Journal of Applied Toxicology

Cover image for Vol. 33 Issue 6

June 2013

Volume 33, Issue 6

Pages 399–526

  1. Review Article

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communications
    1. Cellular-signaling pathways unveil the carcinogenic potential of chemicals (pages 399–409)

      Giel Hendriks, Bob van de Water, Willem Schoonen and Harry Vrieling

      Version of Record online: 22 JAN 2013 | DOI: 10.1002/jat.2845

      Upon chemical-induced damage of biomolecules, molecular sensors will activate general and damage-specific cellular response pathways that provide protection against the (geno)toxic and potential carcinogenic properties of chemicals. visualization of the cellular signaling pathways that are activated upon exposure provides a powerful means to identify the primary mode of action of (geno)toxic compounds and will improve the in vitro health risk and carcinogenicity hazard prediction.

  2. Research Articles

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communications
    1. Ketamine induces motor neuron toxicity and alters neurogenic and proneural gene expression in zebrafish (pages 410–417)

      Jyotshna Kanungo, Elvis Cuevas, Syed F. Ali and Merle G. Paule

      Version of Record online: 2 NOV 2011 | DOI: 10.1002/jat.1751

      Ketamine, a pediatric anesthetic, adversely affects motor neuron development in zebrafish in vivo and alters the expression of specific genes involved in neurodevelopment.

    2. Effect of lipopolysaccharide on alteration of phospholipids and their fatty acid composition in spleen and thymus by in vitro metabolic labeling (pages 418–425)

      Jayaraja Sabarirajan, Panneerselvam Vijayaraj, Mary Sarkar and Vasanthi Nachiappan

      Version of Record online: 11 NOV 2011 | DOI: 10.1002/jat.1752

      Lipopolysaccharide (LPS) is a known endotoxin and a potent immune modulator. LPS induction leads to acute respiratory distress syndrome (ARDS). ARDS is a threatening disease with high mortality rate. The immunological effect of LPS on spleen and thymus is well documented; conversely membrane phospholipid (PL) importance has not yet been studied. We aimed to investigate the influence of LPS on spleen and thymus phospholipid, their fatty acid composition by [32P]-labeling in rats, it showed significant alterations.

    3. Molecular cytogenetic evaluation of the mechanism of genotoxic potential of amsacrine and nocodazole in mouse bone marrow cells (pages 426–433)

      Sabry M. Attia

      Version of Record online: 11 NOV 2011 | DOI: 10.1002/jat.1753

      The mechanism of genotoxic potential of amsacrine and nocodazole was investigated by micronucleus test complemented by fluorescence in situ hybridization assay using mouse centromeric and telomeric probes. The present study demonstrated for the first time that amsacrine has high incidences of clastogenicity and low incidences of aneugenicity whereas nocodazole has high incidences of aneugenicity and low incidences of clastogenicity during mitotic phases. The assay also showed that chromosomes can be enclosed in the micronuclei before and after centromere separation.

    4. Mitochondrial and liver oxidative stress alterations induced by N-butyl-N-(4-hydroxybutyl)nitrosamine: relevance for hepatotoxicity (pages 434–443)

      Maria M. Oliveira, José C. Teixeira, Cármen Vasconcelos-Nóbrega, Luis M. Felix, Vilma A. Sardão, Aura A. Colaço, Paula A. Oliveira and Francisco P. Peixoto

      Version of Record online: 16 NOV 2011 | DOI: 10.1002/jat.1763

    5. Toxicokinetic study of melamine in the presence and absence of cyanuric acid in rats (pages 444–450)

      Jing Pang, Guo-Qing Li, Cong-Ran Li, Xin-Yi Yang, Xi Lu, Xin-Xin Hu, Qian-Qian Zhai, Wei-Xin Zhang, Jian-Dong Jiang and Xue-Fu You

      Version of Record online: 17 NOV 2011 | DOI: 10.1002/jat.1764

      A toxicokinetic study was conducted to compare the toxicokinetics of melamine (MEL) in the presence and absence of cyanuric acid (CYA), and to elucidate the correlation between toxicity and kinetic properties of MEL. CYA co-administration could lower absorption, slower excretion and induce tissue accumulation of MEL, which correlated well with the generation and development of renal toxicity. In conclusion, co-administration with CYA leads to the alteration of the kinetic characteristics of MEL, which provides an additional explanation to renal toxicity.

    6. Cytotoxicity of dental resin composites: an in vitro evaluation (pages 451–457)

      Pietro Ausiello, Angela Cassese, Claudia Miele, Francesco Beguinot, Franklin Garcia-Godoy, Bruno Di Jeso and Luca Ulianich

      Version of Record online: 26 NOV 2011 | DOI: 10.1002/jat.1765

      The purpose of this study was to evaluate the cytotoxic effect of two light cured restorative materials with and without BisGma resin respectively (Clearfil Majesty Posterior, Clearfil Majesty Flow) and a self curing one (Clearfil DC Core Automix) when applied to the fibroblast cell line NIH-3T3. All the composite materials tested caused a decrease of cell proliferation, albeit at different degrees. However, only Clearfil DC Core Automix induced cell death, very likely by increasing apoptosis.

    7. Mrp2 is involved in the efflux and disposition of fosinopril (pages 458–465)

      Benjamin R. Green and Lisa J. Bain

      Version of Record online: 17 NOV 2011 | DOI: 10.1002/jat.1767

      The highly prescribed ACE inhibitor, fosinopril, was 2.4-fold less toxic and was retained at a 4.5-fold lower level in multidrug resistance-associated protein 2 (MRP2)-transfected cells compared with control cells. When fosinopril was coadministered with methoxtrexate, a known MRP2 substrate, its cellular retention was increased in vitro, and fosinopril altered the disposition of methotrexate in vivo. These findings will help increase our understanding of the role that MRP2 plays in altering the retention and disposition of co-administered pharmaceuticals.

    8. Cardiovascular risk assessment of atypical antipsychotic drugs in a zebrafish model (pages 466–470)

      Sung Hak Lee, Hong Rye Kim, Rong Xun Han, Reza K. Oqani and Dong Il Jin

      Version of Record online: 26 NOV 2011 | DOI: 10.1002/jat.1768

      Zebrafish serve as an excellent model for assessing drug-induced cardiotoxicity. The cardiovascular risk assessment of six atypical antipsychotic drugs; aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone, was done by zebrafish model. Visual endpoints (llethality, edema, hemorrhage, abnormal body shape and motility) were evaluated as general toxicity endpoints, and the change rate of heart beat as the cardiovascular toxicity endpoint. The zebrafish presents a potentially useful in vivo preclinical model for assessment of the adverse effects of atypical antipsychotic drugs.

    9. Organ differences in the impact of p27kip1 deficiency on carcinogenesis induced by N-methyl-N-nitrosourea (pages 471–479)

      Kumiko Ogawa, Toshiya Murasaki, Satoshi Sugiura, Makoto Nakanishi and Tomoyuki Shirai

      Version of Record online: 19 DEC 2011 | DOI: 10.1002/jat.1770

      To evaluate the impact of p27 on carcinogenesis in various organs, N-methyl-N-nitrosourea (MNU) was given to p27 knock-out mice. Although the incidences of the lesions in the forestomach, fundic and pyloric glands did not differ among the p27 genotypes, those of the lung and the thymus were significantly increased in p27 null males as compared to both wild and hetero animals. These findings suggest that p27 does not control the cell cycle equally in all organs affected by MNU-induced carcinogenesis.

    10. High doses of 2,2′-dithienyl diselenide cause systemic toxicity in rats: an in vitro and in vivo study (pages 480–487)

      Pietro Maria Chagas, Cristiani Folharini Bortolatto, Ethel Antunes Wilhelm and Cristina Wayne Nogueira

      Version of Record online: 19 DEC 2011 | DOI: 10.1002/jat.1777

      Introduction: The potential toxicity of DTDS has not been studied. Material and Methods: Effect of DTDS on sulfhydryl enzymes activities was investigated in vitro and single oral doses were administered in rats. Results: DTDS inhibited δ-ALA-D and Na+–K+-ATPase activities, these effects were restored by DTT, and elicited thiol oxidase-like activity. In vivo, DTDS caused systemic toxicity. Discussion: Interaction with cisteinyl residues seems to mediate the inhibitory effects in vitro. Moreover, high oral doses of DTDS induced toxicity in rats.

    11. Deoxyactein Isolated from Cimicifuga racemosa protects osteoblastic MC3T3-E1 cells against antimycin A-induced cytotoxicity (pages 488–494)

      Eun Mi Choi

      Version of Record online: 19 DEC 2011 | DOI: 10.1002/jat.1784

      Deoxyactein is one of the major constituents isolated from Cimicifuga racemosa. In the present study, we investigated the protective effects of deoxyactein on antimycin A induced toxicity in osteoblastic MC3T3-E1 cells. Pretreatment with deoxyactein prior to antimycin A exposure significantly reduced antimycin A-induced cell damage by preventing mitochondrial membrane potential dissipation, complex IV inactivation, ATP loss, [Ca2+]i elevation, and oxidative stress. Moreover, deoxyactein increased the activation of PI3K, Akt, and CREB inhibited by antimycin A.

    12. Effects of DDT and triclosan on tumor-cell binding capacity and cell-surface protein expression of human natural killer cells (pages 495–502)

      Tasia Hurd-Brown, Felicia Udoji, Tamara Martin and Margaret M. Whalen

      Version of Record online: 21 JUN 2012 | DOI: 10.1002/jat.2767

      1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) and triclosan (TCS) are found in human blood and decrease the lytic function of human natural killer (NK) cells. This study examined concentrations of DDT and TCS that decrease lytic function for alteration of NK binding to tumor targets. Results indicated that some loss of NK lytic function could be accounted for by loss of binding function and that loss of binding function is accompanied by a loss cell-surface proteins important in binding function.

    13. Tributyltin and dibutyltin alter secretion of tumor necrosis factor alpha from human natural killer cells and a mixture of T cells and natural killer cells (pages 503–510)

      Kelsi Hurt, Tasia Hurd-Brown and Margaret Whalen

      Version of Record online: 10 OCT 2012 | DOI: 10.1002/jat.2822

      Human natural killer (NK) cells and a mixture of T and NK (T/NK) cells were exposed to tributyltin (TBT) (200 - 2.5 nM) and dibutyltin (DBT) (5 -  0.05 μM) for 24 h, 48 h, and 6 day. TBT (200 - 2.5 nM) decreased TNFα secretion from NK cells. 200 nM TBT decreased secretion while 100 - 5 nM TBT increased secretion in T/NK cells. DBT (high concentration) decreased TNFα secretion while lower concentrations increased secretion in both NK cells and T/NK cells.

  3. Short Communications

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communications
    1. Low-dose probenecid selectively inhibits urinary excretion of phenolsulfonphthalein in rats without affecting biliary excretion (pages 511–515)

      Yong-Jun Shin, Joo Hyun Lee, Ju-Hee Oh and Young-Joo Lee

      Version of Record online: 7 DEC 2011 | DOI: 10.1002/jat.1778

      The optimal dosage range of probenecid that can selectively inhibit urinary excretion of anionic compounds in rats without inhibition of biliary excretion was determined. Treatment with 100, 200 or 400mgkg−1 probenecid decreased both CLr and CLb of PSP, whereas 2 and 10 mgkg−1 decreased only CLr. The ED50 of probenecid for inhibiting CLr and CLb were 0.925 and 23.9mgkg−1, respectively. A low dose of probenecid selectively inhibits urinary excretion of PSP without affecting biliary excretion.

    2. 3-(3,4-Dihydroxyphenyl)adenine, a urinary DNA adduct formed in mice exposed to high concentrations of benzene (pages 516–520)

      Petr Mikeš, Václav Šístek, Jan Krouželka, Antonín Králík, Emil Frantík, Jaroslav Mráz and Igor Linhart

      Version of Record online: 15 FEB 2012 | DOI: 10.1002/jat.2716

      Low concentrations of 7-(3,4-dihydroxyphenyl)guanine and 3-(3,4-dihydroxyphenyl)adenine (DHPA), an easily depurinating DNA adduct derived from 1,2-benzoquinone, was detected in the urine of mice repeatedly exposed to benzene vapours at 1800 mg m−3, 6 h per day. It was found in eight out of total 30 urine samples at concentrations of 352 ± 146 pg ml−1. Conversion of benzene to DHPA was estimated to 2.2 × 10−6 % of the absorbed dose. Search for the other five nucleobase adducts derived from benzene was negative.

    3. Nonclinical vaccine safety evaluation: advantages of continuous temperature monitoring using abdominally implanted data loggers (pages 521–526)

      Patricia Kaaijk, Arno A. J. van der Ark, Geert van Amerongen and Germie P. J. M. van den Dobbelsteen

      Version of Record online: 8 MAR 2012 | DOI: 10.1002/jat.2720

      Fever has been reported as the most common adverse event after vaccination in infants and children. For this reason it is important that prior to clinical testing of a new vaccine, change in body temperature following vaccination is tested carefully in nonclinical animal studies. In the present study implanted temperature loggers were successfully used to define an adequate fixed time point to be applied in determining rectal body temperature in a formal GLP toxicology study with a new vaccine candidate.