photochemical transformation plays an important role in the transport of carbon nanotubes in natural aquatic systems. © 2012 Elsevier Ltd. All rights reserved.


Kim W.-K.,Korea Institute of Toxicology | Lee S.-K.,Korea Institute of Toxicology | Jung J.,Korea University
Journal of Hazardous Materials | Year: 2010

In this study, the toxicological effects of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) toward the common carp, Cyprinus carpio, were evaluated by assessing the responses of five biomarkers, including DNA single-strand breaks (COMET), vitellogenin (VTG) concentration, and the activities of 7-ethoxyresorufin-O-deethylase (EROD), acetylcholinesterase (AChE) and catalase (CAT). Upon PFOA exposure, both the VTG concentration and CAT activity were significantly increased, while there was a negligible change in the responses of other biomarkers when compared to the control. Upon PFOS exposure, a significant increase in the DNA single-strand breaks was observed, while the responses of other biomarkers were not significantly altered when compared to the control. Standardized scores of biomarker responses were visualized using star plots and computed as the integrated biomarker response (IBR). As expected from the different biomarker responses, PFOA and PFOS showed totally different patterns of star plots. Additionally, the IBR values were well correlated with the logarithmic concentrations of PFOA and PFOS (R2=0.9434 and 0.9511, respectively). These results suggest that the IBR might be a useful tool for quantification of various biomarker responses induced by toxic chemicals. © 2010 Elsevier B.V.


Younis H.S.,Isis Pharmaceuticals | Crosby J.,Isis Pharmaceuticals | Huh J.-I.,Korea Institute of Toxicology | Lee H.S.,Korea Institute of Toxicology | And 3 more authors.
Blood | Year: 2012

A strategy to produce sufficient anticoagulant properties with reduced risk of bleeding may be possible through inhibition of factor XI (FXI), a component of the intrinsic coagulation cascade. The objective of this work was to determine the safety profile of ISIS 416858, a 2′-methoxyethoxy (2′-MOE) antisense oligonucleotide inhibitor of FXI, with focus on assessment of bleeding risk. Cynomolgus monkeys administered ISIS 416858 (4, 8, 12, and 40 mg/kg/wk, subcutaneous) for up to 13 weeks produced a dose-dependent reduction in FXI (mRNA in liver and plasma activity) and a concomitant increase in activated partial thromboplastin time (APTT). ISIS 416858 (20 or 40 mg/kg/wk) reduced plasma FXI activity by 80% at 4 weeks of treatment that resulted in a 33% increase in APTT by 13 weeks with no effects on PT, platelets, or increased bleeding following partial tail amputation or gum and skin laceration. The dose-dependent presence of basophilic granules in multiple tissues in ISIS 416858-treated animals was an expected histologic change for a 2′-MOE antisense oligonucleotide, and no toxicity was attributed to hepatic FXI reduction. Basophilic granules reflect cellular drug uptake and subsequent visualization on hematoxylin staining. These results suggest that ISIS 416858 has an acceptable preclinical safety profile and is a promising clinical candidate to treat thrombotic disease. © 2012 by The American Society of Hematology.


Kim J.,Korea Institute of Toxicology | Kim S.,Korea Institute of Toxicology | Lee S.,Korea Institute of Toxicology
Nanotoxicology | Year: 2011

Silver nanoparticles (AgNPs) are increasingly used in various fields. However, little is known about the environmental effects of widespread use of products containing AgNPs. The objective of this study was to determine the ecotoxicity caused by AgNPs. The 48-h effective concentration 50 (EC50) values for Daphnia magna of suspensions of 60 nm and 300 nm AgNPs were 1.0 (95% confidence interval [CI] = 0.1-1.3) and 1.4 (95% CI = 0.3-2.1) μg Ag/l, respectively. The 96 h LC50 values for Oryzias latipes of 60 nm and 300 nm AgNP suspensions were 28 (95% CI = 23-34) and 67 (95% CI = 45-108) μg Ag/l, respectively. To show that toxicity is caused only by Ag+ and not by AgNPs, Ag+ was adsorbed onto the synthesized sorbents packed in a column and D. magna was exposed to the column-passed-300 nm AgNP suspensions. There was no acute toxicity with the AgNP suspensions not containing Ag +. © 2011 Informa UK, Ltd.


Um M.Y.,Korea Food Research Institute | Hwang K.H.,Korea Institute of Toxicology | Ahn J.,Korea Food Research Institute | Ha T.Y.,Korea Food Research Institute
Basic and Clinical Pharmacology and Toxicology | Year: 2013

Curcumin is a well-known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high-fat/cholesterol diet (HFD)-induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body-weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p < 0.05). The levels of total cholesterol, fasting glucose and insulin in serum were decreased, and HFD-induced impairment of insulin sensitivity was improved by curcumin supplementation (p < 0.05). Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation. Moreover, curcumin activated AMP-activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator-activated receptor alpha. By contrast, curcumin suppressed the HFD-mediated increases in sterol regulatory element-binding protein-1, acetyl-CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression. Taken together, these findings indicate that curcumin attenuates HFD-induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis. © 2013 Nordic Pharmacological Society.


Seo J.-S.,Korea Institute of Toxicology
Journal of the Korean Society for Applied Biological Chemistry | Year: 2012

Mycobacterium aromativorans JS19b1T, isolated from a polycyclic aromatic hydrocarbon (PAH)-contaminated site in Hilo, Hawaii, USA, was studied for its degradation of dibenzothiophene (DBT) as a sole carbon source. Strain JS19b1T degraded 100% of DBT (40 mg/L) within 11 days incubation through branched metabolic pathways, including dioxygenation on C-1,2 and C-3,4 positions and monooxygenation on sulfur atom. The metabolites were isolated and identified by gas chromatography-mass spectrometry. Dibenzothiophene-5,5′-dioxide was transformed from sulfur oxidation of DBT. Cis-dibenzothiophene dihydrodiols were detected as initial dioxygenation products. Two ring cleavage products of dibenzothiophene diols were detected as trans-4-(3-hydroxybenzo[b]thiophen-2-yl)-2-oxobut-3-enoic acid and trans-4-(2-hydroxy-benzo[b]thiophen-3-yl)-2-oxobut-3-enoic acid, which could be produced by meta-cleavage of dibenzothiophene-1,2-diol and dibenzothiophene-3,4-diol, respectively. The detection of benzothienopyranone strongly supported that M. aromativorans JS19b1T can degrade DBT through 1,2- and/or 3,4-dioxygenations followed by meta-cleavage. The ring cleavage products were further transformed into 2,2′-dithiosalicylic acid via 2-mercaptobenzoic acid. These results suggested that strain JS19b1T has diverse lateral dioxygenase and metabolic enzyme systems. The diverse DBT metabolic pathways in JS19b1T gave a new insight to the bacterial degradation of aromatic compounds. © 2012 The Korean Society for Applied Biological Chemistry.

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