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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 & Issues
Volume 32, Issue 3 - Jul 2016
Volume 32, Issue 2 - Apr 2016
Volume 32, Issue 1 - Jan 2016
Selecting the target year
Shedding New Lights with the Breakthrough Ideas to Understand Current Trends in Modern Toxicology
Bae, Ok-Nam ; Lee, Joo Young ;
Toxicological Research, volume 32, issue 1, 2016, Pages 1~3
DOI : 10.5487/TR.2016.32.1.001
Advancing Risk Assessment through the Application of Systems Toxicology
Sauer, John Michael ; Kleensang, Andre ; Peitsch, Manuel C. ; Hayes, A. Wallace ;
Toxicological Research, volume 32, issue 1, 2016, Pages 5~8
DOI : 10.5487/TR.2016.32.1.005
Risk assessment is the process of quantifying the probability of a harmful effect to individuals or populations from human activities. Mechanistic approaches to risk assessment have been generally referred to as systems toxicology. Systems toxicology makes use of advanced analytical and computational tools to integrate classical toxicology and quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Three presentations including two case studies involving both in vitro and in vivo approaches described the current state of systems toxicology and the potential for its future application in chemical risk assessment.
Advances in the Development and Validation of Test Methods in the United States
Casey, Warren M. ;
Toxicological Research, volume 32, issue 1, 2016, Pages 9~14
DOI : 10.5487/TR.2016.32.1.009
The National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) provides validation support for US Federal agencies and the US Tox21 interagency consortium, an interagency collaboration that is using high throughput screening (HTS) and other advanced approaches to better understand and predict chemical hazards to humans and the environment. The use of HTS data from assays relevant to the estrogen receptor signaling data pathway is used as an example of how HTS data can be combined with computational modeling to meet the needs of US agencies. As brief summary of US efforts in the areas of biologics testing, acute toxicity, and skin sensitization will also be provided.
Addressing Early Life Sensitivity Using Physiologically Based Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation
Yoon, Miyoung ; Clewell, Harvey J. III ;
Toxicological Research, volume 32, issue 1, 2016, Pages 15~20
DOI : 10.5487/TR.2016.32.1.015
Physiologically based pharmacokinetic (PBPK) modeling can provide an effective way to utilize in vitro and in silico based information in modern risk assessment for children and other potentially sensitive populations. In this review, we describe the process of in vitro to in vivo extrapolation (IVIVE) to develop PBPK models for a chemical in different ages in order to predict the target tissue exposure at the age of concern in humans. We present our on-going studies on pyrethroids as a proof of concept to guide the readers through the IVIVE steps using the metabolism data collected either from age-specific liver donors or expressed enzymes in conjunction with enzyme ontogeny information to provide age-appropriate metabolism parameters in the PBPK model in the rat and human, respectively. The approach we present here is readily applicable to not just to other pyrethroids, but also to other environmental chemicals and drugs. Establishment of an in vitro and in silico-based evaluation strategy in conjunction with relevant exposure information in humans is of great importance in risk assessment for potentially vulnerable populations like early ages where the necessary information for decision making is limited.
Toxicity and Carcinogenicity of Dichlorodiphenyltrichloroethane (DDT)
Harada, Takanori ; Takeda, Makio ; Kojima, Sayuri ; Tomiyama, Naruto ;
Toxicological Research, volume 32, issue 1, 2016, Pages 21~33
DOI : 10.5487/TR.2016.32.1.021
Dichlorodiphenyltrichloroethane (DDT) is still used in certain areas of tropics and subtropics to control malaria and other insect-transmitted diseases. DDT and its metabolites have been extensively studied for their toxicity and carcinogenicity in animals and humans and shown to have an endocrine disrupting potential affecting reproductive system although the effects may vary among animal species in correlation with exposure levels. Epidemiologic studies revealed either positive or negative associations between exposure to DDT and tumor development, but there has been no clear evidence that DDT causes cancer in humans. In experimental animals, tumor induction by DDT has been shown in the liver, lung, and adrenals. The mechanisms of hepatic tumor development by DDT have been studied in rats and mice. DDT is known as a non-genotoxic hepatocarcinogen and has been shown to induce microsomal enzymes through activation of constitutive androstane receptor (CAR) and to inhibit gap junctional intercellular communication (GJIC) in the rodent liver. The results from our previously conducted 4-week and 2-year feeding studies of p,p'-DDT in F344 rats indicate that DDT may induce hepatocellular eosinophilic foci as a result of oxidative DNA damage and leads them to hepatic neoplasia in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT.
Autophagy in Ischemic Livers: A Critical Role of Sirtuin 1/Mitofusin 2 Axis in Autophagy Induction
Chun, Sung Kook ; Go, Kristina ; Yang, Ming-Jim ; Zendejas, Ivan ; Behrns, Kevin E. ; Kim, Jae-Sung ;
Toxicological Research, volume 32, issue 1, 2016, Pages 35~46
DOI : 10.5487/TR.2016.32.1.035
No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation between sirtuin 1, mitophagy and ischemic liver injury.
Pyruvate Kinase M2: A Novel Biomarker for the Early Detection of Acute Kidney Injury
Cheon, Ji Hyun ; Kim, Sun Young ; Son, Ji Yeon ; Kang, Ye Rim ; An, Ji Hye ; Kwon, Ji Hoon ; Song, Ho Sub ; Moon, Aree ; Lee, Byung Mu ; Kim, Hyung Sik ;
Toxicological Research, volume 32, issue 1, 2016, Pages 47~56
DOI : 10.5487/TR.2016.32.1.047
The identification of biomarkers for the early detection of acute kidney injury (AKI) is clinically important. Acute kidney injury (AKI) in critically ill patients is closely associated with increased morbidity and mortality. Conventional biomarkers, such as serum creatinine (SCr) and blood urea nitrogen (BUN), are frequently used to diagnose AKI. However, these biomarkers increase only after significant structural damage has occurred. Recent efforts have focused on identification and validation of new noninvasive biomarkers for the early detection of AKI, prior to extensive structural damage. Furthermore, AKI biomarkers can provide valuable insight into the molecular mechanisms of this complex and heterogeneous disease. Our previous study suggested that pyruvate kinase M2 (PKM2), which is excreted in the urine, is a sensitive biomarker for nephrotoxicity. To appropriately and optimally utilize PKM2 as a biomarker for AKI requires its complete characterization. This review highlights the major studies that have addressed the diagnostic and prognostic predictive power of biomarkers for AKI and assesses the potential usage of PKM2 as an early biomarker for AKI. We summarize the current state of knowledge regarding the role of biomarkers and the molecular and cellular mechanisms of AKI. This review will elucidate the biological basis of specific biomarkers that will contribute to improving the early detection and diagnosis of AKI.
Associations of Low Environmental Exposure to Multiple Metals with Renal Tubular Impairment in Korean Adults
Lim, Hyungryul ; Lim, Ji-ae ; Choi, Jong Hyuk ; Kwon, Ho-jang ; Ha, Mina ; Kim, Heon ; Park, Jung-duck ;
Toxicological Research, volume 32, issue 1, 2016, Pages 57~64
DOI : 10.5487/TR.2016.32.1.057
Recently several studies reported that the renal toxicity of lead (Pb) and cadmium (Cd) may exist in even a low level exposure. In terms of the deterioration of tubular function, it affects the loss of divalent metals and leads to other complications, so renal tubular effect of heavy metals should be well managed. Considering the exposure to heavy metals in reality, it is hard to find the case that human is exposed to only one heavy metal. We designed a cross-sectional study using Korean Research Project on the Integrated Exposure Assessment (KRIEFS) data to investigate the renal effects of multiple metal exposure in general population. We used blood Pb and urinary Cd as exposure measures, and urinary N-acetyl-
-D-glucosaminidase (NAG) and
-MG) as renal tubular impairment outcome. We conducted linear regression to identify the association between each heavy metal and urinary NAG and
-MG. And then, we conducted linear regression including the interaction term. Of 1953 adults in KRIEFS (2010~2011), the geometric mean of blood Pb and urinary Cd concentration was
), respectively. In urinary Cd, the strength of the association was also high after adjusting (urinary NAG:
, p < 0.001; urinary
, p = 0.002). Finally, we identified the positive interactions for the two renal biomarkers. The interaction effect of the two heavy metals of
-MG was greater than that of NAG. It is very important in public health perspective if the low level exposure to multiple heavy metals has an interaction effect on kidney. More epidemiological studies for the interaction and toxicological studies on the mechanism are needed.
Cadmium Exposure and Potential Health Risk from Foods in Contaminated Area, Thailand
Chunhabundit, Rodjana ;
Toxicological Research, volume 32, issue 1, 2016, Pages 65~72
DOI : 10.5487/TR.2016.32.1.065
Man-made cadmium (Cd) emissions can be transported between environmental matrices and the food chain. Food is the primary source of Cd exposure among general population as a consequence of the bioconcentration of Cd from soil. Chronic Cd exposure has been reported to be associated with chronic kidney disease, osteoporosis, diabetes, cardiovascular disease and cancer. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established the safe level of Cd intake as provisional tolerable monthly intake (PTMI) of
in 2010. The major food groups that contribute to the most Cd exposure are rice and grains, shellfish and sea food, meat including edible offal, and vegetables. A number of studies reported the high Cd contaminated levels in foods from polluted areas in Thailand. The results are of high concern since the contaminations occur in foods that are major Cd contributors. Thus, in this review, the current situations of Cd contaminated foods in polluted areas of Thailand are summarized. In addition, the Cd intakes from selected scenarios are estimated to assess the potential health risk to consumers and the suggestions are also included.
Different Regulation of p53 Expression by Cadmium Exposure in Kidney, Liver, Intestine, Vasculature, and Brain Astrocytes
Lee, Jin-Yong ; Tokumoto, Maki ; Hattori, Yuta ; Fujiwara, Yasuyuki ; Shimada, Akinori ; Satoh, Masahiko ;
Toxicological Research, volume 32, issue 1, 2016, Pages 73~80
DOI : 10.5487/TR.2016.32.1.073
Chronic exposure to cadmium (Cd) is known to adversely affect renal function. Our previous studies indicated that Cd induces p53-dependent apoptosis by inhibiting gene expression of the ubiquitin-conjugating enzyme (Ube) 2d family in both human and rat proximal tubular cells. In this study, the effects of Cd on protein expression of p53 and apoptotic signals in the kidney and liver of mice exposed to Cd for 12 months were examined, as well as the effects of Cd on p53 protein levels and gene expression of the Ube2d family in various cell lines. Results showed that in the kidney of mice exposed to 300 ppm Cd for 12 months, there was overaccumulation of p53 proteins in addition to the induction of apoptosis, which was triggered specifically in the proximal tubules. Interestingly, the site of apoptosis was the same as that of p53 accumulation in the proximal tubules. In the liver of mice chronically exposed to Cd, gene expression of the Ube2d family tended to be slightly decreased, together with slight apoptosis without the accumulation of p53 protein. In rat small intestine epithelial (IEC-6) cells, Cd decreased not only the p53 protein level but also gene expression of Ube2d1, Ube2d2 and Ube2d4. In human brain microvascular endothelial cells (HBMECs), Cd did not suppress gene expression of the Ube2d family, but increased the p53 protein level. In human brain astrocytes (HBASTs), Cd only increased gene expression of UBE2D3. These results suggest that Cd-induced apoptosis through p53 protein is associated with renal toxicity but not hepatic toxicity, and the modification of p53 protein by Cd may vary depending on cell type.
A Rapid and Sensitive Detection of Aflatoxin-producing Fungus Using an Optimized Polymerase Chain Reaction (PCR)
Bintvihok, Anong ; Treebonmuang, Supitchaya ; Srisakwattana, Kitiya ; Nuanchun, Wisut ; Patthanachai, Koranis ; Usawang, Sungworn ;
Toxicological Research, volume 32, issue 1, 2016, Pages 81~87
DOI : 10.5487/TR.2016.32.1.081
Aflatoxin B1 (AFB1) is produced by Aspergillus flavus growing in feedstuffs. Early detection of maize contamination by aflatoxigenic fungi is advantageous since aflatoxins exert adverse health effects. In this study, we report the development of an optimized conventional PCR for AFB1 detection and a rapid, sensitive and simple screening Real-time PCR (qPCR) with SYBR Green and two pairs of primers targeting the aflR genes which involved aflatoxin biosynthesis. AFB1 contaminated maize samples were divided into three groups by the toxin concentration. Genomic DNA was extracted from those samples. The target genes for A. flavus were tested by conventional PCR and the PCR products were analyzed by electrophoresis. A conventional PCR was carried out as nested PCR to verify the gene amplicon sizes. PCR-RFLP patterns, obtained with Hinc II and Pvu II enzyme analysis showed the differences to distinguish aflatoxin-producing fungi. However, they are not quantitative and need a separation of the products on gel and their visualization under UV light. On the other hand, qPCR facilitates the monitoring of the reaction as it progresses. It does not require post-PCR handling, which reduces the risk of cross-contamination and handling errors. It results in a much faster throughout. We found that the optimal primer annealing temperature was
. The optimized template and primer concentration were
respectively. SYBR Green qPCR of four genes demonstrated amplification curves and melting peaks for tub1, afIM, afIR, and afID genes are at
respectively. Consequently, it was found that the four primers had elevated annealing temperatures, nevertheless it is desirable since it enhances the DNA binding specificity of the dye. New qPCR protocol could be employed for the determination of aflatoxin content in feedstuff samples.