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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 31, Issue 4 - Dec 2015
Volume 31, Issue 3 - Sep 2015
Volume 31, Issue 2 - Jun 2015
Volume 31, Issue 1 - Mar 2015
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Influence of Toxicologically Relevant Metals on Human Epigenetic Regulation
Ryu, Hyun-Wook ; Lee, Dong Hoon ; Won, Hye-Rim ; Kim, Kyeong Hwan ; Seong, Yun Jeong ; Kwon, So Hee ;
Toxicological Research, volume 31, issue 1, 2015, Pages 1~9
DOI : 10.5487/TR.2015.31.1.001
Environmental toxicants such as toxic metals can alter epigenetic regulatory features such as DNA methylation, histone modification, and non-coding RNA expression. Heavy metals influence gene expression by epigenetic mechanisms and by directly binding to various metal response elements in the target gene promoters. Given the role of epigenetic alterations in regulating genes, there is potential for the integration of toxic metal-induced epigenetic alterations as informative factors in the risk assessment process. Here, we focus on recent advances in understanding epigenetic changes, gene expression, and biological effects induced by toxic metals.
Gambogic Acid Disrupts Toll-like Receptor4 Activation by Blocking Lipopolysaccharides Binding to Myeloid Differentiation Factor 2
Lee, Jin Young ; Lee, Byung Ho ; Lee, Joo Young ;
Toxicological Research, volume 31, issue 1, 2015, Pages 11~16
DOI : 10.5487/TR.2015.31.1.011
Our body's immune system has defense mechanisms against pathogens such as viruses and bacteria. Immune responses are primarily initiated by the activation of toll-like receptors (TLRs). In particular, TLR4 is well-characterized and is known to be activated by gram-negative bacteria and tissue damage signals. TLR4 requires myeloid differentiation factor 2 (MD2) as a co-receptor to recognize its ligand, lipopolysaccharides (LPS), which is an extracellular membrane component of gram-negative bacteria. Gambogic acid is a xanthonoid isolated from brownish or orange resin extracted from Garcinia hanburyi. Its primary effect is tumor suppression. Since inflammatory responses are related to the development of cancer, we hypothesized that gambogic acid may regulate TLR4 activation. Our results demonstrated that gambogic acid decreased the expression of pro-inflammatory cytokines (
, IL-6, IL-12, and
) in both mRNA and protein levels in bone marrow-derived primary macrophages after stimulation with LPS. Gambogic acid did not inhibit the activation of Interferon regulatory factor 3 (IRF3) induced by TBK1 overexpression in a luciferase reporter gene assay using IFN-
-PRD III-I-luc. An in vitro kinase assay using recombinant TBK1 revealed that gambogic acid did not directly inhibit TBK1 kinase activity, and instead suppressed the binding of LPS to MD2, as determined by an in vitro binding assay and confocal microscopy analysis. Together, our results demonstrate that gambogic acid disrupts LPS interaction with the TLR4/MD2 complex, the novel mechanism by which it suppresses TLR4 activation.
Loss of Hfe Function Reverses Impaired Recognition Memory Caused by Olfactory Manganese Exposure in Mice
Ye, Qi ; Kim, Jonghan ;
Toxicological Research, volume 31, issue 1, 2015, Pages 17~23
DOI : 10.5487/TR.2015.31.1.017
Excessive manganese (Mn) in the brain promotes a variety of abnormal behaviors, including memory deficits, decreased motor skills and psychotic behavior resembling Parkinson's disease. Hereditary hemochromatosis (HH) is a prevalent genetic iron overload disorder worldwide. Dysfunction in HFE gene is the major cause of HH. Our previous study has demonstrated that olfactory Mn uptake is altered by HFE deficiency, suggesting that loss of HFE function could alter manganese-associated neurotoxicity. To test this hypothesis, Hfe-knockout (
) and wild-type (
) mice were intranasally-instilled with manganese chloride (
5 mg/kg) or water daily for 3 weeks and examined for memory function. Olfactory Mn diminished both short-term recognition and spatial memory in
mice, as examined by novel object recognition task and Barnes maze test, respectively. Interestingly,
mice did not show impaired recognition memory caused by Mn exposure, suggesting a potential protective effect of Hfe deficiency against Mn-induced memory deficits. Since many of the neurotoxic effects of manganese are thought to result from increased oxidative stress, we quantified activities of anti-oxidant enzymes in the prefrontal cortex (PFC). Mn instillation decreased superoxide dismutase 1 (SOD1) activity in
mice, but not in
mice. In addition, Hfe deficiency up-regulated SOD1 and glutathione peroxidase activities. These results suggest a beneficial role of Hfe deficiency in attenuating Mn-induced oxidative stress in the PFC. Furthermore, Mn exposure reduced nicotinic acetylcholine receptor levels in the PFC, indicating that blunted acetylcholine signaling could contribute to impaired memory associated with intranasal manganese. Together, our model suggests that disrupted cholinergic system in the brain is involved in airborne Mn-induced memory deficits and loss of HFE function could in part prevent memory loss via a potential up-regulation of anti-oxidant enzymes in the PFC.
Ethnic Differences in the Metabolism of Toluene: Comparisons between Korean and Foreign Workers Exposed to Toluene
Kim, Ki-Woong ; Won, Young Lim ; Ko, Kyung Sun ;
Toxicological Research, volume 31, issue 1, 2015, Pages 25~32
DOI : 10.5487/TR.2015.31.1.025
The objectives of this study were to investigate the individual characteristics, lifestyle habits, exposure levels, and genetic diversity of xenobiotic-metabolizing enzymes involved in toluene metabolism in Korean and foreign workers exposed to toluene at a manufacturing plant. This study was conducted to determine the effects of culture or ethnicity on toluene metabolism. The results showed that blood and urinary toluene concentrations were dependent on the level of exposure to toluene. We analyzed the correlation between toluene metabolism and genetic diversity in glutathione S-transferase (GST) (M1), GSTT1, and cytochrome p-450 (CYP)
as well as lifestyle habits (smoking, drinking, and exercise habits). The results revealed significant correlations between toluene metabolism and GSTM1 and GSTT1 genetic diversity, as well as smoking and exercise.
Improved Therapeutic Profiles of PLA
-Free Bee Venom Prepared by Ultrafiltration Method
Lee, Hyunkyoung ; Pyo, Min-Jung ; Bae, Seong Kyeong ; Heo, Yunwi ; Kim, Choul Goo ; Kang, Changkeun ; Kim, Euikyung ;
Toxicological Research, volume 31, issue 1, 2015, Pages 33~40
DOI : 10.5487/TR.2015.31.1.033
Bee venom (BV) has long been used in traditional Eastern and Western medicine for chronic inflammation, pain and skin therapy. Human exposure to BV, however, often causes unwanted adverse effects and is even fatal in some cases. Phospholipase
) of BV is now suspected to play a key role in these adverse effects. We investigated the potential use of
-free bee venom (PBV) as a replacement for BV in cosmetic products. PBV prepared by molecular weight cut-off ultrafiltration exhibits a superior profile in comparison with regular BV, by inhibiting elastase activity and suppressing the induction of nitric oxide (NO) and metalloproteinase-9 (MMP-9), while retaining the effects of cell proliferation and protection against ultraviolet B (UVB)-induced damage in human dermal fibroblast cells. PBV thus appears to be more promising than BV as a cosmetic ingredient with a reduced potential for adverse reactions in the recipient.
Safety Assessment of Mainstream Smoke of Herbal Cigarette
Bak, Jong Ho ; Lee, Seung Min ; Lim, Heung Bin ;
Toxicological Research, volume 31, issue 1, 2015, Pages 41~48
DOI : 10.5487/TR.2015.31.1.041
Owing to the increase in price of cigarettes in Korea, herbal cigarettes have received increasing attention as a non-smoking aid; however, its safety has hardly been studied. We analyzed some of the toxic components in the mainstream smoke of herbal cigarettes, performed a mutagenicity test on smoke condensates for safety assessment, and compared the results with the corresponding values of a general cigarette with the same tar content. Herbal cigarette "A" was smoked using automatic smoking machine under ISO conditions in a manner similar to general cigarette "T". The tar content measured was higher than that inscribed on the outside of a package. The mainstream smoke of herbal cigarette "A" did not contain detectable levels of tobacco-specific nitrosamines and nicotine. Carbon monoxide and benzo(
)pyrene contents in herbal cigarette "A" were higher than those in the general cigarette "T". The phenolic contents such as hydroquinone, resorcinol, and catechol in herbal cigarette "A" were higher than those in the general cigarette "T", but cresol contents in herbal cigarette "A" were lower than those in the general cigarette "T". The content of aromatic amines such as 4-aminobiphenyl in herbal cigarette "A" was higher than that in the general cigarette "T"; however, this difference was not statistically significant. On the other hand, 1-aminonaphthalene, 2-aminonaphthalene, and 3-aminobiphenyl contents in herbal cigarette "A" were lower than those in the general cigarette "T". The smoke condensates of herbal cigarette "A" exhibited a higher mutagenic potential than the condensates from the general cigarette "T" at the same concentration. We concluded that the mainstream smoke of herbal cigarette contains some toxic components, the smoke condensates of herbal cigarettes are mutagenic similar to general cigarette because of combustion products, and that the evaluation of the chemical and biological safety of all types of herbal cigarettes available on the market.
Assessing the Systemic Toxicity in Rabbits after Sub Acute Exposure to Ocular Irritant Chemicals
Reshma, Cherian Sebastian ; Sruthi, Sudhakaran ; Syama, Santhakumar ; Gayathri, Vishwanath ; Mohanan, Parayanthala Valappil ;
Toxicological Research, volume 31, issue 1, 2015, Pages 49~59
DOI : 10.5487/TR.2015.31.1.049
Eye is a highly vascularised organ. There are chances that a foreign substance can enter the systemic circulation through the eye and cause oxidative stress and evoke immune response. Here the eyes of rabbits were exposed, for a period of 7 days, to 5 known ocular irritants: Cetyl pyridinium chloride (CPC), sodium salicylate (SS), imidazole (IMI), acetaminophen (ACT) and nicotinamide (NIC). The eyes were scored according to the draize scoring. Blood collected from the treated rabbit were analyzed for haematological and biochemical parameters. After sacrifice, histological analysis of the eye and analysis of pro-inflammatory biomarkers (
, IL-8 and
) in the cornea using ELISA was carried out. Spleen was collected and the proliferation capacities of spleenocytes were analyzed. Liver and brain were collected and assessed for oxidative stress. The eye irritation potential of the chemicals was evident from the redness and swelling of the conjunctiva and cornea. Histopathological analysis and ELISA assay showed signs of inflammation in the eye. However, the haematological and biochemical parameters showed no change. Spleenocyte proliferations showed only slight alterations which were not significant. Also oxidative stress in the brain and liver were negligible. In conclusion, chemicals which cause ocular irritation and inflammation did not show any systemic side-effects in the present scenario.
Single Oral Dose Toxicity Test of Blue Honeysuckle Concentrate in Mice
Kim, Hyung-Soo ; Park, Sang-In ; Choi, Seung-Hoon ; Song, Chang-Hyun ; Park, Soo-Jin ; Shin, Yong-Kook ; Han, Chang-Hyun ; Lee, Young Joon ; Ku, Sae-Kwang ;
Toxicological Research, volume 31, issue 1, 2015, Pages 61~68
DOI : 10.5487/TR.2015.31.1.061
The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency.
Subchronic Oral Dose Toxicity of Freeze-dried Powder of Allomyrina dichotoma Larvae
Noh, Jung-Ho ; Yun, Eun-Young ; Park, Heejin ; Jung, Kyung-Jin ; Hwang, Jae Sam ; Jeong, Eun Ju ; Moon, Kyoung-Sik ;
Toxicological Research, volume 31, issue 1, 2015, Pages 69~75
DOI : 10.5487/TR.2015.31.1.069
The objective of this study was to investigate the toxicological information of freeze-dried powder from Allomyrina dichotoma (A. dichotoma) larvae as a food ingredient. The powder, suspended in distilled water, was administered once daily by oral gavage to four groups of Sprague-Dawley (SD) rats at dose levels of 0 (vehicle control), 250, 850, and 2500 mg/kg/day. After 13 wks of repeated administration, the standard toxicological parameters such as mortality, clinical signs, body weight, food consumption, ophthalmologic examination, clinical pathology, organ weights and macro/microscopic examination were applied for assessment of general toxicity. In addition, serum IgE and histamine levels were determined to evaluate allergenicity. The freeze-dried powder from A. dichotoma larvae did not produce treatment-related changes or findings in any toxicological parameters in either sex of any dosed groups except for slight increases in serum histamine levels at 2500 mg/kg/day. The changes were considered not to be adverse since the magnitude was minimal. In conclusion, the NOAEL (No Observed Adverse Effect Level) of the freeze-dried powder from A. dichotoma larvae was determined to be 2500 mg/kg/day or more in both sexes of SD rats and it is considered a candidate to be edible material.
Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs
Nam, Chunja ; Hwang, Jae-Sik ; Kim, Myoung-Jun ; Choi, Young Whan ; Han, Kyoung-Goo ; Kang, Jong-Koo ;
Toxicological Research, volume 31, issue 1, 2015, Pages 77~88
DOI : 10.5487/TR.2015.31.1.077
Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.