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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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Mitochondria in Cancer Energy Metabolism: Culprits or Bystanders?
Kim, Aekyong ;
Toxicological Research, volume 31, issue 4, 2015, Pages 323~330
DOI : 10.5487/TR.2015.31.4.323
Cancer is a disease characterized by uncontrolled growth. Metabolic demands to sustain rapid proliferation must be compelling since aerobic glycolysis is the first as well as the most commonly shared characteristic of cancer. During the last decade, the significance of metabolic reprogramming of cancer has been at the center of attention. Nonetheless, despite all the knowledge gained on cancer biology, the field is not able to reach agreement on the issue of mitochondria: Are damaged mitochondria the cause for aerobic glycolysis in cancer? Warburg proposed the damaged mitochondria theory over 80 years ago; the field has been testing the theory equally long. In this review, we will discuss alterations in metabolic fluxes of cancer cells, and provide an opinion on the damaged mitochondria theory.
Treatment of BG-1 Ovarian Cancer Cells Expressing Estrogen Receptors with Lambda-cyhalothrin and Cypermethrin Caused a Partial Estrogenicity Via an Estrogen Receptor-dependent Pathway
Kim, Cho-Won ; Go, Ryeo-Eun ; Choi, Kyung-Chul ;
Toxicological Research, volume 31, issue 4, 2015, Pages 331~337
DOI : 10.5487/TR.2015.31.4.331
Synthetic pyrethroids (SPs) are the most common pesticides which are recently used for indoor pest control. The widespread use of SPs has resulted in the increased exposure to wild animals and humans. Recently, some SPs are suspected as endocrine disrupting chemicals (EDCs) and have been assessed for their potential estrogenicity by adopting various analyzing assays. In this study, we examined the estrogenic effects of lambda-cyhalothrin (LC) and cypermethrin (CP), the most commonly used pesticides in Korea, using BG-1 ovarian cancer cells expressing estrogen receptors (ERs). To evaluate the estrogenic activities of two SPs, LC and CP, we employed MTT assay and reverse-transcription polymerase chain reaction (RT-PCR) in LC or CP treated BG-1 ovarian cancer cells. In MTT assay, LC (
) and CP (
) significantly induced the growth of BG-1 cancer cells. LC or CP-induced cell growth was antagonized by addition of ICI 182,720 (
), an ER antagonist, suggesting that this effect appears to be mediated by an ER-dependent manner. Moreover, RT-PCR results showed that transcriptional level of cyclin D1, a cell cycle-regulating gene, was significantly up-regulated by LC and CP, while these effects were reversed by co-treatment of ICI 182,780. However, p21, a cyclin D-ckd-4 inhibitor gene, was not altered by LC or CP. Moreover,
expression was not significantly changed by LC and CP, while down-regulated by E2. Finally, in xenografted mouse model transplanted with human BG-1 ovarian cancer cells, E2 significantly increased the tumor volume compare to a negative control, but LC did not. Taken together, these results suggest that LC and CP may possess estrogenic potentials by stimulating the growth of BG-1 ovarian cancer cells via partially ER signaling pathway associated with cell cycle as did E2, but this estrogenic effect was not found in in vivo mouse model.
Endosulfan Induces CYP1A1 Expression Mediated through Aryl Hydrocarbon Receptor Signal Transduction by Protein Kinase C
Han, Eun Hee ; Kim, Hyung Gyun ; Lee, Eun Ji ; Jeong, Hye Gwang ;
Toxicological Research, volume 31, issue 4, 2015, Pages 339~345
DOI : 10.5487/TR.2015.31.4.339
CYP1A1 is a phase I xenobiotic-metabolizing enzyme whose expression is mainly driven by AhR. Endosulfan is an organochlorine pesticide used agriculturally for a wide range of crops. In this study, we investigated the effect of endosulfan on CYP1A1 expression and regulation. Endosulfan significantly increased CYP1A1 enzyme activity as well as mRNA and protein levels. In addition, endosulfan markedly induced XRE transcriptional activity. CH-223191, an AhR antagonist, blocked the endosulfan-induced increase in CYP1A1 mRNA and protein expression. Moreover, endosulfan did not induce CYP1A1 gene expression in AhR-deficient mutant cells. Furthermore, endosulfan enhanced the phosphorylation of calcium calmodulin (CaM)-dependent protein kinase (CaMK) and protein kinase C (PKC). In conclusion, endosulfan-induced up-regulation of CYP1A1 is associated with AhR activation, which may be mediated by PKC-dependent pathways.
Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice
Alsulimani, Helal Hussain ; Ye, Qi ; Kim, Jonghan ;
Toxicological Research, volume 31, issue 4, 2015, Pages 347~354
DOI : 10.5487/TR.2015.31.4.347
Excess manganese (Mn) is neurotoxic. Increased manganese stores in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. We previously showed that the transport and neurotoxicity of manganese after intranasal instillation of the metal are altered in Hfe-deficient mice, a mouse model of the iron overload disorder hereditary hemochromatosis (HH). However, it is not fully understood whether loss of Hfe function modifies Mn neurotoxicity after ingestion. To investigate the role of Hfe in oral Mn toxicity, we exposed Hfe-knockout (
) and their control wild-type (
) mice to
in drinking water (5 mg/mL) for 5 weeks. Motor coordination and spatial memory capacity were determined by the rotarod test and the Barnes maze test, respectively. Brain and liver metal levels were analyzed by inductively coupled plasma mass spectrometry. Compared with the water-drinking group, mice drinking Mn significantly increased Mn concentrations in the liver and brain of both genotypes. Mn exposure decreased iron levels in the liver, but not in the brain. Neither Mn nor Hfe deficiency altered tissue concentrations of copper or zinc. The rotarod test showed that Mn exposure decreased motor skills in
mice, but not in
mice (p = 0.023). In the Barns maze test, latency to find the target hole was not altered in Mn-exposed
compared with water-drinking
mice. However, Mn-exposed
mice spent more time to find the target hole than Mn-drinking
mice (p = 0.028). These data indicate that loss of Hfe function impairs spatial memory upon Mn exposure in drinking water. Our results suggest that individuals with hemochromatosis could be more vulnerable to memory deficits induced by Mn ingestion from our environment. The pathophysiological role of HFE in manganese neurotoxicity should be carefully examined in patients with HFE-associated hemochromatosis and other iron overload disorders.
Effects of Styrene-metabolizing Enzyme Polymorphisms and Lifestyle Behaviors on Blood Styrene and Urinary Metabolite Levels in Workers Chronically Exposed to Styrene
Kim, Ki-Woong ;
Toxicological Research, volume 31, issue 4, 2015, Pages 355~361
DOI : 10.5487/TR.2015.31.4.355
The aim of this study was to investigate whether genetic polymorphisms of CYP2E1, GSTM1, and GSTT1 and lifestyle habits (smoking, drinking, and exercise) modulate the levels of urinary styrene metabolites such as mandelic acid (MA) and phenylglyoxylic acid (PGA) after occupational exposure to styrene. We recruited 79 male workers who had received chronic exposure in styrene fiberglass-reinforced plastic manufacturing factories. We found that serum albumin was significantly correlated with blood styrene/ambient styrene (BS/AS), urinary styrene (US)/AS, and US/BS ratios as well as urinary metabolites, that total protein correlated with US/MA and US/PGA ratios, and that low density lipoprotein (LDL)-cholesterol significantly correlated with US/BS, US/MA, and US/PGA ratios. Multiple logistic regression analyses using styrene-metabolizing enzyme genotypes and lifestyle habits as dependent variables and blood and urine styrene concentrations and urine styrene metabolite levels as independent variables revealed that
was associated with the MA/US ratio and GSTM1 with US/BS, that a smoking habit was associated with US/AS and MA/US ratios and MA and PGA levels, and that regular exercise was correlated with PGA/US. In conclusion, the results suggested that genetic polymorphisms of styrene-metabolizing enzymes, lifestyle behaviors, and albumin and LDL-cholesterol serving as homeostasis factors together are involved in styrene metabolism.
Antioxidant Activity and Anti-wrinkle Effects of Aceriphyllum rossii Leaf Ethanol Extract
Ha, Bi Gyeon ; Park, Min Ah ; Lee, Chae Myoung ; Kim, Young Chul ;
Toxicological Research, volume 31, issue 4, 2015, Pages 363~369
DOI : 10.5487/TR.2015.31.4.363
We evaluated the antioxidant activity and anti-wrinkle effects of Aceriphyllum rossii leaf ethanol extract (ARLEE) in vitro using human dermal fibroblasts. The total polyphenol and flavonoid contents of ARLEE were 578.6 and 206.3 mg/g, respectively. At a concentration of
, the electron-donating ability of ARLEE was 87.1%. In comparison with the vehicle, ARLEE treatment at
significantly increased type I procollagen synthesis (p < 0.01) by 50.7%. In vitro ARLEE treatment (10 mg/mL) inhibited collagenase and elastase activity by 97.1% and 99.2%, respectively. Compared with the control, ascorbic acid treatment at
significantly decreased matrix metalloproteinase (MMP)-1 protein expression (p < 0.01) by 37.0%. ARLEE treatment at
significantly decreased MMP-1 protein expression (p < 0.01) by 46.1%. Ascorbic acid and ARLEE treatments at
significantly decreased MMP-1 mRNA expression (p < 0.01) by 26.1% and 36.1%, respectively. From these results, we conclude that ARLEE has excellent antioxidant activity and even better anti-wrinkle effects than ascorbic acid in human dermal fibroblasts. These results suggest that ARLEE could be used in functional cosmetics for the prevention or alleviation of skin wrinkles induced by ultraviolet rays.
Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats
Lee, JooBuom ; Lee, Kyungsun ; Choe, Keunbum ; Jung, Hyunseob ; Cho, Hyunseok ; Choi, Kiseok ; Kim, Taegon ; Kim, Seojin ; Lee, Hyeong-Seok ; Cha, Mi-Jin ; Song, Si-Whan ; Lee, Chul Kyu ; Chun, Gie-Taek ;
Toxicological Research, volume 31, issue 4, 2015, Pages 371~392
DOI : 10.5487/TR.2015.31.4.371
TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of
. Rats received TS-DP2 intravenously at doses of 250, 500, and
once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2
and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was
, and no observed adverse effect level (NOAEL) in females was
in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (
) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.
A Study on Subchronic Inhalation Toxicity of 1-Chloropropane
Chung, Yong Hyun ; Han, Jeong Hee ; Lee, Yong-Hoon ;
Toxicological Research, volume 31, issue 4, 2015, Pages 393~402
DOI : 10.5487/TR.2015.31.4.393
This study was conducted to measure toxicity of 1-chloropropane (CAS No. : 540-54-5). According to the OECD Test Guideline 413 (Subchronic inhalation toxicity: 90-day study), SD rats were exposed to 0, 310, 1,250, and 5,000 ppm of 1-chloropropane for 6 h/day, 5 day/week for 13 weeks via whole-body inhalation. Mortality, clinical signs, body weights, food consumption, motor activity, ophthalmoscopy, hematology, serum chemistry, urinalysis, organ weights, gross and histopathological findings were compared between control and all tested groups. No mortality or remarkable clinical signs were examined during the study. No gross lesions or adverse effects on body weight, food consumption, motor activity, ophthalmoscopy, urinalysis, hematology, organ weights were observed in any of male or female rats in all tested groups. In serum biochemistry, glucose was significantly decreased in males of 1,250 and 5,000 ppm groups compared to control group in dose-dependent relationship. In histopathological examination, vacuolation of acinar cells was observed in pancreas of all male and female groups exposed to 1-chloropropane. In conclusion, no observable adverse effect level (NOAEL) was considered to be below 310 ppm/6 h/day, 5 day/week for rats.
Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats
Han, Chung-Tack ; Kim, Myoung-Jun ; Moon, Seol-Hee ; Jeon, Yu-Rim ; Hwang, Jae-Sik ; Nam, Chunja ; Park, Chong-Woo ; Lee, Sun-Ho ; Na, Jae-Bum ; Park, Chan-Sung ; Park, Hee-Won ; Lee, Jung-Min ; Jang, Ho-Song ; Park, Sun-Hee ; Han, Kyoung-Goo ; Choi, Young Whan ; Lee, Hye-Yeong ; Kang, Jong-Koo ;
Toxicological Research, volume 31, issue 4, 2015, Pages 403~414
DOI : 10.5487/TR.2015.31.4.403
Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes.
Job Stress and Neuropeptide Response Contributing to Food Intake Regulation
Kim, Ki-Woong ; Won, Yong Lim ; Ko, Kyung Sun ; Kang, Seong-Kyu ;
Toxicological Research, volume 31, issue 4, 2015, Pages 415~420
DOI : 10.5487/TR.2015.31.4.415
The purpose of the present study is to investigate the correlations between food intake behavior and job stress level and neuropeptide hormone concentrations. Job strain and food intake behavior were first identified using a self-reported questionnaire, concentrations of neuropeptide hormones (adiponectin, brain derived neurotrophic factor [BDNF], leptin, and ghrelin) were determined, and the correlations were analyzed. In the results, job strain showed significant correlations with adiponectin (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.001~1.498; p < 0.05) and BDNF (OR, 0.793; 95% CI, 0.646~0.974; p < 0.05), and ghrelin exhibited a significant correlation with food intake score (OR, 0.911; 95% CI, 0.842~0.985, p < 0.05). These results suggest that job stress affects food intake regulation by altering the physiological concentrations of neuropeptide hormones as well as emotional status.