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Volume 37 , Issue 1
February
Showing 1-21 articles out of 21 articles from the selected issue
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Original Article
  • Mohamed Mohany, Mostafa El-Feki, Inas Refaat, Olivier Garraud, Gamal B ...
    Volume 37 (2012) Issue 1 Pages 1-11
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Previous studies have shown that thymoquinone (TQ) exerts protective effects in some models of pesticide-induced immunotoxicity. However, no data exist regarding its possible modulatory effect during imidacloprid (IC)-induced toxicity. Therefore, the aim of this study was to investigate the impact of TQ on IC-induced immunotoxicity. Sixty adult male albino rats were divided into three groups of twenty animals each. The control group was given distilled water orally, while the IC-treated group was orally administered 0.01 LD50 (0.21 mg/kg body weight) of IC insecticide daily for 28 days. The animals in the third group (IC/TQ group) received the same IC dose as the IC-treated group for 28 days in addition to an intraperitoneal (I.P.) injection of TQ (1 mg/kg) once every 7 days. We found that IC induced significant increases (P < 0.05) in total leukocyte counts, total immunoglobulins (Igs) (especially IgGs), the hemagglutination of antibodies, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and malondialdehyde (MDA) compared to the control group. In contrast, significant decreases (P < 0.05) in phagocytic activity, chemokine expression and chemotaxis were observed in the IC-treated group, as were severe histopathological lesions in the liver, spleen and thymus. Notably, TQ supplementation ameliorated the biochemical, histopathological, and immunological changes induced by IC by increasing phagocytic activity, chemokinesis, chemotaxis, immunoglobulin levels, and the hemagglutination of antibodies, as well as by decreasing hepatic enzymes and serum MDA levels. Taken together, our data reveal the benefits of TQ supplementation for ameliorating IC toxicity by decreasing oxidative stress and enhancing immune efficiency.
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  • Haslan Roslie, Kok Meng Chan, Nor Fadilah Rajab, Saraswathi S. Velu, S ...
    Volume 37 (2012) Issue 1 Pages 13-21
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    A series of 22 stilbene derivatives based on resveratrol were synthesized incorporating acetoxy-, benzyloxy-, carboxy-, chloro-, hydroxy- and methoxy functional groups. We examined the cytotoxicity of these 22 stilbenes in human K562 chronic myelogenous leukemia cells. Only four compounds were cytotoxic namely 4’-hydroxy-3-methoxystilbene (15), 3’-acetoxy-4-chlorostilbene (19), 4’-hydroxy-3,5-dimethoxystilbene or pterostilbene (3) and 3,5-dibenzyloxy-4’-hydroxystilbene (28) with IC50s of 78 µM, 38 µM, 67 µM and 19.5 µM respectively. Further apoptosis assessment on the most potent compound, 28, confirmed that the cells underwent apoptosis based on phosphatidylserine externalization and loss of mitochondrial membrane potential. Importantly, we observed a concentration-dependent activation of caspase-9 as early as 2 hr with resultant caspase-3 cleavage in 28-induced apoptosis. Additionally, a structure-activity relationship (SAR) study proposed a possible mechanism of action for compound 28. Taken together, our data suggests that the pro-apoptotic effects of 28 involve the intrinsic mitochondrial pathway characterized by an early activation of caspase-9.
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  • Hiroyuki Asano, Satoki Fukunaga, Yoshihito Deguchi, Satoshi Kawamura, ...
    Volume 37 (2012) Issue 1 Pages 23-31
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Apoptosis controls erythroid homeostasis by balancing survival and death of erythroid cells. The mitochondrial pathway of apoptosis involves regulation of apoptotic events caused by the Bcl-2 family proteins, including the anti-apoptotic and pro-apoptotic members. However, little has been reported on the role of the anti-apoptotic Bcl-2 family members in rat late-stage erythroblasts that are no longer erythropoietin (EPO)-dependent. In the present study, to investigate this we analyzed changes in apoptosis-related factors that occurred in vitro. EPO stimulation resulted in reduced apoptotic cell death of the late-stage erythroblasts accompanied by decreased caspase-3 and caspase-9 activities, which is indicative of the induction of apoptosis through the mitochondrial pathway. Analysis of mRNA expression of the Bcl-2 family proteins demonstrated that EPO stimulation up-regulated the Bcl-xL mRNA, resulting in decreases in the mRNA ratios of Bak, Bax, and Bad to Bcl-xL. Also, the mRNA ratios of Bak and Noxa to Mcl-1 were decreased, mainly due to up-regulation of Mcl-1 mRNA. These results showed a close association between reduced apoptotic cell death and increased mRNA levels of Bcl-xL and Mcl-1 in the presence of EPO. Thus, the present study suggests that Bcl-xL may be an important anti-apoptotic factor of rat late-stage erythroblasts as has been reported in murine erythroblasts. Moreover, the results also indicate the possibility that Mcl-1 may act on the rat late-stage erythroblasts as an anti-apoptotic factor.
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  • Yoshimasa Kurata, Futoshi Makinodan, Nobuaki Shimamura, Masanobu Katoh
    Volume 37 (2012) Issue 1 Pages 33-49
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    We compared the metabolic profile of di (2-ethylhexyl) phthalate (DEHP) in juveniles and fetus between rats and marmosets. STUDY-I: 14C-DEHP (100 and 2,500 mg/kg) was singly administered to juvenile and adult marmosets by gavage. Cmax of the radioactivity in juvenile marmosets was 6.45 and 31 µg eq./g, respectively. The radioactivity excreted mainly into feces; however, at least 10% of the radioactivity was absorbed even at 2,500 mg/kg. No abnormal accumulation was observed in the male reproductive organs. STUDY-II: 14C-DEHP (100 mg/kg) was singly administered to juveniles of rat and marmoset. The plasma radioactivity in marmosets was about 5% to 9% of that in rats. Free forms of  mono-2-ethylhexyl phthalate (MEHP) and its oxidized metabolites such as oxo-, OH-, and COOH-MEHP were detected as the main compositions in rat plasma. In marmosets, free form of MEHP was also detected as a major composition, but not for oxidized MEHP metabolites. In rats, oxidized MEHP metabolites were excreted into urine as unconjugated forms. MEHP and its oxidized metabolites were also detected in marmoset urine; however, they were mostly glucuronized. No specific accumulation of the radioactivity was noted in the testes of either species; however, the radioactivity concentration in the marmoset testes was much lower than that in rats. STUDY-III: 14C-DEHP (100 mg/kg) was singly administered to dams on gestation day 130 for marmosets and day 20 for rats. In either species, no specific accumulation of radioactivity was noted in the testis of fetuses from the dams treated with 14C-DEHP; however, the radioactivity in the rat testis was about 20-times higher than that in the marmoset. Major metabolite components in rat whole fetal tissue were free forms of MEHP, OH-MEHP, and oxo-MEHP. Free form of MEHP was also detected as only a peak in the marmoset fetal tissue.
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  • Chongtham Rajlakshmi, Jagat Kumar Roy, Amit Kumar Rai, Asima Bhattacha ...
    Volume 37 (2012) Issue 1 Pages 51-61
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Zidovudine (3’-Azido-2’, 3’-dideoxythymidine, AZT, ZDV) is routinely used as one of the component of antiretroviral therapy to prevent transmission of the HIV infection from mother to child. The drug, when given during pregnancy can give rise to myriad toxicities as reported in previous studies on human, animal and in-vitro experiments. The present study was an attempt to explore the Zidovudine teratogenesis in F1 and F2 generation of mice following initial maternal exposure to Zidovudine during pregnancy, through delivery and lactation. The F1 generation actually would have got the exposure during embryonic development and infant stages. Pregnant Swiss mice were treated orally with ZDV 50 mg/kg/day or distilled water (control), from day eighth of gestation, through delivery and continued for first ten days of lactation. The F1 generation litters were raised and mated to produce F2 generation mice. An interesting phenotype of “healthy” and “sick” was noted in F2 generation but not in the F1 generation. In F2 generation 35% died on different postnatal day during 120 days of follow up period. Chromosomal study from bone marrow of F1 and F2 showed various chromosomal aberrations. Lipodystrophy and hepatotoxicity was observed in “sick” mice. The study generated a hypothesis of recessive mutation and concludes that Zidovudine is a transplacental genotoxic agent. The result of present study therefore suggests the need to study the effect of zidovudine in human subjects for a longer period of time to rule out similar genotoxic effect.
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  • Mutsuko Hirata-Koizumi, Sakiko Fujii, Masatoshi Furukawa, Atsushi Ono, ...
    Volume 37 (2012) Issue 1 Pages 63-79
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Male and female rats were given perfluorooctadecanoic acid (PFOdA) by gavage at 40, 200 or 1,000 mg/kg/day, and each female was mated with a male in the same dose group after 14-day administration. Males were dosed for 42 days and females were dosed throughout the gestation period until day 5 of lactation. One female given 1,000 mg/kg/day was euthanized on day 18 of gestation due to a moribund condition; however, no other treatment-related clinical signs of toxicity were observed. Body weights fell at 1,000 mg/kg/day from day 28 through the administration period in males and throughout gestation and lactation in females. Red blood cell count, hemoglobin level and hematocrit were decreased at 200 and 1,000 mg/kg/day in males and activated partial thromboplastin time was prolonged at 1,000 mg/kg/ day in females. Histopathological examination revealed hepatic changes, such as centrilobular hypertrophy and necrosis, in males given 200 and 1,000 mg/kg/day and in females given 1,000 mg/kg/day. Pancreatic zymogen granule was decreased in both sexes at 1,000 mg/kg/day. As for reproductive and developmental toxicity, there were decreases in the number of corpora lutea, implantation, total number of pups born and the number of live pups on postnatal days 0 and 4 at 1,000 mg/kg/day. At this dose, birth weights of pups were decreased and postnatal body weight gain was inhibited. Based on these findings, the NOAEL of PFOdA was considered to be 40 mg/kg/day for repeated dose toxicity and 200 mg/kg/day for reproductive/developmental toxicity.
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  • Tomoko Fujitani, Ken-ichi Ohyama, Akihiko Hirose, Tetsuji Nishimura, D ...
    Volume 37 (2012) Issue 1 Pages 81-89
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    A possible teratogenicity of multi-wall carbon nanotube (MWCNT) was assessed using ICR mice. MWCNTs were suspended in 2% carboxymethyl cellulose and given intraperitoneally or intra­tracheally to pregnant ICR mice on day 9 of the gestation. All fetuses were removed from the uterus on day 18 of the gestation, and were examined for external and skeletal anomalies. In the intraperitoneal study, various types of malformation were observed in all MWCNT-treated groups (2, 3, 4 and 5 mg/kg body weight, intraperitoneal). In contrast, such malformations were observed in groups given 4 or 5 mg/kg body weight, but not in that treated with 3 mg/kg in the intratracheal study. In either study, the number of litters having fetuses with external malformation and that of litters having fetuses with skeletal malformations were both increased in proportion to the doses of MWCNT. The present results are the first to report that MWCNT possesses the teratogenicity at least under the present experimental conditions. Mechanism(s) to result such malformations is yet unclear and further experiment is necessary.
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  • Toshinori Yoshida, Naoki Ikemi, Yukiko Takeuchi, Koichi Ebino, Sayuri ...
    Volume 37 (2012) Issue 1 Pages 91-104
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Cyflumetofen is a novel acaricide which is highly active against phytophagous mites. As a part of safety assessment, a repeated dose 90-day oral toxicity study of cyflumetofen was conducted in Fischer (F344/DuCrj) rats of both sexes. Technical grade cyflumetofen was administered in feed to groups of 10 males and 10 females at dose levels of 0, 100, 300, 1,000, and 3,000 ppm. Prothrombin time was prolonged in males at 3,000 ppm and plasma globulin levels were decreased in females at 1,000 and 3,000 ppm. At necropsy, enlarged and whitish adrenals were observed in females at 3,000 ppm. There were statistically significant increases in relative liver weight (ratio to body weight) in males and relative adrenal weight in females in the 1,000 ppm group; increased relative liver and kidney weights in both sexes at 3,000 ppm, and increased absolute and relative weights of adrenals in females at 3,000 ppm. Increased absolute liver weight was also noted in males at 3,000 ppm. Histopathologically, at 1,000 and 3,000 ppm males had diffuse vacuolation and females had diffuse hypertrophy of adrenal cortical cells. In addition, vacuolation of ovarian interstitial gland cells was noted in females at 1,000 and 3,000 ppm. There were no treatment-related changes in any parameters for either sex in other dose groups. Based on these results, the no-observed-adverse-effect level (NOAEL) of cyflumetofen was judged to be 300 ppm for both sexes (16.5 mg/kg/day for males and 19.0 mg/kg/day for females).
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  • Shiro Watanabe, Koichi Tsuneyama
    Volume 37 (2012) Issue 1 Pages 105-121
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Three types of animal bile preparation, bear bile (BB), cattle bile (CB) and pig bile (PB) differ in bile acid composition and are supposed to exert different pharmacotoxicological actions. Dietary supplementation with CB at 1% (w/w) for 4 weeks decreased triacylglycerol (TAG) level but increased total cholesterol (CHO) level in serum, which were associated with fatty liver injury in mice. The increased levels of cholesterol esters (CE) and monounsaturated fatty acids (MUFA) in the serum and liver were observed in the mice fed the CB-supplemented diet. Lipid abnormalities and fatty liver injury observed in the mice fed the CB diet were not induced by the supplementation with BB and PB. The supplementation with cholic acid (CA), the most abundant bile acid in CB, could induce lipid abnormalities and fatty liver injury, which were indistinguishable from those induced by CB supplementation. CB and CA supplementation induced similar changes in the expression levels of mRNAs in the liver. Thus, CB induced lipid abnormalities and fatty liver injury, which can be attributed to the actions of CA contained in CB. The inabilities of BB and PB to induce lipid abnormalities and fatty liver injury are supposed to be due to their limited contents of CA.
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  • Kozue Yaginuma-Sakurai, Katsuyuki Murata, Miyuki Iwai-Shimada, Kunihik ...
    Volume 37 (2012) Issue 1 Pages 123-130
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    The hair-to-blood ratio and biological half-life of methylmercury in a one-compartment model seem to differ between past and recent studies. To reevaluate them, 27 healthy volunteers were exposed to methylmercury at the provisional tolerable weekly intake (3.4 µg/kg body weight/week) for adults through fish consumption for 14 weeks, followed by a 15-week washout period after the cessation of exposure. Blood was collected every 1 or 2 weeks, and hair was cut every 4 weeks. Total mercury (T-Hg) concentrations were analyzed in blood and hair. The T-Hg levels of blood and hair changed with time (p < 0.001). The mean concentrations increased from 6.7 ng/g at week 0 to 26.9 ng/g at week 14 in blood, and from 2.3 to 8.8 µg/g in hair. The mean hair-to-blood ratio after the adjustment for the time lag from blood to hair was 344 ± 54 (S.D.) for the entire period. The half-lives of T-Hg were calculated from raw data to be 94 ± 23 days for blood and 102 ± 31 days for hair, but the half-lives recalculated after subtracting the background levels from the raw data were 57 ± 18 and 64 ± 22 days, respectively. In conclusion, the hair-to-blood ratio of methylmercury, based on past studies, appears to be underestimated in light of recent studies. The crude half-life may be preferred rather than the recalculated one because of the practicability and uncertainties of the background level, though the latter half-life may approximate the conventional one.
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  • Koichi Tomoda, Kaoru Kubo, Yasue Nishii, Yoshifumi Yamamoto, Masanori ...
    Volume 37 (2012) Issue 1 Pages 131-138
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Cigarettes smoke (CS) limits food intake and body weight increase. Ghrelin and leptin are hormones regulating appetite and energy balance. While ghrelin increases food intake and causes a positive energy balance, leptin decreases food intake and enhances a negative energy balance. To investigate the possible role of ghrelin and leptin regarding the negative energy balance caused by CS, 10-week old male Wistar rats (n = 10) were exposed to CS from 30 cigarettes twice a day for 5 days a week for four weeks. In the smoking group, food intake and body weight gain were less than those in the non-smoking group (n = 10) during the entire CS exposure. In the smoking group, the plasma levels of acyl ghrelin were significantly higher (75.9 ± 5.1 fmol/ml versus 46.5 ± 3.3 fmol/ml, p < 0.01), while those of leptin were significantly lower than those in the non-smoking group (434.9 ± 41.1 ng/ml versus 744.0 ± 45.4 ng/ml, p < 0.01) after the final CS exposure. However, the plasma des-acyl ghrelin levels were not affected by CS exposure. These results suggested that acyl ghrelin and leptin levels in plasma may change to compensate for the negative energy balance by CS.
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  • Mohd Javed Akhtar, Maqusood Ahamed, Mohd Fareed, Salman A. Alrokayan, ...
    Volume 37 (2012) Issue 1 Pages 139-148
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Despite the great interest in nanoparticles (NPs) safety, no comprehensive test paradigm has been developed. Oxidative stress has been implicated as an explanation behind the toxicity of NPs. It is reported that sulphoraphane (SFN) present in cruciferous vegetables like cauliflower and broccoli has potential to protect cells from oxidative damage and inflammation. However, protective role of SFN in nanotoxicity is not explored. We investigated the protective effect of SFN against the toxic response of copper oxide (CuO) NPs in mouse embryonic fibroblasts (BALB 3T3). Results showed that CuO NPs induced dose-dependent (5-15 µg/ml) cytotoxicity in BALB 3T3 cells demonstrated by MTT and lactate dehydrogenase (LDH) assays. CuO NPs were also found to induce oxidative stress in dose-dependent manner indicated by induction of reactive oxygen species (ROS) and lipid peroxidation (LPO) and depletion of glutathione and glutathione reductase. Co-treatment of BALB 3T3 cells with SFN (6 µM) significantly attenuated the cytotoxicity, ROS generation and oxidative stress caused by CuO NPs. Moreover, we found that co-treatment of another antioxidant N-acetyl-cysteine (NAC) (2 mM) also significantly attenuated glutathione depletion caused by CuO NPs but protection from the loss of cell viability due to CuO NPs exposure was not significant. We believe this is the first report showing that SFN significantly protected the BALB 3T3 cells from CuO NPs toxicity, which is mediated through generation of oxidants and depletion of antioxidants. Consequently, protective mechanism of SFN against CuO NPs toxicity was different from NAC that should be further investigated.
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  • Yasuhiro Nakamura, Ken-ichi Ohba, Keiji Suzuki, Hisayoshi Ohta
    Volume 37 (2012) Issue 1 Pages 149-156
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Female Wistar rats were given Cd (as CdCl2) at a dose of 0, 1, 2, and 5 mgCd/kg/day by gastric tube daily for 6 consecutive days each week for 10 weeks. After the birth, newborn rats were sacrificed on day 1 and at 4 weeks. Mother rats were sacrificed after 4 weeks of lactation The concentrations of Cd in uterus and placenta, and metallothionein (MT) in the uterus of mother rats were determined. The concentrations of Cd in kidney and liver of newborn rats were also determined. Expression of iso-MT genes (I, II, and III) in the uterus of mother rats was measured using RT-PCR. The Cd concentration in the liver of newborn rats at the first day after birth was higher than in the kidney, while the concentration in the kidney of newborn rats at the fourth week after the birth was significantly higher than in the liver. The uterine MT concentration increased with accumulation of Cd; however, the MT concentration did not increase enough to prevent Cd transport to the fetus. On the other hand, it was considered that more Cd was transported as the chemical form of nonMT-Cd from mother rat, and accumulated in the liver rather than kidney of the fetus. Based on analyses of the Cd distribution in the liver and kidney of newborn rats, we speculate that MT in the uterus and placenta does not play a significant role in preventing Cd transport through the placenta from the uterus to the fetus.
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  • Qun Chen, Yan Gao, XiBin Kao, JingHong Chen, WanLi Xue, YongMin Xiong, ...
    Volume 37 (2012) Issue 1 Pages 157-167
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    NO plays an important role in cartilage destruction by inducing apoptosis of chondrocytes. Here we investigated the role of c-Jun N-terminal kinase (JNK) signal transduction pathways in the apoptosis induced by NO donor sodium nitroprusside (SNP) in rabbit articular chondrocytes. We used Annexin V-FITC/PI flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) assay to detect apoptosis rate. The expressions of p38, NF-κB p65, caspase-3 and p53 genes at protein levels were measured by Western blotting assay. RT-PCR was performed to show the mRNA expression of caspase-3, and the activity of caspase-3 was also detected. To investigate the effect of JNK-specific inhibitor SP600125, chondrocytes were pretreated with SP600125 ahead of SNP treatment. Treatment with SNP accelerated apoptosis in a concentration dependent manner, while such acceleration was reduced by SP600125 pretreatment. Moreover, we found that SP600125 significantly decreased NO-induced NF-κB, p53, caspase-3 protein expressions and caspase-3 mRNA expression, as well as intracellular caspase-3 activity (P < 0.05). Collectively, these data suggest that JNK plays an important role through stimulating NF-κB, p53 and caspase-3 activation.
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  • Kyoumi Nakazato, Katsuyuki Nakajima, Takamitsu Nakano, Tsukasa Kodaira ...
    Volume 37 (2012) Issue 1 Pages 169-175
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Metallothionein (MT) is known to be involved in various physiological roles and diseases. However, a standard method for MT measurement has not been established until recently. Therefore, we have developed an easy and specific enzyme-linked immunosorbent assays (ELISA) to determine MT-1 and MT-2. In order to evaluate the method we developed, MT-1/2 in liver, kidney and brain was determined in wild type (WT), MT-1/2 knockout (KO) and MT-3 KO mice, with and without Cd treatment. MT 1/2 in urine was determined in genetically disordered LEC rats (an animal model of Wilson disease). MT-1/2 concentrations in the liver, kidney and brain in MT-1/2 KO mice were significantly lower compared to those of WT and MT-3 KO mice. MT-1/2 concentrations in the livers of WT mice significantly increased with Cd administration, but not in MT-1/2 KO mice. Similar results were observed by immunohistochemical staining. To confirm the molecular weight (MW) of MT detected in organs by the ELISA, analysis with a Sephadex G-75 was performed. Two peaks of MT-1/2 (MW small and large) were detected in WT and MT-3 KO mice. The small MT peak was mostly depleted in MT 1/2-KO mice, while a large MT peak remained. A significant increase in MT-1/2 concentration was detected in the urine of LEC rats with age and especially at the hepatitis stage. In conclusion, MT-1/2 ELISA and immunohistochemical staining was highly correlated with MT-1/2 determination in experimental animal specimens and could be a robust analytical tool for physiological and toxicological studies.
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  • Atsumi Yamaguchi, Tomoko Fujitani, Ken-ichi Ohyama, Dai Nakae, Akihiko ...
    Volume 37 (2012) Issue 1 Pages 177-189
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    Possible effects of multi-wall carbon nanotubes (MWCNTs) on immune and inflammatory responses were examined in mice. Female ICR mice were given a single intraperitoneal administration (2 mg/kg body weight) of either MWCNTs, carbon black (CB), or crocidolite (blue asbestos) and controls received a vehicle of 2% sodium carboxymethyl cellulose (CMC Na). In the peritoneal cavity of MWCNT-administered mice, the liver had changed to a rounded shape and fibrous adhesions were seen on internal organs. Peritoneal cells overexpressed mRNA for genes of T helper (Th)2 cytokines (interleukin [IL]-4, IL-5, and IL-13), Th17 cytokine (IL-17), pro-inflammatory cytokines/chemokines (IL-1β, IL-33, tumor necrosis factor α, and monocyte chemotactic protein-1), and myeloid differentiation factor 88 for at least 2 weeks after the administration of MWCNTs, while those of Th1 cytokine genes (IL-2 and interferon γ) were overexpressed several weeks later and expression levels remained high up to 20 weeks. In MWCNT-treated mice, the numbers of leukocytes, monocytes, and granulocytes in the peripheral blood and the expression of the leukocyte adhesion molecules, cluster of differentiation (CD)49d and CD54, on granulocytes were increased 1 week after administration and remained high up to week 20. Production of ovalbumin-specific IgM and IgG1 was enhanced by MWCNTs. These changes were not observed after CB or crocidolite administration. Thus, this study showed that MWCNTs exhibited sustained stimulating effects on immune and inflammatory responses, unlike the other mineral fibers with structural similarities.
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  • Nobuhiko Miura, Yukie Yanagiba, Katsumi Ohtani, Masaharu Mita, Masako ...
    Volume 37 (2012) Issue 1 Pages 191-196
    Released: February 01, 2012
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    Circadian timing largely modifies efficacy of many medicinal drugs. This viewpoint has been applied in the clinical medicine, known as chronotherapy. We think this viewpoint should also be introduced into toxicology as “chronotoxicology”, however, information about the diurnal variation in toxicant sensitivity is still very scarce. We present here a clear and reproducible diurnal variation of cadmium (Cd)-induced mortality in mice. Male ICR mice kept under standard condition (12 hr light/dark cycle, lights on at 08:00) were injected with CdCl2 (7.2 mg/kg, one shot) intraperitoneally at different time points in the day (zeitgeber time (ZT) 0, 4, 8, 12, 16 or 20). Survival number was determined at 14 days after injection. Interestingly, mice were sensitive to Cd acute toxicity at ZT8, while tolerant at mid-dark to early-light phase (ZT16, ZT20 and ZT0). Hepatic GSH level showed small daily fluctuation, lowest at ZT8 and highest at ZT20, and this fluctuation was similar to the diurnal variation of Cd sensitivity. In contrast, hepatic metallothionein (MT) level was not significant in these time points, although their level also showed small daily fluctuation. Our results indicated that Cd-induced mortality had clear diurnal variation, and suggested that the hepatic GSH level was one of the important factors for determination of this Cd-induced diurnal mortality.
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Letter
  • Kazuhisa Hara, Tetsuya Matsuoka, Takuma Hara, Kei Wakabayashi, Mutsumi ...
    Volume 37 (2012) Issue 1 Pages 197-205
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    For the local irritation caused by Doxorubicin hydrochloride (DXR) which have leaked to the subcutis from the vein, the usefulness of the model using the auricular subcutis of rabbits was examined. DXR was administered to the subcutis in the ear auricle, abdominal region and dorsal region, and the local irritation reactions induced were evaluated according to the Draize criteria, by comparison of the damaged area and by the histopathological method. Macroscopic formations of erythema, edema and eschar were observed in the auricular subcutis, but there were no changes in the abdominal or dorsal subcutis. Histopathological examination showed changes such as edema, hemorrhage and necrosis at all administration sites and the changes were most severe in the auricular subcutis among the 3 regions. The reactions in the ear auricle observed were closest to the skin damage noted in humans by administration of DXR. In order to find out why the degree of local damage is different in these 3 regions, Evans blue was administered to these regions to compare its diffusibility in these regions. The diffusibility of Evans blue was lowest in the ear auricle. It is estimated that the difference in the local damage induced by DXR in these regions might be due to the difference in the retention time of DXR in the subcutis. Therefore, the evaluation for local irritation using the auricular subcutis model in rabbits is considered to be useful for estimation of skin damage caused by leakage of DXR to the subcutis.
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  • Tetsuya Matsuoka, Yasumoto Mizoguchi, Ryo Haneda, Ema Otsuka, Hiroyasu ...
    Volume 37 (2012) Issue 1 Pages 207-214
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    In our previous study on the effects of restricted feeding on pregnant rabbits (Matsuoka et al., 2009), animals given 20 g/day of diet on and after gestation day 6 (GD 6) showed significant changes in blood coagulation-related parameters suggesting a tendency to bleed and a decrease in serum concentration of progesterone, an important factor to maintain pregnancy, on GD 22, and a half of them showed serum progesterone concentrations less than 4.0 ng/ml which resulted in abortions on and after GD 23. In the present study, the effects of restricted feeding of 20 g/day from GD 6 to GD 22 on embryo-fetal and placental development on GD 23 as well as on blood coagulation-related parameters and serum progesterone concentrations on GD 22 were examined in pregnant rabbits. As compared with the non-restricted feeding (Not-treated, NT) group, the restricted feeding (RF) group showed lower values of platelets, fibrinogen, activated partial thromboplastin time (APTT) and antithrombin III (ATIII) and a longer prothrombin time (PT), reflecting an inhibition of blood coagulation, and a decrease in serum progesterone concentration on GD 22. Cesarean section performed on GD 23 revealed that the RF group showed a tendency towards an increase in the embryo-fetal death index and lower body weights and placental volumes compared with the NT group. Histological examination of the placenta in the RF group revealed that the labyrinth zone was thin and many glycogen-containing cells still remained in the basal zone, suggesting a delay in placental growth.
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Toxicogenomics/proteomics Report
  • Anuran Chatterjee, Inna Diordieva, Kenji Yumoto, Ruth K. Globus, Sharm ...
    Volume 37 (2012) Issue 1 Pages 215-217
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    To determine the chronic effects of heavy ion irradiation, an antibody based proteomic microarray technology was applied to monitor alterations in the serum proteome, six months after whole body irradiation of adult male C57Bl/6 mice with 0.5 Gray of 56Fe. Out of 507 proteins, irradiation reduced expression of 25 proteins and enhanced expression of 12 proteins in serum (> 5% change relative to sham-irradiated controls). Of the 25 proteins found to be down-regulated, Poly ADP Ribose Polymerase (PARP) was 13% lower in the 0.5Gy mice and among the up-regulated proteins, beta-Tubulin was found to be 10% higher in the 0.5Gy group compared to the sham-irradiated 0Gy controls. Thus, irradiation with a relatively low dose of heavy ions caused persistent and selective changes in serum levels of proteins that are typically intracellular, suggesting chronic genotoxic damage.
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  • Masayuki Uehara, Ayako Nishio, Satoshi Inoue, Kiyoshi Matsumoto
    Volume 37 (2012) Issue 1 Pages 219-222
    Released: February 01, 2012
    JOURNALS FREE ACCESS
    We performed DNA microarray analysis on the white blood cells (WBCs) of rats housed on solid and grid cage flooring. The expression levels of 50 genes were found to increase more than 2-fold in the WBCs on grid cage flooring, including many genes encoding proteins involved in inflammatory or immune responses. It is therefore suggested that the health and welfare of laboratory rats is likely to be improved by housing rats on solid floors.
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