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

• Molecular & Cellular Toxicology
• /
• 제1권2호
• /
• pp.130-136
• /
• 2005

The purpose of this study was to evaluate whether the interactions between maternal folate deficiency and methylenetetrahydrofolate reductase (MTHFR) polymorphism increase the risk of elevated maternal serum homocysteine, short gestation and reduced infant birthweight. Healthy pregnant (n = 170; 24-28 gestational weeks; 20-40 years old) women were analyzed for the MTHFR genotype and serum levels of folate and homocysteine, and were then followed for gestational age and infant birthweight. The mean infant birthweight was highest in mothers carrying MTHFR CC and with a normal folate range, and they were followed by mothers carrying MTHFR CT or TT and a normal range of folate or a folate deficiency. Birthweight was the lowest in mothers whose carrying MTHFR CC with folate deficiency. Using two way ANOVA, we found that folate level and the MTHFR polymorphism interacted to affect birth-weight of infants (p=0.05). Among those mothers carrying MTHFR CC, those with folate deficiency showed a 543 g reduction in infant birthweight compared with those with normal folate levels. However, infant birthweight was no different for mothers, those who with folate deficiency compared to those with normal range of folate among mothers carrying the MTHFR CT or TT genotypes. This study suggests an interaction between maternal serum folate and the MTHFR polymorphisms of the mother on the risk of delivering reduced birthweight offspring. Folate supplementation of folate deficient pregnant women with the MTHFR wild type is suggested to reduce the risk of low birthweight.

• Molecular & Cellular Toxicology
• /
• 제1권2호
• /
• pp.111-115
• /
• 2005

Ultraviolet (UV) radiation to mammalian skin is known to alter cellular function via generation of Reactive Oxygen Species (ROS), DNA damage and DNA lesions, such as pyrimidine dimmers and photoproducts, which could lead to DNA mutation if they are not repaired. In this study, we have investigated the reduction of DNA damage and of apoptosis with a particular attention to genetic effect of paeoniflorin in Normal Human Epidermal Keratinocytes (NHEK). After UVB irradiation from $10\;to\;500mJ/cm^{2}$ to NHEK, Mean Tail Moments (MTM) were increased with UVB dose increase. The greatest amount of strand breaks was induced at $500mJ/cm^{2}$ of UVB. Even at the lowest dose of UVB ($10mJ/cm^{2}$), change in MTM was detected (P<0.0001). Pretreated cell with 0.1% paeoniflorin maximally reduced the level of DNA damage to about 21.3%, compared to untreated cell. In the lower concentrations less than 0.01% of paeoniflorin, MTM had a small increase but paeoniflorin still had reductive effects of DNA damage. We measured the apoptosis suppression of paeoniflorin with annexin V flous staining kit. As we observed under the fluorescence microscopy to detect apoptosis in the irradiated cell, the fluorescence intensity was clearly increased in the untreated cell, but decreased in treated cells with paeoniflorin. These results suggest that paeoniflorin reduces the alteration of cell membranes and prevents DNA damage. Therefore, the use of paeoniflorin as a free radical scavenger to reduce the harmful effects of UV lights such as chronic skin damage, wrinkling and skin cancer can be useful to prevent the formation of photooxidants that result in radical damage.

• Molecular & Cellular Toxicology
• /
• 제1권2호
• /
• pp.99-105
• /
• 2005

Perchloroethylene (tetrachloroethylene, PCE), a dry cleaning and degreasing solvent, can enter ground-water through accidental leak or spills. PCE can be degraded to trichloroethylene (TCE), 1, 1-dichloroethylene (DCE) and vinyl chloride (VC) as potential bio-product. These compounds have been reported that they can cause clinical diseases and cytotoxicity. However, only a little genotoxic information of these compounds has been known. In this study, we investigated DNA single strand breaks of PCE, TCE, DCE and VC by single cell gel electrophoresis assay, (comet assay) which is a sensitive, reliable and rapid method for DNA single strand breaks with mouse lymphoma L5178Y cells. From these results, $37.5\;{\mu}g/ml$ of PCE, $189\;{\mu}g/ml$ of TCE and $56.4\;{\mu}g/ml$ of DCE were revealed significant DNA damages in the absence of S-9 metabolic activation system meaning direct-acting mutagen. And in the presence of S-9 metabolic activation system, $41.5\;{\mu}g/ml$ of PCE, $328.7\;{\mu}g/ml$ of TCE and $949\;{\mu}g/ml$ of DCE were induced significant DNA damage. In the case of VC, it was revealed a significant DNA damage in the presence of S-9 metabolic activation system. Therefore, we suggest that chloroethylene compounds (PCE, TCE, DCE and VC) may be induced the DNA damage in a mammalian cell.

• Molecular & Cellular Toxicology
• /
• 제1권2호
• /
• pp.73-77
• /
• 2005

Nickel is the one of potent environmental, the occupational pollutants and the classified human carcinogens. It is a serious hazard to human health, when the metal exposure. To prevent human diseases from the heavy metals, it is seemingly important that understanding of how nickel exerts their toxicity and carcinogenic effect at a molecular and a genomic level. The process of nickel absorption has been demonstrated as phagocytosis, iron channel and diffusion. Uptaked nickel has been suggested to induce carcinogenesis via two pathways, a direct DNA damaging pathway and an indirect DNA damaging pathway. The former was originated from the ability of metal to generate Reactive Oxygen Species (ROS) and the reactive intermediates to interact with DNA directly. Ni-generated ROS or Nickel itself, interacts with DNAs and histones to cause DNA damage and chromosomal abnormality. The latter was originated from an indirect DNA damage via inhibition of DNA repair, or condensation and methylation of DNA. Cells have ability to protect from the genotoxic stresses by changing gene expression. Microarray analysis of the cells treated with nickel or nickel compounds, show the specific altered gene expression profile. For example, HIF-I (Hypoxia-Inducible Factor I) and p53 were well known as transcription factors, which are upregulated in response to stress and activated by both soluble and insoluble nickel compounds. The induction of these important transcription factors exert potent selective pressure and leading to cell transformation. Genes of metallothionein and family of heat shock proteins which have been known to play role in protection and damage control, were also induced by nickel treatment. These gene expressions may give us a clue to understand of the carcinogenesis mechanism of nickel. Further discussions on molecular and genomic, are need in order to understand the specific mechanism of nickel toxicity and carcinogenicity.

• Molecular & Cellular Toxicology
• /
• 제5권1호
• /
• pp.75-82
• /
• 2009

Saengshik is an uncooked and powdered functional food composed of various edible plants, and has been consumed widely due to its health benefits and convenient uptake. Recently, superfine ground saengshik, which contains a certain extent of nanoscale particles, has been commercialized to enhance efficacy, but its safety has not been determined. This study was conducted to evaluate the food safety of superfine saengshik (SS) through general toxicity examination after oral uptake in mice compared to conventional fine saengshik (FS). The SS particle size distribution was 0.479-26.303 f.1m in diameter, with about 68.92% of particles with a diameter < $0.955{\mu}m$. From our safety evaluation, the number of white blood cells (WBCs) and biochemical values in the serum fell into the normal range, and the weight of organs showed no significant difference between FS and SS groups. Histological observation of the liver, small intestine and large intestine did not show any abnormal or pathological findings under light microscopy. Our results suggest that oral intake of SS is not harmful to mice in terms of general toxicity.

• Molecular & Cellular Toxicology
• /
• 제5권1호
• /
• pp.67-74
• /
• 2009

Exposures to environmental chemicals that mimic endogenous hormones are proposed for a number of adverse health effects, including infertility, abnormal prenatal and childhood development and above all cancers. In addition, recently miRNA (micro RNA) has been recognized to play an important role in various diseases and in cellular and molecular responses to toxicants. In this study, endocrine disrupting environmental toxicant, nonylphenol (NP) was treated to MCF-7 (Human breast cancer cell) and HepG2 (Human hepatocellular liver carcinoma) cell line at 3 hrs and 48 hrs time point and miRNA analysis using $mirVana^{TM}$ miRNA bioarray was performed and compared with total mRNA microarray data for the same cell line and treatment. Robust data quality was achieved through the use of dye-swap. Analysis of microarray data identifies a total of 20 and 11 miRNA expressions at 3 hrs and 48 hrs exposure to NP in MCF-7 cell line and a total of 14 and 47 miRNA expression at 3 hrs and 48 hrs exposure respectively to NP in HepG2 cell line. Expression profiling of the selected miRNA (let-7c, miR-16, miR-195, miR-200b, miR200c, miR-205, and miR-589) reveals changes in the expression of target genes related to metabolism, immune response, apoptosis, and cell differentiation. The present study can be informative and helpful to understand the role of miRNA in molecular mechanism of chemical toxicity and their influence on hormone dependent disease. Also this study may prove to be a valuable tool for screening potential estrogen mimicking pollutants in the environment.

• Molecular & Cellular Toxicology
• /
• 제5권2호
• /
• pp.99-107
• /
• 2009

Naphthalene is bicyclic aromatic compound that is widely used in various domestic and commercial applications including lavatory scent disks, soil fumigants and moth balls. Exposure to naphthalene results in the development of bronchiolar damage, cataracts and hemolytic anemia in humans and laboratory animals. However, little information is available regarding the mechanism of naphthalene toxicity. We investigated gene expression profiles and potential signature genes in human hepatocellular carcinoma HepG2 cells and human promyelocytic leukemia HL-60 cells after 3 h and 48 h incubation with the IC$_{20}$ and IC$_{50}$ of naphthalene by using 44 k agilent whole human genome oligomicroarray and operon human whole 35 k oligomicroarray, respectively. We identified 616 up-regulated genes and 2,088 down-regulated genes changed by more than 2-fold by naphthalene in HepG2 cells. And in HL-60, we identified 138 up-regulated genes and 182 down-regulated genes changed by more than 2-fold. This study identified several interesting targets and functions in relation to naphthalene-induced toxicity through a gene ontology analysis method. Apoptosis and cell cycle related genes are more commonly expressed than other functional genes in both cell lines. In summary, the use of in vitro models with global expression profiling emerges as a relevant approach toward the identification of biomarkers associated with toxicity after exposure to a variety of environmental toxicants.

• Molecular & Cellular Toxicology
• /
• 제5권2호
• /
• pp.133-140
• /
• 2009

Caveolin may be a molecular target for modulation of aging process in cochlear hair cells and have association with oxotoxicity. First we investigated the basal expression of caveolin-1, caveolin-2, caveolin-3, nitric oxide synthase, and superoxide dismutase in UB/OC-1 cochlear hair cell line. By using a RNA interference technique, we investigated whether down-regulation of caveolin influenced telomerase activity and reactive oxygen species (ROS) production in cochlear hair cells. In addition, cisplatin and gentamycin, known ototoxic drugs, were administered to the cochlear cells to determine their impact on caveolin expression. Further attempts at elucidating cellular aging mechanism with caveolin and ototoxic drugs were carried out. The main discoveries were the presence of caveolin-1 in UB/OC-1 cells and that down-regulation of caveolin-1 reduced protein kinase A activity. Telomerase was activated by caveolin down-regulation and caveolin down-regulation inhibited oxidative stress at the mitochondrial level. When cisplatin and gentamycin were administered to the cochlear hair cells during a caveolin expression state, a decrease in telomerase activity and increase ROS activity was observed. Caveolin-1 may modulate the senescent mechanisms in cochlear cells. An increase in caveolin-1 levels can lead to ROS production in the mitochondria which may cause ototoxicity.

• Molecular & Cellular Toxicology
• /
• 제5권1호
• /
• pp.51-57
• /
• 2009

Quantum Dot (QD) nanoparticles are used in various industrial applications, such as diagnostic, drug delivery, and imaging agents of biomedicine. Although QDs are extensively used in many medical science, several studies have been demonstrated the potential toxicity of nanoparticles. The first objective of this study was to investigate the nanotoxicity of QDs in the HaCaT human keratinocyte cell line by focusing on gene expression pattern. In order to evaluate the effect of QDs on gene expression profile in HaCaT cells, we analyzed the differential genes which related to oxidative stress and antioxidant defense mechanisms by using human cDNA microarray and PCR array. A human cDNA microarray was clone set, which was sorted for a list of genes correlated with cell mechanisms. We tried to confirm results of cDNA microarray by using PCR array, which is pathway-focused gene expression profiling technology using Real-Time PCR. Although we could not find the exactly same genes in both methods, we have screened the effects of QDs on global gene expression profiles in human skin cells. In addition, our results show that QD treatment somehow regulates cellular pathways of oxidative stress and antioxidant defense mechanisms. Therefore, we suggest that this study can enlarge our knowledge of the transcriptional profile and identify new candidate biomarker genes to evaluate the toxicity of nanotoxicology.