Journal of Applied Toxicology

Cover image for Vol. 35 Issue 9

September 2015

Volume 35, Issue 9

Pages 971–1072

  1. Hypothesis Review

    1. Top of page
    2. Hypothesis Review
    3. Review Article
    4. Research Articles
    5. Letter to the Editor
    1. You have full text access to this OnlineOpen article
      Adverse Outcome Pathways can drive non-animal approaches for safety assessment (pages 971–975)

      Natalie Burden, Fiona Sewell, Melvin E. Andersen, Alan Boobis, J. Kevin Chipman, Mark T. D. Cronin, Thomas H. Hutchinson, Ian Kimber and Maurice Whelan

      Article first published online: 5 MAY 2015 | DOI: 10.1002/jat.3165

      This article explores how the development and application of Adverse Outcome Pathways (AOPs) could benefit the science and practice of chemical safety assessment, with a particular focus on how their use in practice could reduce reliance on traditional animal toxicity tests. This includes discussion of the key areas where current and future initiatives should be focused to enable the translation of AOPs into routine chemical safety assessment, and lasting 3Rs benefits.

  2. Review Article

    1. Top of page
    2. Hypothesis Review
    3. Review Article
    4. Research Articles
    5. Letter to the Editor
    1. Integrating mitochondriomics in children's environmental health (pages 976–991)

      Kelly J. Brunst, Andrea A. Baccarelli and Rosalind J. Wright

      Article first published online: 5 JUN 2015 | DOI: 10.1002/jat.3182

      While numerous environmental exposures have been shown to impact childhood health, many of the mechanisms involved are unclear. Mitochondria are sensitive to environmental insults and are thought to be central players. It is intuitive that mitochondria play an important role in the disease processes given that every cell of our body is dependent on energy metabolism. Many of the effects of the environment are initiated in utero and integrating mitochondriomics into children's environmental health studies is a critical priority.

  3. Research Articles

    1. Top of page
    2. Hypothesis Review
    3. Review Article
    4. Research Articles
    5. Letter to the Editor
    1. Molecular mechanisms of human thyrocyte dysfunction induced by low concentrations of polychlorinated biphenyl 118 through the Akt/FoxO3a/NIS pathway (pages 992–998)

      Hongwei Guo, Hui Yang, Huanhuan Chen, Wen Li, Jinmei Tang, Pei Cheng, Yuchun Xie, Yun Liu, Guoxian Ding, Dai Cui, Xuqin Zheng and Yu Duan

      Article first published online: 2 FEB 2015 | DOI: 10.1002/jat.3032

      Related protein and gene expression levels were observed in a low dose of 2,3′,4,4′,5-pentachlorobiphenyl (PCB118)-exposed human thyroid epithelial cells. We concluded that a low dose of PCB118 could activate the PI3k/Akt pathway, increase the phosphorylation level of FoxO3a protein, and decrease the protein and gene expression level of sodium/iodide symporter (NIS). Our results suggest that PCB118 may induce thyrocyte dysfunction through the Akt/FoxO3a/NIS signalling pathway.

    2. Effects of lithium on growth, maturation, reproduction and gene expression in the nematode Caenorhabditis elegans (pages 999–1006)

      Ayako Inokuchi, Ryoko Yamamoto, Fumiyo Morita, Shota Takumi, Hiromi Matsusaki, Hiroshi Ishibashi, Nobuaki Tominaga and Koji Arizono

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3058

      This study was conducted to clarify the biological effects of lithium compounds on Caenorhabditis elegans. Our findings suggest that LiCl and Li2CO3 potentially affect the biological and physiological function in C. elegans associated with alteration of the gene expression such as cytochrome P450, ABC transporter, glutathione S-transferase, and lipid metabolism genes. The results also provide experimental support for the utility of toxicogenomics by integrating gene expression profiling into a toxicological study of an environmentally important organism such as C. elegans.

    3. Bupropion treatment increases epididymal contractility and impairs sperm quality with no effects on the epididymal sperm transit time of male rats (pages 1007–1016)

      Marilia Martins Cavariani, Luiz Ricardo de Almeida Kiguti, Josiane de Lima Rosa, Gabriel Adan de Araújo Leite, Patrícia Villela e Silva, André Sampaio Pupo and Wilma De Grava Kempinas

      Article first published online: 2 FEB 2015 | DOI: 10.1002/jat.3089

      Bupropion is used as smoking cessation and antidepressant drug. We evaluated the effects of bupropion on reproductive aspects of male rats and on the epididymal duct in vitro contractility. Bupropion 15 mg/kg increased the epididymal duct contractility; at 30 mg/kg bupropion impaired sperm quality increasing the incidence of non-progressive sperm. Although male sexual behavior and fertility were not modified at both doses, these results suggest the importance of studies evaluating the effects of bupropion on the human male sperm quality.

    4. You have free access to this content
      Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates? (pages 1017–1029)

      Natalie Mesens, Alexander D. Crawford, Aswin Menke, Pham Duc Hung, Freddy Van Goethem, Rik Nuyts, Erik Hansen, Andre Wolterbeek, Jacky Van Gompel, Peter De Witte and Camila V. Esguerra

      Article first published online: 6 FEB 2015 | DOI: 10.1002/jat.3091

      We evaluated lfabp10a as an endpoint for assessing the hepatotoxic effects in zebrafish larvae, and expression analysis was found to be a valid marker, as statistical significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes. To assess the applicability for assessing human relevant DILI, 14 drugs were tested that have been marketed for human use, classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity and was capable of distinguishing between hepatotoxic and non-hepatotoxic chemical analogues.

    5. Enhanced QSAR models for drug-triggered inhibition of the main cardiac ion currents (pages 1030–1039)

      Barbara Wiśniowska, Aleksander Mendyk, Jakub Szlęk, Michał Kołaczkowski and Sebastian Polak

      Article first published online: 5 JAN 2015 | DOI: 10.1002/jat.3095

      The changing cardiac safety testing paradigm suggests a shift towards in silico models of cellular electrophysiology and assessment of concomitant block of multiple ion channels. In this study a set of four enhanced 2D-QSAR models, predicting ion currents (IKr, IKs, Ina and ICaL) changes were developed. The models combine in vitro study parameters and physico-chemical descriptors. Proposed models provide information which can guide decisions regarding the risk, and thus avoidance of exclusion of potentially safe and effective drugs.

    6. Endocrine-disrupting potentials of equine estrogens equilin, equilenin, and their metabolites, in the medaka Oryzias latipes: in silico and DNA microarray studies (pages 1040–1048)

      Masaya Uchida, Hiroshi Ishibashi, Ryoko Yamamoto, Akiko Koyanagi, Teruhiko Kusano, Nobuaki Tominaga, Yasuhiro Ishibashi and Koji Arizono

      Article first published online: 22 JAN 2015 | DOI: 10.1002/jat.3098

      Although several previous studies have demonstrated the presence of equine estrogens in the aquatic environment, limited data are currently available on the endocrine-disrupting potentials in fish and the risks they pose to aquatic organisms. To investigate the interactions of major equine estrogens equilin (Eq) and equilenin (Eqn), as well as their metabolites 17α-dihydroequilin, 17β-dihydroequilin, 17α-dihydroequilenin and 17β-dihydroequilenin, with the estrogen receptor α (ERα) of medaka (Oryzias latipes), a three-dimensional model of the ligand-binding domain (LBD) of ERα was built in silico, and docking simulations were performed.

    7. Quantitative toxicoproteomic analysis of zebrafish embryos exposed to a retinoid X receptor antagonist UVI3003 (pages 1049–1057)

      Liang Zheng, Jianlan Yu, Huahong Shi, Liang Xia, Qi Xin, Qiang Zhang, Heng Zhao, Ji Luo, Wenhai Jin, Daoji Li and Junliang Zhou

      Article first published online: 11 JAN 2015 | DOI: 10.1002/jat.3099

      Retinoid X receptor (RXR) antagonists, including some environmental endocrine disruptors, have a teratogenic effect on vertebrate embryos. To investigate the toxicological mechanism on the protein expression level, a quantitative proteomic study was conducted to analyze the proteome alterations of zebrafish (Danio rerio) embryos exposed to gradient concentrations of a representative RXR antagonist UVI3003. Using isobaric Tags for Relative and Absolute Quantitation (iTRAQ) labeling coupled nano high-performance liquid chromatography-tandem mass spectrometry (nano HPLC-MS/MS), in total 6592 proteins were identified, among which 195 proteins were found to be differentially expressed by more than a two-fold change in exposed groups compared with the control.

    8. Bisphenol A exposure induces metabolic disorders and enhances atherosclerosis in hyperlipidemic rabbits (pages 1058–1070)

      Chao Fang, Bo Ning, Ahmed Bilal Waqar, Manabu Niimi, Shen Li, Kaneo Satoh, Masashi Shiomi, Ting Ye, Sijun Dong and Jianglin Fan

      Article first published online: 23 JAN 2015 | DOI: 10.1002/jat.3103

      Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were used to investigate the detrimental effects of bisphenol A (BPA), which has much more common features with humans than mouse and rat especially in the metabolism and cardiovascular system. BPA exposure resulted in insulin resistance, prominent adipose accumulation, hepatic steatosis and myocardial injury. Moreover, BPA exposure also accelerated the development of atherosclerosis in the aortic arch. BPA may exert its toxic effects through eliciting endoplasmic reticulum (ER) stress and an inflammatory reaction.

  4. Letter to the Editor

    1. Top of page
    2. Hypothesis Review
    3. Review Article
    4. Research Articles
    5. Letter to the Editor
    1. Circulating mir-208a fails as a biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients (pages 1071–1072)

      Vagner Oliveira-Carvalho, Ludmila Rodrigues Pinto Ferreira and Edimar Alcides Bocchi

      Article first published online: 5 JUN 2015 | DOI: 10.1002/jat.3185