Molecular & Cellular Toxicology
대한독성유전 단백체학회 (The Korean Society of Toxicogenomics and Toxicoproteomics)
- 계간
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- 1738-642X(pISSN)
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- 2092-8467(eISSN)
과학기술표준분류
- 보건의료 > 의생명과학
Aim & Scope
Molecular & Cellular Toxicology publishes original research and reviews in all areas of the complex interaction between the cell´s genome (the sum of all genes within the chromosome), chemicals in the environment, and disease. Acceptable manuscripts are the ones that deal with some topics of environmental contaminants, including those that lie in the domains of analytical chemistry, biochemistry, pharmacology and toxicology with the aspects of molecular and cellular levels. Emphasis will be placed on toxic effects observed at relevant genomics and proteomics, which have direct impact on drug development, environment health, food safety, preventive medicine, and forensic medicine. The journal is committed to rapid peer review to ensure the publication of highest quality original research and timely news and review articles.
https://www.editorialmanager.com/mact/default.aspx KSCI KCI SCOPUS SCI SCIE제4권4호
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Benzene and ethylbenzene (BE), the volatile organic compounds (VOCs) are common constituents of cleaning and degreasing agents, paints, pesticides, personal care products, gasoline and solvents. VOCs are evaporated at room temperature and most of them exhibit acute and chronic toxicity to human. Chronic exposure of benzene is responsible for myeloid leukemia and also ethylbenzene is also recognized as a possible carcinogen. To evaluate the BE effect on human, whole human genome 35 K oligonucleotide microarray were screened for the identification of the differential expression profiling. We identified 280 up-regulated and 201 down-regulated genes changed by more than 1.5 fold by BE exposure. Functional analysis was carried out by using DAVID bioinformatics software. Clustering of these differentially expressed genes were associated with immune response, cytokine-cytokine receptor interaction, toll-like signaling pathway, small cell lung cancer, immune response, apoptosis, p53 signaling pathway and MAPKKK cascade possibly constituting alternative or subordinate pathways of hematotoxicity and immune toxicity. Gene ontology analysis methods including biological process, cellular components, molecular function and KEGG pathway thus provide a fundamental basis of the molecular pathways through BEs exposure in human lymphoma cells. This may provides a valuable information to do further analysis to explore the mechanism of BE induced hematotoxicity.
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Chang, Jae-Jin;Jeon, Su-Yeon;Song, Ji-Ye;Kim, Jin-Hee;Li, Lan;Park, Dae-Hun;Lee, Yun-Lyul;Park, Jeong-Joo;Woo, Dong-Wook;Kim, Gi-Jin;Lee, Min-Jae 278
The X-linked inhibitor of apoptosis (XIAP) is a member of a novel family of inhibitors of apoptosis and has several BIR domains (BIR1, BIR2, and BIR3) and a carboxy-terminal RING zinc-finger. Since suppressionof apoptosis is fundamentally important for carcinogenesis and tumor growth, we investigated the expression and function of XIAP in DEN-induced carcinogenesis using rat model. Wistar rats were injected intraperitoneally with DEN at a dose of 50 mg/kg in twice a week for 12 weeks (Group II) and 16 weeks (Group III) followed by the recovery periods, respectively. The evaluation of DEN-induced carcinogenesis carried out the blood, RT-PCR, histopathological and western blot analysis. The level of blood chemistry including GOT/GPT, albumin, and total bilirubin were significantly exchanged comparing to control and Group I/Group II. The expression of albumin and collagen mRNA were significantly exchanged (P<0.05) in both groups. In addition, AFP mRNA expression decreased more after recovery periods than Group II. XIAP was expressed constitutively in normal rat liver as well as DEN-induced Groups I and Group II. In addition, XIAP expression increased more in Group I with 4 weeks recovery periods than Group I. However, XIAP expression shown to increase in Group lI, otherwise, it was decreased in Group II with 10 weeks repair periods. Taken together, these results suggest the alteration of XIAP expression could be involved in hepatocellular carcinogenesis. -
Crocin is one of the major components of gardenia fruit and saffron which are widely used as natural food colorants and as traditional Chinese medicines. However, the genotoxicity data on crocin are not sufficient for safety evaluation. The purpose of this study was the examination of the genotoxicity on crocin from gardenia yellow in bacterial and mammalian cells, using various genotoxic battery testing assays and the influence of crocin on methyl methanesulfonate (MMS) and
${H_2}{O_2}$ -induced DNA damage in vitro, using single cell gel electrophoresis (comet) assay. From results, no considerable mutagenicity and clastogenicity were seen in bacteria and mammalian cells treated with crocin, by Ames test, chromosomal aberration assay,${tk}^{+/-}$ gene forward mutation assay and comet assay. And, post-treatment with crocin significantly suppressed${H_2}{O_2}$ -induced DNA damage in a dose-dependent manner. In conclusion, the findings of the present study and other previous observations indicate that crocin has no genotoxic potential. And it showed that crocin clearly repressed the genotoxic potency of${H_2}{O_2}$ . These results suggest that anti-oxidative effects of crocin may be involved in the protective effects of DNA damage. -
Woo, Seon-Ock;Son, Sung-Hee;Park, Hong-Seog;Vulpe, Chris D.;Ryu, Jae-Chun;Yum, Seung-Shic 293
To screen the differentially expressed genes in cadmuim-exposed marine medaka fish (Oryzias javanicus), a candidate marine test fish for ecological toxicity, the differential display polymerase chain reaction (DD-PCR) was carried out, since the genome-wide gene expression data are not available in this fish species yet. A total of 35 clones were isolated from cadmium-exposed fish and their nucleotide sequences were analyzed. The differentially expressed gene candidates were categorized to response to stimulus (3); ion binding (3); DNA binding (1); protein binding (6); carbohydrate binding (1); metabolic process (4); biological regulation (3); cellular process (2); protein synthesis (2); catalytic activity (2); sense of sight (1); immune (1); neurohormone (1); signaling activity (1); electron carrier activity (1) and others (3). For real-time quantitative RT-PCR, we selected catalase, glucose-6-phosphate dehydrogenase, heat shock protein 70, and metallothionein and confirmed that cadmium exposure enhanced induction of these four genes. -
We investigated high light-induced alterations in antioxidant enzymes by exposing green vegetative cells of the alga Haematococcus pluvialis to excess irradiance to induce the production of astaxanthin, a carotenoid pigment. Total activity of catalase decreased approximately 70% after high light exposure, whereas glutathione peroxidase (GPX) activity was slightly enhanced. Total activity of superoxide dismutase and ascorbate peroxidase (APX) also slightly decreased. Overall, we did not observe dramatically elevated levels of antioxidant isozymes, although APXn, GPX2, and GPX3 isozyme increased slightly.
${H_2}{O_2}$ content increased about sixfold after high light exposure, demonstrating severe cellular oxidative stress, whereas lipid peroxidation was notably reduced. Concomitantly, astaxanthin accumulation increased about sevenfold. This result suggests that probably massively accumulated astaxanthin may be one of the antioxidant protector against high light stress. -
AAD16034 is an alginate lyase from Pseudoalteromonas sp. IAM14594. A very close homologue with known 3D structure exists (marine bacterium Pseudoalteromonas sp. strain no. 272). A three-dimensional structure of AAD16034 was generated based on this template (PDB code: 1J1T) by comparative modeling. The modeled enzyme exhibited a jelly-roll like structure very similar to its template structure. Both enzymes possess the characteristic alginate sequence YFKhG+Y-Q. Since AAD16034 displays enzymatic activity for poly-M alginate, docking of a tri-mannuronate into the modeled structure was performed. Two separate and adjacent binding sites were found. The ligand was accommodated inside each binding site. By considering both binding sites, a plausible binding pose for the poly-M alginate polymer could be deduced. From the modeled docking pose (i.e., the most important factor that attracts alginate polymer into this lyase) the most likely interaction was electrostatic. In accordance with a previous report, the hydroxyl group of Y345 was positioned close to the
${\alpha}$ -hydrogen of${\beta}$ -mannuronate, which was suitable to initiate a${\beta}$ -elimination reaction. K347 was also very near to the carboxylatemoiety of the ligand, which might stabilize the dianion intermediate during the${\beta}$ -elimination reaction. This implies that the characteristic alginate sequence is absolutely crucial for the catalysis. These results may be exploited in the design of novel enzymes with desired properties. -
Zebrafish were exposed to commercial silver nanoparticles (
${\sim}$ 10-20 nm) at 0.4 and 4 ppm during cadual fin regeneration. The silver was in the$Ag^+$ ionic form. Fin regeneration was slow in the group exposed to the lower concentration. The cadual fin, gill, and muscle were assayed after 48 hours and subjected to histological analysis. In all tissues sampled, fish exposed to nanoparticles exhibited infiltration, large mitochondria with empty matrices, and accumulation of nano-sized silver in blood vessels. The results suggested mitochondrial damage and induction of inflammation. Microarray analysis of RNA from young zebrafish (52 hours post-fertilization) that were exposed to nanometer-sized silver particles, showed alteration in expression of the p53 gene pathway related to apoptosis. Gene expression changes in the nanoparticle-treated zebrafish led to phenotypic changes, reflecting increased apoptosis. -
Hong, Mee-Suk;Kim, Hye-Kyung;Shin, Dong-Hoon;Song, Dae-Kyu;Ban, Ju Yeon;Kim, Bum Shik;Chung, Joo-Ho 318
Obesity is an increasing worldwide health problem that is strongly related to the imbalance of food intake and energy metabolism. It was well-known that several substances in the hypothalamus regulate food intake and energy metabolism. We planned an integrative study to elucidate the mechanism of the development of obesity. Firstly, to find candidate genes with the marvelous effect, the different expression in the hypothalamus between ob/ob and 48-h fasting mice was investigated by using DNA microarray technology. As a result, we found 3 genes [peroxisome proliferator activated receptor, gamma, coactivator 1 alpha (Ppargc1a), calmodulin 1 (Calm1), and complexin 2 (Cplx2)] showing the different hypothalamic expression between ob/ob and 48-h fasting mice. Secondly, a genetic approach on PPARGC1A gene was performed, because PPARGC1A acts as a transcriptional coactivator and a metabolic regulator. Two hundred forty three obese female patients with body mass index (BMI)${\geq}$ 25 and 285 control female subjects with BMI 18 to<23 were recruited according to the Classification of Korean Society for the Study of Obesity. Among the coding single nucleotide polymorphisms (cSNPs) of PPARGC1A, 2 missense SNPs (rs8192678, Gly482Ser; rs3736265, Thr612Met) and 1 synonymous SNP (rs3755863, Thr528Thr) were selected, and analyzed by PCR-RFLP and pyrosequencing. For the analysis of genetic data, chi-square ($X^2$ ) test and EH program were used. The rs8192678 was significantly associated with obese women (P<0.0006; odds ratio, 1.5327; 95% confidence interval, 1.2006-1.9568). Haplotypes also showed significant association with obese women ($X^2$ =33.28, P<0.0008). These results suggest that PPARGC1A might be related to the development of obesity. -
Park, Han-Jin;Seo, Jeong-Wook;Oh, Jung-Hwa;Lee, Sun-Hee;Lee, Eun-Hee;Kim, Choong-Yong;Yoon, Seok-Joo 323
Surrogate tissue analysis incorporating -omics technologies has emerged as a potential alternative method for evaluating toxic effect of the tissues which are not accessible for sampling. Among the recent applications, blood including whole blood, peripheral blood lymphocytes and peripheral blood mononuclear cells (PBMCs) was suggested as a suitable surrogate tissue in determining toxicant exposure and effect at the pre- or early clinical stage. In this application, we investigated transcriptomic profiles in astemizole treated Cynomolgus monkey's PBMCs. PBMCs were isolated from 4-6 years old male monkeys at 24 hr after administration45 Helvetica Light (10 mg/kg, 30 mg/kg). Gene expression profiles of astemizole treated monkey's PBMCs were determined using Affymetrix$GeneChip^{(R)}$ Human Genome U133 plus 2.0 arrays. The expression levels of 724 probe sets were significantly altered in PBMCs at 10 or 30 mg/kg after astemizole administration following determination of paired t-test using statistical criteria of${\geq}$ $1.5-fold changes at P<0.05. Gene expression patterns in PBMCs showed a considerable difference between astemizole 10 and 30 mg/kg administration groups in spite of an administration of the same chemical. However, close examination using Ingenuity Pathway Analysis (IPA) software revealed that several gene sets related to cardiotoxicity were deregulated at astemizole 10 and 30 mg/kg administration groups. The deregulation of cardiac hypertrophy related genes such as TXN, GNAQ, and MAP3K5 was observed at 10 mg/kg group. In astemizole 30 mg/kg group, genes involved in cardiotoxicity including cardiac necrosis/cell death, dilation, fibrosis, and hypertrophy were also identified. These results suggest that toxicogenomic approach using PBMCs as surrogate tissues will contribute to assess toxicant exposures and identify biomarkers at the pre-clinical stage. -
Sohn, Sung-Hwa;Lee, Hyo-Eun;Lee, Beom-Joon;Kim, Sung-Hoon;Shin, Min-Kyu;Hong, Moo-Chang;Bae, Hyun-Su;Kim, Yang-Seok 331
This study was conducted to quantitatively evaluate the recovery effects of herbal medicines on acetaminophen-induced hepatotoxicity. In the present study, the recovery effects of 251 herbal medicines on THLE-2 cells that had been damaged by acetaminophen were evaluated using an MTS assay. THLE-2 cells were cultured in 96-well plates and then pretreated with or without 60${\mu}M$ acetaminophen (${IC}_{50}$ value: 35.84) for 1 hr. Next, different herbal medicines were added to the wells, after which the cells were reincubated at$37^{\circ}C$ for 24 hr. After first round of screening, the candidate herbal medicines were selected based on a recovery rate of greater than 40% and their efficacy were then determined by dose response kinetic analysis. Among these extracts, 8 herbal medicines (Terminalia chebula, Pueraria lobata, Acronychia laurifolia, Lopatherum gracile, Oroxylum indicum, Cynanchum atratum, Senecio scandens, and Sophora flavescens) had a strong recovery effect on acetaminophen-induced damage in THLE-2 cells. Dose response non-linear regression analysis demonstrated that Senecio scandens showed the best recovery rate (98%), and that its${EC}_{50}$ was 19.54 ng/mL. Additional studies of these herbal medicines should be conducted to determine if they possess novel therapeutic agents for the prevention or treatment of liver disorders. -
Yeast RAD2, a yeast homolog of human XPG gene, is an essential element of nucleotide excision repair (NER), and its deletion confers UV sensitivity and NER deficiency. 6-Azauracil (6AU) sensitivity of certain rad2 mutants revealed that RAD2 has transcription elongation function. However, the fundamental mechanism by which the rad2 mutations confer 6AU sensitivity was not clearly elucidated yet. Using an insertional mutagenesis, PUF4 gene encoding a yeast pumilio protein was identified as a deletion suppressor of rad2
${\Delta}$ 6AU sensitivity. Microarray analysis followed by confirmatory RT-qPCR disclosed that RAD2 and PUF4 regulated expression of HPT1 and URA3. Overexpression of HPT1 and URA3 rescued the 6AU sensitivity of rad2${\Delta}$ and puf4${\Delta}$ mutants. These results indicate that 6AU sensitivity of rad2 mutants is in part ascribed to impaired expression regulation of genes in the nucleotide metabolism. Based on the results, the possible connection between impaired transcription elongation function of RAD2/XPG and Cockayne syndrome via PUF4 is discussed. -
Ko, Jeong-Hyeon;Kang, Ju-Hee;Park, Chang-Shin;Shin, Dong-Wun;Kim, Ji-Hye;Kim, Hoon;Han, Seung-Baik 348
Bisphenol A (BPA), an environmental endocrine disrupter, enters the human body continuously in food and drink. Young children are likely to be more vulnerable than adults to chemical exposure due to the immaturities of their organ systems, rapid physical development, and higher ventilation, metabolic rates, and activity levels. The direct effect of BPA on peripheral tissue might also be of importance to the development of insulin resistance. However, the influence that BPA has on insulin signaling molecules in skeletal muscle has not been previously investigated. In this study, we examined the effect of BPA on fasting blood glucose (FBG) in post-weaned Wistar rats and on insulin signaling proteins in C2C12 skeletal muscle cells. Subsequently, we investigated the effects of BPA on insulin-mediated Akt phosphorylation in C2C12 myotubes. In rats, BPA treatment (0.1-1,000 ng/mL for 24 hours) resulted in the increase of FBG and plasma insulin levels, and reduced insulin-mediated Akt phosphorylation. Furthermore, the mRNA expression of insulin receptor (IR) was decreased after 24 hours of BPA treatment in C2C12 cells in a dose-dependent manner, whereas the mRNA levels of other insulin signaling proteins, including insulin receptor substrate-1 (IRS-1) and 5'-AMP-dependent protein kinase (AMPK), were unaffected. Treatment with BPA increased GLUT4 expression and protein tyrosine phosphatase 1B (PTP1B) activity in C2C12 myotubes, but not in protein levels. We conclude that exposure to BPA can induce insulin resistance by decreasing IR gene expression, which is followed by a decrease in insulin- mediated Akt activation and increased PTP1B activity. -
Kang, Rhee-Hun;Hahn, Sang-Woo;Choi, Myoung-Jin;Lee, Hwa-Young;Chang, Hun-Soo;Jeong, Yoo-Jung;Paik, Jong-Woo;Lim, Se-Won;Kim, Young-En;Lee, Min-Soo 355
This study aimed to determine the relationship between the C825T polymorphism in the G-protein${\beta}$ 3-subunit (GNB3) gene and the response to citalopram in a Korean population with major depressive disorder (MDD). Citalopram was administered for 8 weeks to the 84 MDD patients who completed this study. All subjects were examined using the Structured Clinical Interview for DSM-IV, and the severity of depression was assessed using the 21-item Hamilton Depression Rating (HAMD-21) scale. A main effect of an interaction of genotype with time on the decrease in the HAMD-21 score during the 8-week study period was not found. ANOVA revealed no significant effects of the GNB3 C825T polymorphism on the decrease in the HAMD-21 score at each time period. Although the C825T polymorphism of the GNB3 gene may affect the pathogenesis of MDD, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to citalopram in Korean patients with MDD. -
Park, Jun-Ho;Cha, Bong-Suk;Chang, Sei-Jin;Koh, Sang-Baek;Eom, Ae-Yong;Lee, Kang-Myeung;Jung, Min-Ye;Choi, Hong-Soon 360
In the last several years, studies on the association of oxidative stress damage with exposure in the work place have been conducted. Xenobiotics create an imbalance of the homeostasis between oxidant molecules and antioxidant defense. By monitoring oxidative stress biomarkers, information was obtained on damages induced by oxidative stress and the toxicity of xenobiotics. In the present study, a Job Exposure Matrix (JEM) was constructed using the data from the Working Environment Measurement (WEM) of painters in the shipyard industry from the past 3 years to assess the exposure status. Additionally, by measuring the concentration of urinary malondialdehyde (MDA), the effect of lipid peroxidation was examined. The subjects consisted of 68 workers who were exposed to mixed organic solvents in the painting process and 25 non-exposure controls. The exposure indices of the exposure groups were significantly different (sprayer: 0.83, touchup: 0.54, assistant: 0.13, P<0.05). The urinary MDA concentration of the exposure group was 48.60${\pm}$ 39.23${\mu}mol$ /mol creatinine, which was significantly higher than 18.03${\pm}$ 16.33${\mu}mol$ /mol creatinine of the control group (P<0.05). From the multiple regression analysis of urinary MDA, the regression coefficient for exposure grade was statistically significant. In future studies, evaluation of the antioxidant levels of subjects should be performed simultaneously with quantitative exposure measurements.