The Journal of Toxicological Sciences
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Volume 39 , Issue 5
October
Showing 1-14 articles out of 14 articles from the selected issue
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Review
  • Hironori Kanda, Yasuhiro Shinkai, Yoshito Kumagai
    Volume 39 (2014) Issue 5 Pages 687-700
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    The accumulation of methylmercury (MeHg) through the daily consumption of large predatory fish poses potential health risks. MeHg has been found to cause Minamata disease, but the full nature of MeHg toxicity remains unclear. Because of its chemical properties, MeHg covalently binds to cellular proteins through their reactive thiols, referred to as S-mercuration, resulting in the formation of protein adducts. In this review, we summarize how the S-mercuration of cellular proteins could be involved in the major mechanisms that have been suggested to underlie MeHg toxicity. Additionally, we introduce our attempts to identify cases of S-mercuration for the research to reveal the true nature of MeHg toxicity.
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Original Article
  • Yan-Zhi Zhao, Jing Jia, Yan-Bo Li, Cai-Xia Guo, Xian-Qing Zhou, Zhi-We ...
    Volume 39 (2014) Issue 5 Pages 701-710
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    While the immunotoxicity of endosulfan has been studied, little is known about its influence on immune function associated with erythrocytes (RBC). The aim of this study was to investigate the possible effects of endosulfan, and any possible mitigation by testosterone propionate (TP), on erythrocyte immune function in a mouse model. To this end, rosette formation [as erythrocyte C3b receptor(E-C3bR) and erythrocyte immune complexes (E-IC)], as well as measures of the erythrocyte C3b receptor rosette-forming enhancing rate (RFER; reflecting immunoenhancing factor activity) and C3b receptor rosette-forming inhibitory rate (RFIR; reflecting immunosuppressive factor activity) were performed. The effects of RBC on regulating NK cell function or T-cell adherence were also analyzed. Lastly, to begin to assess potential mechanisms by which endosulfan could impact on the measured endpoints, CD35, CD58, and CD59 expression on RBC was evaluated; expression/mRNA levels of complement receptor I-related gene/protein y (Crry) on cells/splenic tissues was also assessed. The data show that E-C3bR rosette ratios decreased, and those of E-IC increased, due to endosulfan treatment. In these hosts, RFER (i.e., immunoenhancing factor in plasma) was decreased, but RFIR (i.e., immunosuppressive factor) was unchanged.There were no clear effects from endosulfan on RBC regulatory function against NK or T-cells. Lastly, Crry mRNA levels in tissues/cells from these mice were significantly decreased; however, CD59 and CD58 expression levels were unaffected. The data also show that TP co-treatment reversed or mitigated effects of endosulfan on each endpoint, in part, by two possible mechanisms; the TP may be increasing the activity of the innate immune enhancing factor, or, an anti-oxidant effect of TP might help to protect membrane structures and increase Crry stability on the RBC.
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Toxicomics Report
  • Shuso Takeda, Hiroyuki Okazaki, Eriko Ikeda, Satomi Abe, Yasushi Yoshi ...
    Volume 39 (2014) Issue 5 Pages 711-716
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Metastases are known to be responsible for approximately 90% of breast cancer-related deaths. Cyclooxygenase-2 (COX-2) is involved not only in inflammatory processes, but also in the metastasis of cancer cells; it is expressed in 40% of human invasive breast cancers. To comprehensively analyze the effects of cannabidiolic acid (CBDA), a selective COX-2 inhibitor found in the fiber-type cannabis plant (Takeda et al., 2008), on COX-2 expression and the genes involved in metastasis, we performed a DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are invasive breast cancer cells that express high levels of COX-2, treated with CBDA for 48 hr at 25 µM. The results obtained revealed that COX-2 and Id-1, a positive regulator of breast cancer metastasis, were down-regulated (0.19-fold and 0.52-fold, respectively), while SHARP1 (or BHLHE41), a suppressor of breast cancer metastasis, was up-regulated (1.72-fold) and CHIP (or STUB1) was unaffected (1.03-fold). These changes were confirmed by real-time RT-PCR analyses. Taken together, the results obtained here demonstrated that i) CBDA had dual inhibitory effects on COX-2 through down-regulation and enzyme inhibition, and ii) CBDA may possess the ability to suppress genes that are positively involved in the metastasis of cancer cells in vitro.
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Original Article
  • Su-Ryang Kim, Takashi Kubo, Yukie Kuroda, Maki Hojyo, Takuya Matsuo, A ...
    Volume 39 (2014) Issue 5 Pages 717-723
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    The liver is the central organ of metabolism, but its function varies during development from fetus to adult. In this study, we comprehensively analyzed and compared metabolites in fetal and adult hepatocytes, the major parenchymal cell in the liver, from human donors. We identified 211 metabolites (116 anions and 95 cations) by capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS) in the hepatocytes cultured in vitro. Principal component analysis and hierarchical clustering analysis of the relative amounts of metabolites clearly classified hepatocytes into 2 groups that were consistent with their origin, i.e., the fetus and adult. The amounts of most metabolites in the glycolysis/glyconeogenesis pathway, tricarboxylic acid cycle and urea cycle were lower in fetal hepatocytes than in adult hepatocytes. These results suggest different susceptibility of the fetal and adult liver to toxic insults affecting energy metabolism.
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Original Article
  • Hiroshi Matsumoto, Fumiyo Saito, Masahiro Takeyoshi
    Volume 39 (2014) Issue 5 Pages 725-734
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Carcinogenicity is one of the most serious toxic effects of chemicals, and highly accurate methods for predicting carcinogens are strongly desired for human health. Here, we developed a new prediction system named “CARCINOscreen®” for evaluating the carcinogenic potentials of chemicals using the gene expression profiles of liver tissues from rats after a 28-day repeated dose toxicity study.The prediction formula was generated using a support vector machine with predictive genes selected from68 training chemical datasets; a predictive score was then calculated to predict the carcinogenic potentials of the tested chemicals. To ensure the accuracy of the prediction system, the chemicals were divided into three groups (Groups 1 to 3) according to the resulting hepatic gene expression profiles, and a prediction formula was generated for each group. The prediction system was capable of predicting the carcinogenicity of training carcinogens and non-carcinogens with an accuracy of 92.9% to 100%. The final prediction result was determined based on the maximum prediction value obtained with three independent prediction formulas to build up the CARCINOscreen®. The system was able to predict carcinogenicity accurately in94.1% of the 68 training chemicals. An external validation trial was performed with 16 chemicals, consisting of various carcinogens targeting rat liver or other organs and non-carcinogens. The system identified 68.8% of all the chemicals and 100% of the rat liver carcinogens as carcinogens. Thus, the CARCINOscreen®, a novel system for predicting hepatocarcinogenicity, is a promising tool for the prediction of rat liver carcinogens.
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Toxicomics Report
  • Maki Tokumoto, Jin-Yong Lee, Yasuyuki Fujiwara, Masahiko Satoh
    Volume 39 (2014) Issue 5 Pages 735-738
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Cadmium is a toxic heavy metal that causes severe clinical symptoms in various tissues including the kidney. In this study, activities of transcription factors were measured to identify what type of transcription factor was affected by cadmium in rat proximal tubular cells (NRK-52E cells) using the protein/DNA binding assay. After treatment of NRK-52E cells with 5 µM CdCl2 for 3 hr, nuclear extracts were used for the protein/DNA binding assay. Among 65 transcription factors, cadmium increased the activities of 6 transcription factors by more than 2.0-fold and decreased those of 15 transcription factors by less than 0.5-fold. These findings may provide new information about novel transcription factors associated with the mechanism of cadmium toxicity.
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Original Article
  • Xiao Liang, Yan Tang, Li Duan, Shuqun Cheng, Long Luo, Xianqing Cao, B ...
    Volume 39 (2014) Issue 5 Pages 739-748
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Previous studies demonstrate that benzo(a)pyrene (B(a)P) can affect hippocampal function and cause spatial cognition impairment. However, the mechanism is incomplete. Some evidence implies that B(a)P may cause an oxidative damage linking to the function of the hippocampus and antioxidant can prevent the oxidative damage in rats, but the ATPase and Ca2+ in the hippocampus and the protective effect of butylated hydroxyanisole (BHA) have not been studied. This study aimed to investigate the damage of toxicity further induced by B(a)P in hippocampus and the protective effect of BHA. Ninety-six male Sprague-Dawley (SD) rats were randomly divided into four groups (solvent control group, BHA-group, B(a)P-exposed group and B(a)P-BHA-combination group), with daily administration for 90days. Morris water maze (MWM) was employed to evaluate the learning and memory ability. The levels of malonaldehyde (MDA) content, superoxide dismutase (SOD) activity, Na+-K+-ATPase and Ca2+-Mg2+ATPase activity in hippocampus were measured by commercial kits. The concentration of Ca2+ in rat hippocampus was detected by fluorescent labeling. In behavior test it showed that there was an adverse effect on rats in the B(a)P -group. The levels of MDA content and Ca2+ content were significantly increased in the B(a)P group, while the activities of SOD and ATPase were significantly decreased. In the B(a)P-BHA group, the change of each index diminished significantly. The results suggested that the neurobehavioral toxicity of B(a)P might have a close relationship with oxidative damage, resulted in decreasing of ATPase activities and increasing of Ca2+ concentration in the hippocampus. Furthermore, BHA can prevent these damages.
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Letter
  • Yaichiro Kotake, Yoko Sekiya, Katsuhiro Okuda, Shigeru Ohta
    Volume 39 (2014) Issue 5 Pages 749-754
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Naturally occurring low-molecular weight compounds with a chemical structure like that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline(1BnTIQ), are candidates for the endogenous neurotoxins that cause Parkinson’s disease (PD). 1BnTIQ is an endogenous amine in human CSF and increases in the CSF of patients with PD. It inhibits complex Iand elicits PD-like behavioral abnormalities in monkey and mouse. In this study, we searched metabolites of 1BnTIQ by rat liver S9 using liquid chromatography-tandem mass spectrometry, and identified a dehydrated metabolite, 1-benzyl-3,4-dihydroisoquinoline (1BnDIQ). 1BnDIQ was identified by corresponding mass spectra and precursor ion scans in authentic and complete enzyme samples. Multiple reaction monitoring analysis showed microsome-dependent 1BnDIQ production. We previously reported that 1BnDIQ is more toxic than 1BnTIQ in cytotoxicity study in SH-SY5Y neuroblastoma cells. In addition, 1BnTIQ is reported to pass through the blood-brain barrier of the rat brain, and 1BnDIQ is supposed to be more lipophilic than 1BnTIQ. 1BnDIQ may easily reach the brain, and it might contribute to PD-related neurotoxicity.
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Original Article
  • Haibin Wang, Baoji Hu, Yun Zou, Lulong Bo, Jun Wang, Jinbao Li, Yan Lu ...
    Volume 39 (2014) Issue 5 Pages 755-764
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Activated T cells selectively induced by concanavalin A (Con A) in liver are subsequent efficient resolution of inflammation. Activated T cells infiltrating in liver combined with pro-inflammatory cytokines are the major causes in Con A-induced liver injury. In our study, C57/BL mice were injected with Con A combined with dexmedetomidine or not. ALT and AST in blood and histopathology of liver were measured. T cell infiltration in liver was examined by flow cytometry and pro-inflammatory cytokines including IL-6, IL-10, TNF-α, and IFN-γ in blood were measured by ELISA. The mRNA level of CXCL10 was detected by RT-PCR and the protein level of NF-κB was measured by Western-blot. We found that dexmedetomidine alleviated Con A-induced liver injury by down-regulating levels of ALT and AST in blood and the severity of histopathology, which reflect the severity of hepatitis induced by Con A. In addition, pro-inflammatory cytokines in blood were attenuated by dexmedetomidine. Dexmedetomidine restrained the phosphorylation of NF-κB IκBα and P-65 dramatically which may participate in the regulation of cytokines secretion. Moreover, CXCL10 mRNA attenuated by dexmedetomidine in liver may result in the lower level of CD4+ T cells infiltration in liver. These results suggested that dexmedetomidine might be a potential compound in treating T cell-mediated liver injury.
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Original Article
  • Nawaf Al-Taweel, Elizabeth Varghese, Ana-Maria Florea, Dietrich Büssel ...
    Volume 39 (2014) Issue 5 Pages 765-774
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Breast cancer (BC) is a public health problem all over the world. Cisplatin (CDDP) is an antineoplastic agent with high rate of success in treating cancers. The down side of CDDP treatment is the development of chemo-resistance. Beside DNA damage and activation of p53 signaling pathway, CDDP induces tumor-cell death due to elevation in the intracellular calcium concentration ([Ca2+]i).However, the role of [Ca2+]i in CDDP induced apoptosis of breast cancer cells (MCF-7) is not well understood. Here we investigate the cytotoxic effects of CDDP in relation to [Ca2+]i homeostasis in MCF-7-sensitive and -resistant cell lines. Live-cell imaging using [Ca2+]i sensitive fluorescent dyes was employed to monitor [Ca2+]i CDDP treated MCF-7 cells (0.001-10 µM) and [Ca2+]i modulators i.e. Caffeine (10 mM); Nimodipine (10 µM); Ionomycin (10 µM); Thapsigargin (500 nM). A concentration-dependent increase of[Ca2+]i was observed in CDDP MCF-7 treated cells. From the concentration range tested 100 nM CDDP triggered the highest [Ca2+]i increase (120%; n = 19)while in drug resistant MCF-7 cells the effects of CDDP on [Ca2+]i were reduced as compared with the drug sensitive MCF-7 cells. Furthermore, the CDDP induced cell death correlates with the increase of [Ca2+]i, and thus, significantly lower in the CDDP desensitized cells (p < 0.05). Pre-application of the calcium channel blocker, Nimodipine reduced [Ca2+]i elevation significantly (46.6% increase; n = 26) as well as when a pre-application of Caffeine, Ionomycin or Thapsigargin occurred followed by the subsequent application of CDDP (n = 15; 37.8%, n = 32; 34.9%, n = 21; 53.7% increase respectively).
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Original Article
  • Miwa Takahashi, Kaoru Inoue, Tomomi Morikawa, Saori Matsuo, Seigo Haya ...
    Volume 39 (2014) Issue 5 Pages 775-784
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    We previously reported that neonatal exposure to 17α-ethynylestradiol (EE) led to delayed adverse effects in which age-related anovulation after sexual maturation was accelerated. To identify early indicators of these adverse effects, female Wistar Hannover GALAS rats received a single EE injection (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24 hr of birth. Histopathological changes in ovarian and uterine development were investigated from postnatal day (PND) 14 to 10 weeks of age. Immunohistochemical expression of estrogen receptor alpha (ERα) in the uterus, serum levels of sex-related hormones and gene expression in the hypothalamus were examined. Although neonatal exposure to EE did not affect body growth or ovarian development, serum FSH tended to decrease at doses ≥ 2 μg/kg, and Kiss1 mRNA level in the whole hypothalamus was significantly decreased in all EE-treated groups at PND14.The number of uterine glands at PND21 was suppressed at doses ≥ 20 μg/kg, and ERα expression in the uterine epithelium at estrus stage decreased in a dose-dependent manner at 10 weeks of age. These results demonstrated that the various identified changes that occurred before the appearance of delayed adverse effects could be candidate early indicators.
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Original Article
  • Ko Omura, Takeki Uehara, Yuji Morikawa, Hitomi Hayashi, Kunitoshi Mits ...
    Volume 39 (2014) Issue 5 Pages 785-794
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    We previously reported a toxicogenomics-based prediction model for hepatocarcinogens in which the expression patterns of signature genes following repeated doses of either genotoxic or non genotoxic compounds were similar. Based on the results of our prediction model, we hypothesized that repeated doses of non-genotoxic carcinogens might have initiating potential. Here, we conducted a two stage hepatocarcinogenesis study in rats exposed to the initiating agent nitrosodiethylamine (DEN), and hepatotoxic compounds thioacetamide (TAA), methapyrilene (MP) and acetaminophen (APAP) for 1-2weeks followed by the liver tumor promoter phenobarbital (PB). The duration of initial treatment was determined based on positive results from our prediction model. Combined treatment of 3 or 30 mg/kg of genotoxic DEN and PB induced marked increases in altered hepatocellular foci and a DEN dose-dependent increase in the number and area of glutathione S-transferase-placental form (GST-P)-positive foci. A low number of altered hepatocellular foci were also observed in rats treated with TAA at a dose of 45 mg/kg.MP at a dose of 100 mg/kg induced a very low number of foci, but APAP did not. Hierarchical clustering analysis using gene expression data revealed that 2-week treatment with TAA at a dose of 30 mg/kg and MP at 45 mg/kg induced specific expression of DNA damage-related genes, similar to 1-week treatment with DEN at a dose of 30 mg/kg. These results suggest that TAA and MP induce DNA damage, which partially supports our hypothesis. Although this study does not indicate whether tumor growth in response to these compounds can be assessed in this model, our results suggest that cumulative treatment with non genotoxic TAA might have initiating potential in the liver.
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Original Article
  • Tingzhu Teresa Meng
    Volume 39 (2014) Issue 5 Pages 795-802
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Volatile organic compounds (VOCs) in polyvinyl chloride (PVC) plastic products readily evaporate; as a result, hazardous gases enter the ecosystem, and cause cancer in humans and other animals. Polyethylene vinyl acetate (PEVA) plastic has recently become a popular alternative to PVC since it is chlorine-free. In order to determine whether PEVA is harmful to humans, this research employed the freshwater oligochaete Lumbriculus variegatus as a model to compare their oxygen intakes while they were exposed to the original stock solutions of PEVA, PVC or distilled water at a different length of time for one day, four days or eight days. During the exposure periods, the oxygen intakes in both PEVA and PVC groups were much higher than in the distilled water group, indicating that VOCs in both PEVA and PVC were toxins that stressed L. variegatus. Furthermore, none of the worms fully recovered during the24-hr recovery period. Additionally, the L. variegatus did not clump together tightly after four or eight days’ exposure to either of the two types of plastic solutions, which meant that both PEVA and PVC negatively affected the social behaviors of these blackworms. The LD50 tests also supported the observations above. For the first time, our results have shown that PEVA plastic has adverse effects on living organisms, and therefore it is not a safe alternative to PVC. Further studies should identify specific compounds causing the adverse effects, and determine whether toxic effect occurs in more complex organisms, especially humans.
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Original Article
  • Zhifeng Zhang, Leigang Zheng, Zhenqun Zhao, Jun Shi, Xing Wang, Jian H ...
    Volume 39 (2014) Issue 5 Pages 803-813
    Released: September 20, 2014
    JOURNALS FREE ACCESS
    Oxidative stress represents a major cause of cellular damage and death in pathological conditions including osteoporosis, in which oxidative stress is associated with increased bone resorption and low bone mass. And grape seed proanthocyanidins are a group of polyphenolic bioflavonoids which are known to possess broad pharmacological activity and therapeutic potential, exerting a protective role against oxidant injury. The aim of our study was to investigate whether proanthocyanidins exert an anti-apoptosis effect in osteoblastic MC3T3-E1 cells, via their antioxidant activity. Firstly, we determined the anti-apoptosis effect of proanthocyanidins in osteoblastic MC3T3-E1 cells, which were subject to H2O2 treatment, then we determined the association of the antioxidant activity exerted by proanthocyanidins with their anti-apoptosis effect. Results demonstrated that proanthocyanidins inhibit H2O2-promoted apoptosis in MC3T3-E1 cells, via ameliorating the viability of MC3T3-E1 cells post H2O2 treatment and reducing the apoptotic cell numbers. And the proanthocyanidins treatment also ameliorates the H2O2-induced mitochondrial dysfunction via promoting the mitochondrial membrane potential (MMP) and respiratory chain complex IV, and reducing the mitochondrial free radical production, ROS and mitochondrial superoxide. Moreover, the proanthocyanidins inhibit H2O2-induced apoptosis signaling which is mediated by p53. This study implied a possible anti-osteoporosis effect of proanthocyanidins via their antioxidant and anti-apoptosis activity.
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