The Journal of Toxicological Sciences
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Volume 41 , Issue 3
June
Showing 1-10 articles out of 10 articles from the selected issue
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Original Article
  • Tatsu Fuwa, Jin Suzuki, Toyohito Tanaka, Akiko Inomata, Yoshiko Honda, ...
    Volume 41 (2016) Issue 3 Pages 329-337
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    We examined the effects of three benzofurans [1-(Benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 1-(Benzofuran-2-yl)-N-methylpropan-2-amine (2-MAPB), and 1-(Benzofuran-5-yl)-N-ethylpropan-2-amine (5-EAPB)] on the extracellular monoamine level in mouse corpus striatum by the microdialysis method and compared them with the effects of psychoactive 3,4-Methylenedioxymethamphetamine (MDMA). The effects of benzofurans on the extracellular monoamine level were qualitatively analogous to that of MDMA, with an increase in serotonin (5-HT) level exceeding dopamine (DA) level. The effects of 2-MAPB and 5-EAPB were almost the same as the effect of MDMA. However, 5-MAPB strongly increased extracellular monoamine level than MDMA. These differences in the potency appear to have a structure-activity relationship. The administration of 5-MAPB (1.6 × 10-4 mol/kg B.W.) resulted in the death of two-thirds of the mice. The same dose of MDMA did not cause any deaths. The administration of 5-MAPB (1.6 × 10-4 mol/kg B.W.) produced a 3.41°C ± 0.28°C rise in rectal temperature after 1 hr, whereas the administration of MDMA (1.6 × 10-4 mol/kg B.W.) produced an approximate 1.85°C ± 0.26°C rise. These results suggest that benzofurans have 5-HT toxicity similar to MDMA, and 5-MAPB has a higher risk of lethal intoxication than MDMA. Furthermore, 5-APB, the metabolic product of 5-MAPB demethylation, may be involved in the acute 5-HT toxicity and may cause lethal intoxication in mice.
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Original Article
  • Penjai Thongnuanjan, Sirima Soodvilai, Varanuj Chatsudthipong, Sunhapa ...
    Volume 41 (2016) Issue 3 Pages 339-349
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Cisplatin is widely used as a standard chemotherapy for solid tumors. The major adverse effect of cisplatin is nephrotoxicity in proximal tubular cells, via oxidative stress, DNA damage, cell apoptosis, and inflammation. The aim of this study was to investigate the pharmacological effect and mechanism of fibrate drugs on cisplatin-induced renal proximal tubular cell death. Cisplatin decreased cell viability of LLC-PK1 and HK-2 cells in a dose-dependent manner. Cisplatin-induced apoptosis was attenuated by co-treatment with fenofibrate while less so with clofibrate and bezafibrate. Fenofibrate’s protective effect was not complimented by co-treatment with GW6471, a PPARα antagonist, indicating the protective effect occurred via a PPARα-independent mechanism. Treating cells with cisplatin induced reactive oxygen species (ROS), c-JUN N-terminal kinase (JNK), and p38 kinase (p38), but not extracellular signal-regulated kinase (ERK). Fenofibrate reversed cisplatin-induced JNK and p38 activation, but had no effect on ROS production. The findings suggest fenofibrate’s protective effect on cisplatin-induced cytotoxicity is mediated by inhibition of JNK and p38. Moreover, fenofibrate did not alter cisplatin’s antitumor effect on cancer cell lines including T84, SW-480, HepG2, and SK-LU-1 cells. Therefore, fenofibrate may be a candidate agent for further development as an adjuvant to cisplatin treatment.
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Original Article
  • Yang Zeng, Yoshika Kurokawa, Tin-Tin Win-Shwe, Qin Zeng, Seishiro Hira ...
    Volume 41 (2016) Issue 3 Pages 351-370
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Polyamidoamine (PAMAM) dendrimers have potential for biological applications as delivery systems for genes, drugs, and imaging agents into the brain, but their developmental neurotoxicity remains unknown. We investigated the effects of PAMAM dendrimers with various surface functional groups and multiple generations on neuronal differentiation using human neural progenitor cells at an equal mass concentration. Only PAMAM dendrimers containing amine (NH2) surface groups at concentrations of 10 μg/mL significantly reduced cell viability and neuronal differentiation, compared with non-amine-terminated dendrimers. PAMAM-NH2 with generation (G)3, G4, G5 G6, and G7 significantly decreased cell viability and inhibited neuronal differentiation from a concentration of 5 μg/mL, but G0, G1, and G2 dendrimers did not have any effect at this concentration. Cytotoxicity indices of PAMAM-NH2 dendrimers at 10 μg/mL correlated well with the zeta potentials of the particles. Surface group density and particle number in unit volume is more important characteristic than particle size to influence cytotoxicity for positive changed dendrimers. PAMAM-50% C12 at 1 μg/mL altered the expression level of the oxidative stress-related genes, ROR1, CYP26A1, and TGFB1, which is a DNA damage response gene. Our results indicate that PAMAM dendrimer exposure may have a surface charge-dependent adverse effect on neuronal differentiation, and that the effect may be associated with oxidative stress and DNA damage during development of neural cells.
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Original Article
  • Wei-Feng Xu, Yan-Sen Li, Peng-Yuan Dai, Chun-Mei Li
    Volume 41 (2016) Issue 3 Pages 371-381
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    4-nitrophenol (PNP) is generally regarded as a diesel exhaust particle (DEP). Arginine plays an important role as a new feed additive, possessing highly efficient antioxidant activities. Here we investigated the effects of dietary supplementation with arginine against ovarian damage induced by PNP in rats. A total of thirty-two female rats postnatal day 28 (PND 28) were randomly divided into four groups. Two groups were fed with basal diet or 13 g/kg arginine in diet for 4 weeks, respectively; the other two groups were given PNP (100 mg/kg b.w.) daily by subcutaneous injection for 2 weeks following pretreatment with either basal diet or arginine diet for 2 weeks. The values of body weight gain (BWG), average daily gain (ADG) and percentage weight gain (PWG) upon PNP treatment were significantly reduced than those in other groups. The relative liver weight in the PNP group was significantly decreased compared with the control group. Treatment with PNP significant reduced the number of corpora lutea, although serum 17β-estradiol (E2) and progesterone (P4) concentrations were unchanged. The morphology of the ovaries in PNP-treated rats displayed necrosis, follicular deformation and granulosa cells irregular arrangement. Moreover, exposure to PNP enhanced production of malondialdehyde (MDA) and hydrogen peroxide (H2O2), and decreased the activities of total superoxide dismutase (T-SOD) and catalase (CAT), and the co-administration of arginine can attenuate the oxidative stress caused by PNP. These results suggest that arginine may have a protective effect against ovarian damage induced by PNP owing to its antioxidant capacity effect.
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Original Article
  • Fumiyo Saito, Hiroshi Matsumoto, Yumi Akahori, Masahiro Takeyoshi
    Volume 41 (2016) Issue 3 Pages 383-390
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Carcinogenicity of chemicals in our environment is one of the most important health hazards to humans. Recently, a microarray-based short-term prediction system for the hepatocarcinogenicity of chemicals, named CARCINOscreen®, was developed. Although the system is a promising tool reported to have an ability to predict hepatocarcinogenicity in rats with 92.9% accuracy, it requires specialized equipment and skilled bioinformatics approaches for data analysis. Therefore, we attempted to develop a quantitative PCR (qPCR)-based system as an alternative to microarray-based CARCINOscreen®. Finally, an optimized gene set consisting of four predictive genes (Abcb1b, Eprs, Map3K8, and Igh-6) was selected from among 3,150 combinations of candidate gene sets. The results of training- and validation-phase trials showed that the qPCR-based alternative to the microarray-based CARCINOscreen® could predict the hepatocarcinogenicity of chemicals in rats with 82.8%-86.4% accuracy. One of the predictive genes, Abcb1b, a member of the ATP-binding cassette protein superfamily and multi-drug resistance-associated protein, and the results of this study may indicate a close relation of this gene to the carcinogenicity of chemicals. The prediction performance of the qPCR-based CARCINOscreen®, as well as its user-friendliness and cost efficiency, suggests that this method is promising for application to primary health hazard assessment. Thus, the qPCR-based CARCINOscreen® is considered as a promising tool for predicting the carcinogenicity of chemicals.
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Original Article
  • Devina Saputra, JuOae Chang, Byeong-Jae Lee, Jin-Ha Yoon, Jonghan Kim, ...
    Volume 41 (2016) Issue 3 Pages 391-402
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Manganese (Mn) is used in industrial metal alloys and can be released into the atmosphere during methylcyclopentadienyl manganese tricarbonyl combustion. Increased Mn deposition in the brain after long-term exposure to the metal by inhalation is associated with altered dopamine metabolism and neurobehavioral problems, including impaired motor skills. However, neurotoxic effects of short-term exposure to inhaled Mn are not completely characterized. The purpose of this study is to define the neurobehavioral and neurochemical effects of short-term inhalation exposure to Mn at a high concentration using rats. Male Sprague-Dawley rats were exposed to MnCl2 aerosol in a nose-only inhalation chamber for 3 weeks (1.2 µm, 39 mg/m3). Motor coordination was tested on the day after the last exposure using a rotarod device at a fixed speed of 10 rpm for 2 min. Also, dopamine transporter and dopamine receptor protein expression levels in the striatum region of the brain were determined by Western blot analysis. At a rotarod speed of 10 rpm, there were no significant differences in the time on the bar before the first fall or the number of falls during the two-minute test observed in the exposed rats, as compared with controls. The Mn-exposed group had significantly higher Mn levels in the lung, blood, olfactory bulb, prefrontal cortex, striatum, and cerebellum compared with the control group. A Mn concentration gradient was observed from the olfactory bulb to the striatum, supporting the idea that Mn is transported via the olfactory pathway. Our results demonstrated that inhalation exposure to 39 mg/m3 Mn for 3 weeks induced mild lung injury and modulation of dopamine transporter expression in the brain, without altering motor activity.
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Original Article
  • Youssef Darif, Driss Mountassif, Abdelkarim Belkebir, Younes Zaid, Kau ...
    Volume 41 (2016) Issue 3 Pages 403-416
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Ochratoxin A (OTA) is a natural fungal secondary metabolite that contaminates food and animal feed. Human exposure and involvement of this mycotoxin in several pathologies have been demonstrated worldwide. We investigated OTA immunotoxicity on H9 cells, a human cutaneous CD4+ T lymphoma cell line. Cells were treated with 0, 1, 5, 10, and 20 µM OTA for up to 24 hr. Western blotting revealed increased phosphorylation of all three major mitogen-activated protein kinases (extracellular signal–regulated kinase, c-Jun amino-terminal kinase, p38). OTA triggered mitochondrial transmembrane potential loss and caspase-3 activation. The 24-hr OTA treatment caused marked changes in cell morphology and DNA fragmentation, suggesting the occurrence of apoptotic events that involved a mitochondria-dependent pathway. Moreover, OTA triggered significant modulation of survivin, interleukin 2 (IL-2) and tumor necrosis factor α (TNF-α): mRNA expression of survivin and IL-2 were decreased, while TNF-α was increased. OTA also caused caspase-8 activation in a time-dependent manner, which evokes the death receptor pathway activation; we suspect that this occurred via the autocrine pro-apoptotic effect of TNF-α on H9 cells.
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Original Article
  • Wei Li, Yu-Hong Tian, Ying Liu, Zi Wang, Shan Tang, Jing Zhang, Ying-P ...
    Volume 41 (2016) Issue 3 Pages 417-428
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Platycodin D (PD), a major saponin derived and isolated from the roots of Platycodon grandiflorum, exerts potent growth inhibition and strong cytotoxicity against various cancer cell lines. However, the anti-tumor efficacy of PD on H22 hepatocellular carcinoma remains unknown. In the present study, we aimed to explore the anti-hepatoma activity in vivo and the underlying mechanism of PD in H22 tumor-bearing mice. The results revealed that PD could considerably suppress tumor growth with no significant side effects on immune organs and body weight. Further investigations showed that the levels of serum cytokines, including interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-2 (IL-2), were enhanced by PD administration. On the other hand, PD inhibited the production of vascular endothelial growth factor (VEGF) in serum of H22 tumor mice. Additionally, the observations from H&E and Hoechst 33258 staining results demonstrated that PD noticeably induced apoptosis in H22 hepatocellular carcinoma cells. Importantly, immunohistochemical analysis showed that PD treatment increased Bax expression and decreased Bcl-2 and VEGF expression of H22 tumor tissues in a dose-dependent manner. Taken together, the findings in the present investigation clearly demonstrated that the PD markedly suppressed the tumor growth of H22 transplanted tumor in vivo at least partly via improving the immune functions, inducing apoptosis, and inhibiting angiogenesis.
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Original Article
  • Chien-Lin Lu, Hen-I Lin, Bing-Fang Chen, Guey-Mei Jow
    Volume 41 (2016) Issue 3 Pages 429-437
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Beauvericin (BEA) is a cyclic hexadepsipeptide that derives from Codyceps cicadae. Our previous study results indicated that the cytotoxic effects of BEA on human A549 lung cancer cells BEA occur through an apoptotic pathway, which involves the up-regulation of cytochrome c release from mitochondria, upregulation of caspase 3 activity, and cellular and morphological changes. In this study, we identified that the mitogen-activated protein kinase (MAPK) inhibitor U0126 inhibits the cytotoxic effects of BEA on A549 cells. After exposing human A549 cells to 10 μM BEA, we observed a significant and dose-dependent increase in the percentage of hypoploid (sub-G1) phase cells in the A549 population. Following the pretreatment of the A549 cells with 25 μM U0126, the distribution of A549 cells in the sub-G1 phase decreased significantly. The BEA treatment resulted in a significant increase apoptosis in A549 cells by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Moreover, the MEK1/2 (mitogen-activated protein kinase kinase)-ERK42/44 (extracellular signal-regulated kinases)-90RSK (ribosomal s6 kinase) signaling pathway was activated in BEA-induced apoptotic A549 cells. Furthermore, treatment with MEK1/2 inhibitor U0126 was capable to attenuate the BEA induced typical apoptotic morphological change, apoptotic cells, and MEK1/2-ERK42/44-90RSK signaling pathway. These results suggested that MEK1/2-ERK42/44-90RSK signaling pathway may play a important role in BEA-induced apoptosis in human NSCLC A549 cancer cells.
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Original Article
  • Xin Cao, Yuji Nakamura, Takeshi Wada, Hiroko Izumi-Nakaseko, Kentaro A ...
    Volume 41 (2016) Issue 3 Pages 439-447
    Released: May 17, 2016
    JOURNALS FREE ACCESS
    Since amantadine-induced long QT syndrome has been clinically reported, we investigated its electropharmacological effects to estimate the extent of proarrhythmic risk by using the halothane-anesthetized beagle dogs (n = 4). Amantadine in doses of 0.1, 1 and 10 mg/kg was infused over 10 min with a pause of 20 min under the monitoring of multiple cardiovascular variables. J-Tpeak and Tpeak-Tend were separately measured on the lead II electrocardiogram to precisely analyze the net balance between inward and outward current modifications by amantadine. The low dose increased the ventricular contractile force, but suppressed the intraventricular conduction. The middle dose prolonged the QT interval besides enhancing the changes induced by the low dose. The high dose increased the mean blood pressure, left ventricular end-diastolic pressure and total peripheral resistance, and accelerated the atrioventricular nodal conduction, but decreased the cardiac output besides enhancing the changes induced by the middle dose. A reverse use-dependence was confirmed in the repolarization delay. Amantadine hardly affected the J-Tpeak, but prolonged the Tpeak-Tend. Amantadine can be considered to stimulate Ca2+ channel but inhibit Na+ and K+ channels in the in situ heart. J-Tpeak and Tpeak-Tend analysis suggests that amantadine may possess modest risk for arrhythmia.
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