Journal of Applied Toxicology

Cover image for Vol. 34 Issue 8

August 2014

Volume 34, Issue 8

Pages 810–923

  1. Review Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. Nitroaromatic compounds: Environmental toxicity, carcinogenicity, mutagenicity, therapy and mechanism (pages 810–824)

      Peter Kovacic and Ratnasamy Somanathan

      Article first published online: 16 FEB 2014 | DOI: 10.1002/jat.2980

      Vehicle pollution is an increasing problem in the industrial world. Aromatic nitro compounds comprise a significant portion of the threat. In this review, the class includes nitro derivatives of benzene, biphenyls, naphthalenes, benzanthrone and polycyclic aromatic hydrocarbons, plus nitroheteroaromatic compounds. The numerous toxic manifestations are discussed. An appreciable number of drugs incorporate the nitroaromatic structure. The mechanistic aspects of both toxicity and therapy are addressed in the context of a unifying mechanism involving electron transfer, reactive oxygen species, oxidative stress and antioxidants.

    2. Toxicity of imine–iminium dyes and pigments: electron transfer, radicals, oxidative stress and other physiological effects (pages 825–834)

      Peter Kovacic and Ratnasamy Somanathan

      Article first published online: 22 MAY 2014 | DOI: 10.1002/jat.3005

      Although conjugation is well known as an important contributor to color, there is scant recognition concerning involvement of imine and iminium functions in the physiological effects of this class of dyes and pigments. The group includes the dyes methylene blue, rhodamine, malachite green, fuchsin, crystal violet, auramine and cyanins, in addition to the pigments consisting of pyocyanine, phthalocyanine and pheophytin. The physiological effects consist of both toxicity and beneficial aspects. The unifying theme of electron transfer-reactive oxygen species-oxidative stress is used as the rationale in both cases.

  2. Research Articles

    1. Top of page
    2. Review Articles
    3. Research Articles
    1. Inhibition of cytochrome P450s enhances (+)-usnic acid cytotoxicity in primary cultured rat hepatocytes (pages 835–840)

      Qiang Shi, James Greenhaw and William F. Salminen

      Article first published online: 20 MAY 2013 | DOI: 10.1002/jat.2892

      (+)-Usnic acid (UA) may cause hepatotoxicity. We examined if its metabolism plays a role in toxicity in primary rat hepatocytes. When cytochrome P450 (CYP) activity was suppressed by pan-CYP inhibitor SKF-525A, or CYP1A inhibitor alpha-naphthoflavone, or CYP3A inhibitor ketoconazole, UA induced inhibition of cellular respiration, adenosine triphosphate depletion and cytotoxicity was significantly increased. The CYP2B/2C inhibitor ticlopidine showed no effects. We suggest UA is bio-transformed to less toxic metabolites in rat hepatocytes, mainly by CYP1A and 3A, but not 2B/2C.

    2. N-hexane inhalation during pregnancy alters DNA promoter methylation in the ovarian granulosa cells of rat offspring (pages 841–856)

      Hong Li, Jin Liu, Yan Sun, Wenxiang Wang, Shaozheng Weng, Shihua Xiao, Huiling Huang and Wenchang Zhang

      Article first published online: 6 JUN 2013 | DOI: 10.1002/jat.2893

      This paper carried out the MeDIP-Chip method to investigate the global genomic promoter methylation status of F1 Wistar rats' Ovarian granulosa cells after maternal n-hexane exposure. The Gene Ontology Consortium, the DAVID Functional Annotation Clustering Tool, hierarchical clustering, and KEGG pathway were used to delineate the altered methylation of promoters of gene and find out the gene-enriched clusters.

    3. Dermal irritation of petrolatum in rabbits but not in mice, rats or minipigs (pages 857–861)

      S. A. Chandra, R. A. Peterson, D. Melich, C. M. Merrill, D. Bailey, K. Mellon-Kusibab and R. Adler

      Article first published online: 30 MAY 2013 | DOI: 10.1002/jat.2895

      New Zealand white rabbits treated with white petrolatum for 2 weeks had mild acanthosis, hyperkeratosis, dermal edema with mixed inflammatory cells consistent with dermal irritation. Wistar-Han rats, CD1 mice, C57/BL/6J mice, and Gottingen minipigs did not exhibit clinical or histologic evidence of dermal irritation to petrolatum.

    4. Role of methotrexate exposure in apoptosis and proliferation during early neurulation (pages 862–869)

      Xiuwei Wang, Jianhua Wang, Tao Guan, Qian Xiang, Mingsheng Wang, Zhen Guan, Guannan Li, Zhiqiang Zhu, Qiu Xie, Ting Zhang and Bo Niu

      Article first published online: 9 JUL 2013 | DOI: 10.1002/jat.2901

      In this study, we established an animal model of neural tube defects (NTDs) by use of MTX to investigate the role of apoptosis and proliferation in NTDs. We concluded that MTX caused a folate and folate-associated dysmetabolism, and further induced abnormal apoptosis and proliferation, which may play a critical role in the occurrence of NTDs caused by folate deficiency.

    5. Cytotoxic effects of the quinolone levofloxacin on rabbit meniscus cells (pages 870–877)

      Linlong Wang, Yunpeng Wu, Yang Tan, Xi Fei, Yu Deng, Hong Cao, Biao Chen, Hui Wang, Jacques Magdalou and Liaobin Chen

      Article first published online: 1 JUL 2013 | DOI: 10.1002/jat.2903

      Rabbit meniscus cells were administrated with different concentrations of levofloxacin. After treatment with levofloxacin for 48 h, cells viability was decreased and apoptotic cells increased. Meanwhile, active caspase-3 protein expression level was also increased and mRNA expression level of Bcl-2 decreased. Both mRNA and protein expression levels of MMP-3 and MMP-13 increased. Besides, the mRNA expression levels of TIMP-3 and col1a1 were decreased, while that of iNOS increased. Thus, levofloxacin induced apoptosis and unbalanced MMPs/TIMPs expression in meniscus cells.

    6. DNA fragmentation induced by all-trans retinoic acid and its steroidal analogue EA-4 in C2C12 mouse and HL-60 human leukemic cells in vitro (pages 885–892)

      Raghda S. Alakhras, Georgia Stephanou, Nikos A. Demopoulos, Konstantinos Grintzalis, Christos D. Georgiou and Sotirios S. Nikolaropoulos

      Article first published online: 2 AUG 2013 | DOI: 10.1002/jat.2908

      We (a) investigated the ability of all-trans retinoic acid and its steroidal analogue EA-4 to induce DNA fragmentation by using single cell gel electrophoresis, and (b) quantified the ability of the retinoids under study to induce necrotic/apoptotic small size (0–1 kb) fragmented DNA. We found that they (a) provoke DNA migration due to DNA fragmentation, and (b) induce significantly small fragments of genomic DNA in C2C12 mouse and HL-60 human leukemic cells, as indicated by the quantification of necrotic/apoptotic small DNA fragments.

    7. The alkylphenols 4-nonylphenol, 4-tert-octylphenol and 4-tert-butylphenol aggravate atopic dermatitis-like skin lesions in NC/Nga mice (pages 893–902)

      Kaori Sadakane, Takamichi Ichinose, Hirohisa Takano, Rie Yanagisawa, Eiko Koike and Ken-ichiro Inoue

      Article first published online: 23 AUG 2013 | DOI: 10.1002/jat.2911

      Alkylphenols (4-nonylphenol, 4-tert-octylphenol, and 4-tert-butylphenol) exacerbated mite allergen-induced atopic dermatitis in a mouse model. Alkylphenols tended to increase immunoglobulin levels in serum and increased the expression of inflammatory cytokines in lesions. In contrast, the levels of T-helper 1 cytokines decreased. The uptake of very low levels of alkylphenols may contribute to the current increase in atopic dermatitis.

    8. In vitro protection by pyruvate against cadmium-induced cytotoxicity in hippocampal HT-22 cells (pages 903–913)

      Ethan Poteet, Ali Winters, Luokun Xie, Myoung-Gwi Ryou, Ran Liu and Shao-Hua Yang

      Article first published online: 30 AUG 2013 | DOI: 10.1002/jat.2913

      Cadmium is a toxic metal that inhibits glycolysis indirectly through its actions on the mitochondria. Pyruvate restores glycolysis and mitigates the inhibitory action of cadmium in mitochondria and glycolysis. Our study provided the first in vitro evidence that pyruvate protects against the cytotoxic action of cadmium and that pyruvate might be a potential therapy for cadmium poisoning.

    9. Increased methylmercury toxicity related to obesity in diabetic KK-Ay mice (pages 914–923)

      Megumi Yamamoto, Rie Yanagisawa, Eriko Motomura, Masaaki Nakamura, Mineshi Sakamoto, Motohiro Takeya and Komyo Eto

      Article first published online: 15 NOV 2013 | DOI: 10.1002/jat.2954

      Greater methylmercury (MeHg) toxicity was observed in KK-Ay type 2 diabetic mice compared with that of C57BL/6J mice at the same dose of MeHg per body weight. MeHg-treated KK-Ay mice showed hind-limb clasping in the final stage of the experiment. Body fat gain and low mercury accumulation in adipose tissue increased MeHg concentrations in organs and enhanced MeHg toxicity. Tissue injuries in MeHg-exposed KK-Ay mice were detected by CD204 expression.

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