Journal of Applied Toxicology

Cover image for Vol. 33 Issue 9

September 2013

Volume 33, Issue 9

Pages 861–1035

  1. Review Article

    1. Top of page
    2. Review Article
    3. Research Articles
    1. Application of microPET imaging approaches in the study of pediatric anesthetic-induced neuronal toxicity (pages 861–868)

      Xuan Zhang, Merle G. Paule, Cheng Wang and William Slikker Jr

      Article first published online: 11 FEB 2013 | DOI: 10.1002/jat.2857

      Advances in pediatric and obstetric surgery have resulted in an increase in the complexity, duration, and number of anesthetic procedures. It has been reported that prolonged exposure of the developing brain to clinically relevant concentration of anesthetics that have NMDA antagonist or GABA-mimetic properties, and/or their combinations, resulted in an extensive abnormal pattern of neuroapoptosis, and subsequent cognitive deficits in animals. Molecular imaging using positron emission tomography (PET) is a leading modality for obtaining non- or minimally invasive in vivo measurements of multiple biological processes in various organs. The main focus of this review is to describe molecular imaging approaches that have been used in the study of pediatric anesthetic-induced neuronal toxicity.

  2. Research Articles

    1. Top of page
    2. Review Article
    3. Research Articles
    1. Comparison of the aneugenic properties of nocodazole, paclitaxel and griseofulvin in vitro. Centrosome defects and alterations in protein expression profiles (pages 869–879)

      Polyxeni Zacharaki, Georgia Stephanou and Nikos A. Demopoulos

      Article first published online: 19 MAR 2012 | DOI: 10.1002/jat.2745

      Nocodazole, paclitaxel and the antifungal griseofulvin, with a promising role in cancer treatment, affect microtubule dynamics by different ways. To compare their aneugenic properties we studied: (i) MN induction using CREST analysis, (ii) disturbance of mitotic spindle organization by immunofluorescence, and (iii) alterations in the expression of chromosome segregation regulating protein. We found that the generation of different types of abnormal metaphases dowing to centrosome deffects, as well as the alteration in the expression of proteins regulating chromosome segregation, was dependent on the drug and the cell line treated, reflecting their different effects on microtubule dynamics.

    2. In vivo antigenotoxic activity of watercress juice (Nasturtium officinale) against induced DNA damage (pages 880–885)

      Natalia A. Casanova, Julia I. Ariagno, Marcela M. López Nigro, Gabriela R. Mendeluk, María de los A. Gette, Elisa Petenatti, Luis A. Palaoro and Marta A. Carballo

      Article first published online: 4 APR 2012 | DOI: 10.1002/jat.2746

      In vivo geno- and antigenotoxicity of watercress juice were evaluated using comet assay (blood cells) and micronucleus test (bone marrow). Biopsies of bladder, epididymis and testicles of mice were performed to extend the experimental design. Watercress did not induce genetic damage per se and exhibited protective activity. Analysis of histological changes suggests a probable protective effect. Further studies are needed to establish the protective role of watercress juice against DNA damage.

    3. Extended acute toxicity study of 188Re-liposome in Rats (pages 886–893)

      Liu Chi-Mou, Tsai Chia-Che, Yu Chia-Yu, Lee Wan-Chi, Ho Chung-Li, Chang Tsui-Jung, Chang Chih-Hsien and Lee Te-Wei

      Article first published online: 26 APR 2012 | DOI: 10.1002/jat.2751

      The present study was performed to assess the toxicity of 188Reliposome in Sprague-Dawley rats. None of the rats died and no clinical sign was observed, and only male rats administered 185 MBq of 188Re-liposome displayed a weight loss. Although the WBC counts of both high-dose and medium-dose groups reduced 7-days postinjection, they recovered to a normal range before termination. There was no difference in urinary analyzes, biochemical parameters and histopathological assessments between the 188Re-liposome-treated and control groups.

    4. Usefulness of administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using paraoxon (pages 894–900)

      Georg A. Petroianu, Syed M. Nurulain, Mohamed Shafiullah, Mohamed Y. Hasan, Kamil Kuča and Dietrich E. Lorke

      Article first published online: 19 MAY 2012 | DOI: 10.1002/jat.2760

      The reversible AChE-inhibitors pyridostigmine, metoclopramide, tiapride, ranitidine, physostigmine, tacrine, amiloride, methylene blue, 7-methoxytacrine and K-27 were tested as prophylactic agents before exposure to the irreversible AChE-inhibitor paraoxon. Their efficacy in reducing organophosphorus compound-induced mortality was assessed by Cox survival analysis. Best in vivo protection from paraoxon-induced mortality was achieved by physostigmine or the oxime K-27, the most efficacious pretreatment agent not passing the blood brain barrier.

    5. Comet-FISH studies for evaluation of genetic damage of citalopram in somatic cells of the mouse (pages 901–905)

      Sabry M. Attia, Abdelkader E. Ashour and Saleh A. Bakheet

      Article first published online: 12 FEB 2013 | DOI: 10.1002/jat.2859

      This study was designed to evaluate the genotoxicity of citalopram at the recommended human doses in somatic cells of mice. Mice exposed to citalopram at varying oral doses of 12 or 24 mg/kg for 7 days, exhibited significant increase in the level of DNA-strand breaking and micronuclei formation. Furthermore, by FISH analysis with the centromeric DNA-probe for erythrocyte micronuclei it could be shown that citalopram is aneugen as well as clastogen in somatic cells in vivo.

    6. Potentially estrogenic polychlorinated biphenyls congeners serum levels and its relation with lung cancer (pages 906–914)

      Rogelio Recio-Vega, Alejandra Mendez-Henandez, Antonio Padua y Gabriel, Antonio Jacobo-Avila, Arnulfo Portales-Castanedo, Sandra Hernandez-Gonzalez, Martha Patricia Gallegos-Arreola and Guadalupe Ocampo-Gomez

      Article first published online: 22 JUN 2012 | DOI: 10.1002/jat.2763

      Occupational and accidental exposure to polychlorinated biphenyls (PCBs) has been associated with an increased risk for lung cancer. Our results shown that, the serum levels of three PCB congeners with potential estrogenic activity were higher in lung cancer patients, which could have dual biological effects on lung tissue, not only inducing cell proliferation in non-neoplastic and neoplastic lung cells via estrogen receptor beta, but also increasing endogenous catechol levels.

    7. Influence of the antifolate drug Methotrexate on the development of murine neural tube defects and genomic instability (pages 915–923)

      Jie Zhao, Tao Guan, Jianhua Wang, Qian Xiang, Mingsheng Wang, Xiuwei Wang, Zhen Guan, Qiu Xie, Bo Niu and Ting Zhang

      Article first published online: 13 JUL 2012 | DOI: 10.1002/jat.2769

      Impaired folate metabolism is considered a risk factor for neural tube defects (NTDs), but the relationship between folate dysmetabolism and NTDs remains unclear. The objective of this study was to develop a NTD model, and study the mechanism of NTDs. Methotrexate (MTX), a folate antagonist, induced NTDs in mice, and dihydrofolate reductase (DHFR) activity and folates derivatives concentrations of embryonic tissues decreased significantly. Furthermore, three high-confidence copy number variants (CNVs) were found on chromosome X, which in neural tube tissues may contribute to the development of NTDs.

    8. Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice (pages 924–932)

      Nantiga Virgona, Yuko Taki, Shizuo Yamada and Keizo Umegaki

      Article first published online: 22 JUN 2012 | DOI: 10.1002/jat.2770

      The hepatotoxicity effect of Coleus forskohlii root extract (CFE) standardized to 10% forskolin was tested in male ICR mice. Body and organ weights, food intake, plasma marker enzymes for liver damage and liver tissues histology were recorded. Both dietary CFE dose and time dependently affect the observed parameters whereas forskolin, the principle constituent in CFE, is not responsible for such effects.

    9. Genotoxicity evaluation for single-walled carbon nanotubes in a battery of in vitro and in vivo assays (pages 933–939)

      Makoto Ema, Tadashi Imamura, Hiroshi Suzuki, Norihiro Kobayashi, Masato Naya and Junko Nakanishi

      Article first published online: 5 JUL 2012 | DOI: 10.1002/jat.2772

      Single-walled carbon nanotubes (SWCNTs) had no mutagenicity in S. typhimurium TA98, TA100, TA1535, or TA1537, or in E. coli WP2uvrA, in the absence or presence of metabolic activation. SWCNTs did not increase the number of structural or numerical chromosomal aberrations after short-term or continuous exposure. In the micronucleus test using CD-1 mice, SWCNTs did not affect the proportion of immature erythrocytes, the total proportion of erythrocytes, or the number of micronuclei in immature erythrocytes.

    10. Acute toxicity and tissue distribution of CdSe/CdS-MPA quantum dots after repeated intraperitoneal injection to mice (pages 940–950)

      Md. Mamunul Haque, Hye-Yeon Im, Ji-Eun Seo, Mahbub Hasan, Kyoungja Woo and Oh-Seung Kwon

      Article first published online: 25 JUN 2012 | DOI: 10.1002/jat.2775

      BALB/c mice were injected every 3 days with various doses of CdSe/CdS-MPA QDs. Body weight of the mice treated with 25 mg/kg QDs was significantly decreased from day 7. The QDs were observed in the liver, spleen, lung, and kidneys, but not in brain, or heart. Significantly higher levels of LDH and NADPH oxidase were found in plasma, liver, and spleen. Histopathological examination did not show any tissue toxicity but IL-6 levels were increased in the plasma, liver, and spleen.

    11. Long-term arsenic exposure induces histone H3 Lys9 dimethylation without altering DNA methylation in the promoter region of p16INK4a and down-regulates its expression in the liver of mice (pages 951–958)

      Takehiro Suzuki and Keiko Nohara

      Article first published online: 25 JUN 2012 | DOI: 10.1002/jat.2765

      To understand the relationship between arsenic exposure and epigenetic modifications, in the present study we investigated the effects of long-term exposure to arsenic by focusing on the tumor-related gene expression and gene-specific epigenetic modulations in C57Bl/6 mice. The results of this study indicate that long-term arsenic exposure down-regulates p16INK4a without altering DNA methylation in the normal liver, and suggest that its down-regulation is as a result of histone H3K9me2 by G9a recruitment.

    12. The effect of methylmercury exposure on behavior and cerebellar granule cell physiology in aged mice (pages 959–969)

      Sairam Bellum, Kerry A. Thuett, Bhupinder Bawa and Louise C. Abbott

      Article first published online: 10 AUG 2012 | DOI: 10.1002/jat.2786

      16-20 month old C57BL/6 mice were exposed orally to 5.0 mg methylmercury per kg body weight. Methylmercury-treated aged mice performed significantly worse in open field, foot print analysis and a vertical pole test. Isolated cerebellar granule cells from methylmercury-treated aged mice exhibited higher reactive oxygen species levels and reduced mitochondrial membrane potentials. Aged mice exposed to methylmercury exhibited no greater impairment compared to young adult mice exposed to the same dose, as reported in earlier studies from this lab.

    13. Coffee attenuates fibrosis by decreasing the expression of TGF-β and CTGF in a murine model of liver damage (pages 970–979)

      Jonathan Arauz, Marina Galicia- Moreno, Pedro Cortés-Reynosa, Eduardo Pérez Salazar and Pablo Muriel

      Article first published online: 17 AUG 2012 | DOI: 10.1002/jat.2788

      Cirrhosis was induced by chronic TAA administration and the effects of co-administration of conventional coffee or decaffeinated coffee respectively for 8 weeks were evaluated. TAA administration elevated serum alkaline phosphatase, γ-glutamyl transpeptidase and alanine aminotransferase, liver lipid peroxidation and collagen content. Additionally increased levels of a number of proteins were detected including transforming growth factor-β, connective tissue growth factor and alpha-smooth muscle actin, and matrix metalloproteinase-2, 9 and 13. Coffee suppressed most of the changes produced by TAA.

    14. Acute effects of a low-dose atropine/scopolamine mixture as a food contaminant in human volunteers (pages 980–990)

      Lucija Perharič, Katja Ažman Juvan and Lovro Stanovnik

      Article first published online: 9 AUG 2012 | DOI: 10.1002/jat.2797

      A randomized, double-blind, placebo-controlled, crossover study in 20 healthy, human volunteers, aged 19–28 years, was carried out to refine the Acute Reference Doses (ARfD) of an atropine/scopolamine mixture. Bradycardia was identified as a critical effect. We estimate that the No Observed Adverse Effect Levels (NOAELs) for the atropine/scopolamine mixture are between the dose levels 0.12/0.10 and 0.37/0.29 µg kg–1 body mass (BM). By applying the uncertainty factor of 10, we propose a new provisional ARfD of the mixture, i.e. 0.01 µg kg–1 BM for each alkaloid.

    15. Establishment of transactivation assay systems using fish, amphibian, reptilian and human thyroid hormone receptors (pages 991–1000)

      Tomohiro Oka, Naoko Mitsui-Watanabe, Norihisa Tatarazako, Yuta Onishi, Yoshinao Katsu, Shinichi Miyagawa, Yukiko Ogino, Ryohei Yatsu, Satomi Kohno, Minoru Takase, Yukio Kawashima, Yasuhiko Ohta, Yasunobu Aoki, Louis J. Guillette Jr and Taisen Iguchi

      Article first published online: 30 OCT 2012 | DOI: 10.1002/jat.2825

      Thyroid hormones are essential for the regulation of a wide range of biological processes associated with normal development and metabolism in vertebrates. For the screening of chemicals having potential thyroid hormone and anti-thyroid hormone activities, we have established transient transactivation assay systems. We demonstrate that this in vitro transactivation system can be used for screening chemicals with potential thyroid hormone agonistic and antagonistic activities.

    16. Developmental disorders and altered gene expression in the tropical clawed frog (Silurana tropicalis) exposed to 17α-ethinylestradiol (pages 1001–1010)

      Ikumi Hirakawa, Shinichi Miyagawa, Naoko Mitsui, Maki Miyahara, Yuta Onishi, Yoshihiro Kagami, Teruhiko Kusano, Takashi Takeuchi, Yasuhiko Ohta and Taisen Iguchi

      Article first published online: 6 NOV 2012 | DOI: 10.1002/jat.2836

      The occurrence of oocytes in the testis (testis-ova) is one reproductive disorder and can be used as a valid endpoint when studying disruptive effects of estrogenic chemicals in fish and amphibians. Gonads of the genetically male tropical clawed frog (Silurana tropicalis) exposed developmentally to 17α-ethinylestradiol were analyzed using histopathology, microarray and quantitative PCR. Expression of zpc and 42Sp50 genes was demonstrated to be associated with testis-ova in the S. tropicalis.

    17. The role of the α7 subunit of the nicotinic acetylcholine receptor in the acute toxicosis of methyllycaconitine in mice (pages 1011–1016)

      K. D. Welch, B. T. Green, K. E. Panter, J. A. Pfister and D. R. Gardner

      Article first published online: 8 JAN 2013 | DOI: 10.1002/jat.2851

      The adverse effects of methyllycaconitine (MLA) have been attributed to its competitive antagonism of nicotinic acetylcholine receptors (nAChRs). The objective of this study was to characterize the role of the α7 subunit of nAChRs in the acute toxicosis of MLA by comparing the lethal dose (LD50) of MLA in wild-type mice to mice lacking the α7 subunit. The results from this study suggest that the α7 nAChR does not play an integral role in the acute toxicosis of MLA.

    18. The role of the α7 subunit of the nicotinic acetylcholine receptor on motor coordination in mice treated with methyllycaconitine and anabasine (pages 1017–1026)

      K. D. Welch, J. A. Pfister, D. R. Gardner, B. T. Green and K. E. Panter

      Article first published online: 24 MAY 2013 | DOI: 10.1002/jat.2894

      The objective of this study was to determine if α7 nAChR subunits play a role in the motor coordination deficiencies elicited by nAChR agonists and antagonists by comparing the motor function and coordination of wild-type mice to mice lacking the α7 nAChR subunit after exposure to a non-lethal dose of methyllycaconitine (MLA) or anabasine. The results from this study suggest that the α7 nAChR does not play an integral role in the motor coordination of mice.

    19. Dose-dependent alterations in gene expression and testosterone production in fetal rat testis after exposure to di-n-hexyl phthalate (pages 1027–1035)

      Anne-Marie Saillenfait, Jean-Philippe Sabaté, Alain Robert, Virginie Rouiller-Fabre, Alain-Claude Roudot, Delphine Moison and Flavien Denis

      Article first published online: 11 JUN 2013 | DOI: 10.1002/jat.2896

      Pregnant Sprague–Dawley rats were administered di-n-hexyl phthalate (DnHP) at a broad range of doses (5 to 625 mg kg–1 per day) or DEHP (50 or 625 mg kg–1 per day), by gavage, from gestation day (GD) 12 to 19. A decrease in ex vivo testosterone production by GD 19 fetal testis was observed at doses of 20 mg kg–1 per day and higher. Accordingly, DnHP reduced the expression of several genes involved in steroid synthesis pathway (SRB1, StAR, P450scc, 3βHSD and P450c17) in a dose-dependent manner.

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