• Molecular & Cellular Toxicology
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• 제1권2호
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• pp.137-141
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• 2005

The critical role of folate in the remethylation pathway for methionine synthesis from homocysteine has been well documented. Hyperhomocysteinemia resulting from inadequate folate nutrition has been implicated in increased incidence of macrovascular diseases, colorectal cancer, neural tube defects, etc. Chronic exposure to ethanol impairs folate nutrition and one-carbon metabolism in the liver, which often results in fatty liver due to a defective remetylation process. This study was carried out to investigate the chronic effects of moderate levels of alcohol and dietary folate on plasma homocysteine levels, and on histopathology and biochemical functions of the liver. Rats were raised on experimental diets with three levels of folate (0, 2, 8 mg/kg diet), and 50% ethanol (1.8 ml/kg body weight) was administered intragastically by intubation tubes three times a week for 10 weeks. Plasma homocysteine concentrations were found to be significantly influenced by dietary folate intake and alcohol administration. Among all treatment groups, plasma homocysteine levels were the highest in the animals receiving a combined treatment of folate deficient diet and alcohol administration. Plasma homocysteine concentrations were negatively correlated with folate concentration in the plasma (p<0.01) and liver (p<0.05). Among alcohol treated rats, increase in plasma homocysteine values due to macrovascular and microvascular fatty changes and spotted necrosis were observed more frequently in folate-deficient animals diet than those on folate-adequate and folate supplemented diets in alcohol-treated rats. These results indicate that folate supplementation above the recommended level might be beneficial in the prevention of alcohol-related hyperhomocysteinemia and abnormal histologic changes in the liver.

• 한국환경성돌연변이발암원학회지
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• 제24권2호
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• pp.91-98
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• 2004

Although 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) is a powerful carcinogen in several species, limited model system exist to study carcinogenicity of this compound at cellular level. To enhance our under-standing of carcinogenicity of TCDD at cellular level, we investigated micronucleus (MN) frequency as a index of genetic toxicity and whether TCDD can transform the human cells in culture. Normal human cell lines, skin keratinocyte HaCaT, Chang liver and breast MCF10A cells were used. TCDD did not affect the cell viability of the Chang liver, HaCaT and MCF10A cells. The frequency of micronucleus was increased after treatment of TCDD for 24hr in Chang liver and HaCaT cells, but not changed in MCF10A cells. And we observed putative transformed cells in Chang liver cells exposed to 1 $\mu$M TCDD for 2 weeks. The putative transformed cells were also observed in HaCaT cells with subsequent exposure to TCDD (0.1, 1, 10, 100 nM) for 2 weeks after initial exposure to MNNG, but not observed in MCF10A cells. Collectively, these results indicate that the ability of TCDD to induce micronuclei may be involved in cellular transformation of Chang liver and HaCaT cells. Our putative TCDD-transformed cells of Chang liver and HaCaT are expected to provide a clue to the elucidation of TCDD-induced transformation pathway.

• Molecular & Cellular Toxicology
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• 제3권2호
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• pp.113-118
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• 2007

Chlorobenzenes due to their acute toxicity and the capability of bioaccumulating are of great health and environmental concern. Especially, 1, 2-dichlorobenzene (CAS No. 95-50-1) is used for organic synthesis, dye manufacture, as a solvent and for other applications in chemical industry. Adverse effects of 1, 2-dichlorobenzene includes increases in liver and kidney weights and hepatotoxicity. In this study, we evaluated the genetic toxicity of 1, 2-dichlorobenzene with more advanced methods, in vitro mouse lymphoma assay $tk^{+/-}$ gene assay (MLA) and in vitro mouse supravital micronucleus (MN) assay. 1, 2-Dichlorobenzene appeared the significantly positive results and the induction of large mutant colonies only in the presence of metabolic activation system with MLA. But in vitro testing of 1, 2-dichlorobenzene yielded negative results with supravital MN assay. These results suggest that 1, 2-dichlorobenzene may play a mutagen rather than clastogen in vitro mammalian system.

• 한국환경성돌연변이발암원학회지
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• 제26권1호
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• pp.1-6
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• 2006

To enhance our understanding of toxicity mediated through the pathway by which TCDD stimulates gene expression, we have investigated genes whose expressions are changed after treatment with TCDD and/or MNNG in human Chang liver cell. First, we treated with MNNG and TCDD for two weeks to transform human Chang liver cell. We obtained cell looks like to be transformed and compared the differential gene expression by using cDNA chip (Macrogen) which carrys genes related with signal transduction pathways, oncogenes and tumor suppressor genes, etc. We found that TCDD up- or down-regulated 203 and 111 genes including oncogenes and tumor suppressor genes in human Chang liver cell two fold or more, respectively. Second, we compared the differential gene expression after treatment with TCDD only by using cDNA chip (Superarray) which carrys genes related with cell cycle regulations, and found that TCDD up regulated genes related with cell proliferation as well as cell growth inhibition in human Chang liver cell two fold or more, respectively. These results suggest that toxicity induced by TCDD may reflect sustained alterations in the expression of many genes and that the changes reflect both direct and indirect effects of TCDD.

• 한국축산식품학회지
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• 제23권2호
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• pp.137-144
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• 2003

본 연구에서는 IGFs를 다양한 기능성 유제품에 적용하기 전에 먼저 상업용 IGFs 및 초유로부터 분리.정제된 IGFs의 안전성을 평가하여 새로운 기능성 소재로서의 IGFs의 가능성을 검토해 보고자 하였다. 이를 위하여 독성평가에서 기본적으로 수행되고 있는 단회투여독성시험과 반복투여독성시험을 실시하였다. 단회투여독성시험에서는 R&D Systems사의 Recombinant Human IGF- I 을 시험물질로 하고 생후 4주된 Sprague-Dawley계(♂) 흰쥐(rat)를 실험동물로 하여 개체당 0, 10, 20, 50 $\mu\textrm{g}$씩 투여하는 시험군을 설정한 후, 꼬리정 꼬리정맥에 주사하여 20일간 관찰하면서 체중변화, 식이섭취변화를 측정하고 최종적으로 부검하여 육안검사 및 간장, 신장, 비장에 대한 병리조직검사를 실시한 결과, 명확한 이상소견이 나타나지 않아 모든 시험군에서 급성독성이 확인되지 않았다. 반복투여독성시험에서는 초유로부터 분리.정제된 IGF- I 을 시험물질로 하고 생후 4주된 Sprague-Dawley계(♂) 흰쥐(rat)를 실험동물로 하여 개체당 0, 5, 10, 15 $\mu\textrm{g}$씩 투여하는 시험군을 설정한 후, 14일간 반복적으로 강제경구투여하면서 임상증상을 관찰하면서 체중변화, 식이섭취변화를 측정하였고 최종적으로 부검하여 육안검사 및 간장, 신장, 비장에 대한 병리조직검사를 실시한 결과, 명확한 이상소견이 나타나지 않아 모든 투여농도에서 반복투여독성시험을 비롯한 기본적인 독성평가에 있어서 초유 내 IGF-I의 안전성에는 명확한 이상소견이 없는 것으로 판단되었다.

• International Journal of Stem Cells
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• 제17권2호
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• pp.120-129
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• 2024

Recent amendments to regulatory frameworks have placed a greater emphasis on the utilization of in vitro testing platforms for preclinical drug evaluations and toxicity assessments. This requires advanced tissue models capable of accurately replicating liver functions for drug efficacy and toxicity predictions. Liver organoids, derived from human cell sources, offer promise as a reliable platform for drug evaluation. However, there is a lack of standardized quality evaluation methods, which hinders their regulatory acceptance. This paper proposes comprehensive quality standards tailored for liver organoids, addressing cell source validation, organoid generation, and functional assessment. These guidelines aim to enhance reproducibility and accuracy in toxicity testing, thereby accelerating the adoption of organoids as a reliable alternative or complementary tool to animal testing in drug development. The quality standards include criteria for size, cellular composition, gene expression, and functional assays, thus ensuring a robust hepatotoxicity testing platform.

• Molecular & Cellular Toxicology
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• 제1권2호
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• pp.78-86
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• 2005

Dioxins, especially 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD or dioxin), are ubiquitous environmental contaminants. TCDD is known that it has toxic effects in animals and humans, including chloracne, immune, reproductive and developmental toxicities, carcinogenicity, wasting syndrome and death. TCDD induces a broad spectrum of biological responses, including disruption of normal hormone signaling pathways, reproductive and developmental defects, immunotoxicity, liver damage, wasting syndrome and cancer. Many researches showed that TCDD induces gene expression of transcriptional factors related cell proliferation, signal transduction, immune system and cell cycle arrest at molecular and cellular levels. These toxic actions of TCDD are usually mediated with AhR (receptor, resulted from cell culture, animal and clinical studies). cDNA microarray can be used as a highly sensitive and informative marker for toxicity. Additionally, microarray analysis of dioxin-toxicity is able to provide an opportunity for the development of candidate bridging biomarkers of dioxin-toxicity. Through microarray technology, it is possible to understand the therapeutic effects of agonists within the context of toxic effects, classify new chemicals as to their complete effects on biological systems, and identify environmental factors that may influence safety.

• Molecular & Cellular Toxicology
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• 제4권2호
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• pp.138-143
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• 2008

We investigated if Chlorella vulgaris (CV) has protective effects on cadmium (Cd) induced liver damage in male Sprague-Dawley (SD) rats. Forty rats, aged 5 weeks old and weighed 90-110g, were divided into a control (with Cd free water), 50 ppm of $CdCl_2$ in drinking water treated groups (Chlorella 0% diet group (Cd/CV0%), Chlorella 5% diet group (Cd/CV5%) or Chlorella 10% diet group (Cd/CV10%). All the rats had freely access to water and diet for 8 weeks. The results show that body weight gain and relative liver weight had significantly lower in Cd/CV0%-treated group than in Cd/CV-treated groups. Hepatic Cd contents showed significantly less by feeding CV (P<0.05). Cd/CV0%-treated rats had significantly (P<0.05) higher hepatic T-MTs, and Cd-MTs concentrations, compared to Cd/CV5% or Cd/CV10% treated rats. The MT I/II mRNA was expressed in the liver of all experimental rats. Its expression was more increased in Cd/CV5%- or Cd/CV10%-treated rats, compared to control and Cd-treated rats. Thus, this study suggested that CV would have a protective effect on Cd-treated liver injury by the reduction of Cd concentrations and stimulation of Cd-MT binds in the liver. However, more studies are needed to identify the proper mechanism of CV and liver toxicity.

• Molecular & Cellular Toxicology
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• 제5권4호
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• pp.310-316
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• 2009

Some environmental chemicals have been shown to cause liver-toxicity as the result of bioaccumulation. Particularly, fungicides have been shown to cause varying degrees of hepatictoxicity and to disrupt steroid hormone homeostasis in in vivo models. The principal objective of this study was to evaluate the liver-toxic responses of environmental chemicals-in this case selected fungicides and parasiticides-in order to determine whether or not this agent differentially affected its toxicogenomic activities in hepatic tumor cell lines. To determine the gene expression profiles of 3 fungicides (triadimefon, myclobutanil, vinclozolin) and 1 parasiticide (dibutyl phthalate), we utilized a modified HazChem human array V2. Additionally, in order to observe the differential alterations in its time-dependent activities, we conducted two time (3 hr, 48 hr) exposures to the respective IC20 values of four chemicals. As a result, we analyzed the expression profiles of a total of 1638 genes, and we identified 70 positive significant genes and 144 negative significant genes using four fungicidic and parasiticidic chemicals, using SAM (Significant Analysis of Microarray) methods (q-value<0.5%). These genes were analyzed and identified as being related to apoptosis, stress responses, germ cell development, cofactor metabolism, and lipid metabolism in GO functions and pathways. Additionally, we found 120 genes among those time-dependently differentially expressed genes, using 1-way ANOVA (P-value<0.05). These genes were related to protein metabolism, stress responses, and positive regulation of apoptosis. These data support the conclusion that the four tested chemicals have common toxicogenomic effects and evidence respectively differential expression profiles according to exposure time.

• Molecular & Cellular Toxicology
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• 제3권3호
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• pp.172-176
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• 2007

Butylated hydroxytoluene (BHT) is widely used antioxidant food additives. It has been extensively studied for potential toxicities. BHT appears adverse effects in liver and thyroid. In this study, we evaluated the genetic toxicity of BHT with more advanced methods, in vitro mouse lymphoma assay $tk^{+/-}$ gene assay (MLA) and in vivo mouse supravital micronucleus (MN) assay. BHT did not appear the significantly results in the absence and presence of metabolic activation system with MLA. Also, in vivo testing of BHT yielded negative results with supravital MN assay. These results suggest that BHT itself was not generally considered genotoxic.