Journal of Applied Toxicology

Cover image for Vol. 35 Issue 4

Early View (Online Version of Record published before inclusion in an issue)

Editor-in-Chief: Philip W. Harvey

Impact Factor: 3.174

ISI Journal Citation Reports © Ranking: 2013: 24/87 (Toxicology)

Online ISSN: 1099-1263


  1. 1 - 70
  1. Research Articles

    1. Non-clinical safety and biodistribution of AS03-adjuvanted inactivated pandemic influenza vaccines

      Lawrence Segal, Sandrine Wouters, Danielle Morelle, Gaëlle Gautier, Julien Le Gal, Thomas Martin, Frieke Kuper, Eric Destexhe, Arnaud M. Didierlaurent and Nathalie Garçon

      Article first published online: 27 FEB 2015 | DOI: 10.1002/jat.3130

      To support the clinical development of candidate AS03-adjuvanted pandemic-influenza vaccines, local and systemic toxicity of 3–4 intramuscular (i.m.) injections of AS03, or AS03-adjuvanted or unadjuvanted split-A(H5N1) vaccines was evaluated in rabbits. The biodistribution of split-A(H5N1) vaccines and the constituents of AS03 was explored in mice. All test articles were well tolerated. Treatment-related effects were primarily associated with AS03 and were indicative of a transient mild local inflammation. The biodistribution kinetics of AS03 constituents were consistent with AS03 inducing this inflammation.

    2. Toxicity induced by Basic Violet 14, Direct Red 28 and Acid Red 26 in zebrafish larvae

      Bing Shen, Hong-Cui Liu, Wen-Bin Ou, Grant Eilers, Sheng-Mei Zhou, Fan-Guo Meng, Chun-Qi Li and Yong-Quan Li

      Article first published online: 27 FEB 2015 | DOI: 10.1002/jat.3134

      Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes despite insufficient toxicity data. In this paper, the toxicity of these dyes was assessed in a zebrafish model and the underlying toxic mechanisms were investigated. Treatment with these dyes resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Basic Violet 14 caused hepatotoxicity and Acid Red 26 caused cardiovascular toxicity.

    3. Distribution and biomarkers of carbon-14-labeled fullerene C60 ([14C(U)]C60) in female rats and mice for up to 30 days after intravenous exposure

      Susan C. J. Sumner, Rodney W. Snyder, Christopher Wingard, Ninell P. Mortensen, Nathan A. Holland, Jonathan H. Shannahan, Suraj Dhungana, Wimal Pathmasiri, Li Han, Anita H. Lewin and Timothy R. Fennell

      Article first published online: 27 FEB 2015 | DOI: 10.1002/jat.3110

      A comprehensive investigation of the distribution of polyvinylpyrrolidone-formulated [14C(U)]C60 (suspended in saline to form a 5% polyvinylpyrrolidone–saline suspension) in female rats and mice administered a single or five consecutive daily tail vein injections. Biomarkers of inflammation, cardiovascular injury and oxidative stress were measured to study the biological impact of [14C(U)]C60 exposure. The goals of the investigation were to provide a basic understanding of the distribution, migration, elimination and biological impacts of [14C(U)]C60 in rats and mice.

    4. The effect of Fe2O3 and ZnO nanoparticles on cytotoxicity and glucose metabolism in lung epithelial cells

      Xiaofeng Lai, Yifang Wei, Hu Zhao, Suning Chen, Xin Bu, Fan Lu, Dingding Qu, Libo Yao, Jianyong Zheng and Jian Zhang

      Article first published online: 27 FEB 2015 | DOI: 10.1002/jat.3128

      Cytotoxicity and metabolic reprogramming caused by nanoparticles.

  2. Review Articles

    1. Sertoli cell as a model in male reproductive toxicology: Advantages and disadvantages

      Mariana M. S. Reis, Ana C. Moreira, Mário Sousa, Premendu P. Mathur, Pedro F. Oliveira and Marco G. Alves

      Article first published online: 18 FEB 2015 | DOI: 10.1002/jat.3122

      Several chemicals and mixtures impair male fertility. It is essential to use reliable in vitro models to determine cellular targets and intracellular pathways that mediate chemical toxicity in the males. Sertoli cell (SC), within the testis, is a major target for hormonal signaling. Here, we intend to clarify the unique features that render SCs as excellent candidates for a robust in vitro model to study the deleterious effects of chemicals on male reproductive health.

  3. Research Articles

    1. The effect of a methyl-deficient diet on the global DNA methylation and the DNA methylation regulatory pathways

      Shota Takumi, Kazuyuki Okamura, Hiroyuki Yanagisawa, Tomoharu Sano, Yayoi Kobayashi and Keiko Nohara

      Article first published online: 17 FEB 2015 | DOI: 10.1002/jat.3117

      Methyl-deficient diets are considered to induce DNA methylation changes. However, the contribution of the active DNA demethylation pathways has not been investigated. Here, we investigated the involvement of the active DNA demethylation pathways in the DNA methylation changes by a methyl-deficient diet. Our results suggest that the DNA methylation status is strictly controlled by the balance between the DNA methylation and the active DNA demethylation pathways, despite the upregulation of the active DNA demethylation pathway by a methyl-deficient diet.

    2. Heterozygous p53 knockout mouse model for dehydropyrrolizidine alkaloid-induced carcinogenesis

      Ammon W. Brown, Bryan L. Stegelmeier, Steven M. Colegate, Kip E. Panter, Edward L. Knoppel and Jeffery O. Hall

      Article first published online: 17 FEB 2015 | DOI: 10.1002/jat.3120

      Dehydropyrrolizidine alkaloids (DHPAs) are a large, structurally diverse, potentially carcinogenic group of plant-derived protoxins that are common food contaminates. We utilized a heterozygous p53 knockout mouse model to compare the carcinogenic potential of various DHPAs. Exposure to riddelliine, a model DHPA, increased the odds of tumor development (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). Our research demonstrates the utility of this model for investigation of comparative carcinogenesis of different DHPAs and their N-oxides.

    3. Involvement of mitogen-activated protein kinase and NF-κB signaling pathways in perfluorooctane sulfonic acid-induced inflammatory reaction in BV2 microglial cells

      Jingying Zhu, Wenyi Qian, Yixin Wang, Rong Gao, Jun Wang and Hang Xiao

      Article first published online: 12 FEB 2015 | DOI: 10.1002/jat.3119

      Perfluorooctane sulfonic acid (PFOS) has been used in extensive commercial and industrial applications and is believed to be an emerging persistent organic pollutant. In this paper, we demonstrated that PFOS possesses immunomodulatory potential and exerts its action on inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, in microglial cells. The inflammatory reaction mediated by PFOS was partially via mitogen-activated protein kinases (MAPK) and NF-κB signals. Thus, these findings offer a potential mechanism for the study of proinflammatory activity of PFOS in the central nervous system.

    4. Two-generation reproduction and teratology studies of feeding aditoprim in Wistar rats

      Xu Wang, Ziqiang Tan, Guyue Cheng, Ihsan Awais, Lingli Huang, Dongmei Chen, Yuanhu Pan, Zhenli Liu and Zonghui Yuan

      Article first published online: 7 FEB 2015 | DOI: 10.1002/jat.3121

      The reproduction/development toxicity of aditoprim was evaluated by feeding diets containing 0~1000 mg kg-1, respectively. At 1000 mg kg-1 group, body weights in F0 and F1 rats, fetal body weight and number of viable fetuses in F0 and F1 generation significantly decreased. Teratogenicity study showed that body weights, fetal body lengths, tail lengths, litter weights and number of viable fetuses significantly decreased at 1000 mg kg-1 group. The NOAEL for reproduction/development toxicity of aditoprim was 100 mg kg-1 diet.

    5. Human bone morphogenetic protein-7 does not counteract aristolochic acid-induced renal toxicity

      Marie-Hélène Antoine, Frédéric Debelle, Julie Piccirilli, Fadoua El Kaddouri, Anne-Emilie Declèves, Eric De Prez, Cécile Husson, Frédérique Mies, Marie-Françoise Bourgeade and Joëlle L. Nortier

      Article first published online: 7 FEB 2015 | DOI: 10.1002/jat.3116

      Aristolochic acids (AA) are nephrotoxic and profibrotic agents, leading to chronic kidney disease. As some controversial studies have reported a nephroprotective effect of exogenous recombinant human bone morphogenetic protein (rhBMP)-7 in several models of renal fibrosis, we investigated the putative effect of rhBMP-7 to prevent progressive tubulointerstitial damage after AA intoxication in vitro and in vivo.

    6. Bisphenol A promotes X-linked inhibitor of apoptosis protein-dependent angiogenesis via G protein-coupled estrogen receptor pathway

      Jian Liu, Xin Jin, Nana Zhao, Xiaolei Ye and Chenjiang Ying

      Article first published online: 7 FEB 2015 | DOI: 10.1002/jat.3112

      Our study investigates the mechanisms underlying the pro-angiogenic effects of bisphenol A (BPA). We demonstrated that BPA markedly induces endothelial cell proliferation, migration and tube formation by activating endothelial nitric oxide synthase. BPA-induced nitric oxide generation appeared to be associated with X-linked inhibitor of apoptosis protein, which competes with endothelial nitric oxide synthase for caveolin-1. BPA was shown to exert its pro-angiogenic effect by upregulating X-linked inhibitor of apoptosis protein expression via G protein-coupled estrogen receptor activation but not via estrogen receptor ERα or ERβ.

  4. Review Articles

    1. Safety of Chinese herbal medicines during pregnancy

      Bo Liang, Lu Li, Ling Yin Tang, Qi Wu, Xiao Ke Wu and Chi Chiu Wang

      Article first published online: 7 FEB 2015 | DOI: 10.1002/jat.3108

      Chinese herbal medicines (CHMs) have been used to prevent miscarriage and treat infertility, but their potential toxicity have not been well studied and documented. In this review, clinical trials and animal studies of CHMs for miscarriage and infertility were reviewed to evaluate the safety of CHMs during pregnancy.

  5. Research Articles

    1. Safety assessment of aditoprim acute, subchronic toxicity and mutagenicity studies

      Xu Wang, Ziqiang Tan, Yuanhu Pan, Awais Ihsan, Qianying Liu, Lingli Huang, Guyue Cheng, Dongmei Chen, Yanfei Tao, Zhenli Liu and Zonghui Yuan

      Article first published online: 7 FEB 2015 | DOI: 10.1002/jat.3107

      Aditoprim (ADP) is a new developed dihydrofolate reductase inhibitor. The LD50 was 1400 mg kg-1 body weight (BW) day-1 in rats and 1130 mg kg-1 BW day-1 in mice. In the subchronic study, the main target organ for toxicity of ADP was the liver, and lymphocytic infiltration and hepatocytic necrosis were noted at 1000 mg kg-1 ADP diet group. The genotoxicity of ADP is negative. The NOAEL level for ADP was about 1.44-1.53 mg kg-1 BW day-1 in rats.

    2. Comparative cytotoxicity of dolomite nanoparticles in human larynx HEp2 and liver HepG2 cells

      Maqusood Ahamed, Hisham A. Alhadlaq, Javed Ahmad, Maqsood A. Siddiqui, Shams T. Khan, Javed Musarrat and Abdulaziz A. Al-Khedhairy

      Article first published online: 6 FEB 2015 | DOI: 10.1002/jat.3097

      Dolomite NPs induced cytotoxicity and oxidative stress in HEp2 and HepG2 cells. Cytotoxicity induced by dolomite NPs was efficiently prevented by NAC (ROS scavenger), which suggests that oxidative stress is the primarily cause for cytotoxic response of dolomite NPs.

    3. Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

      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.

    4. Bupropion treatment increases epididymal contractility and impairs sperm quality with no effects on the epididymal sperm transit time of male rats

      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.

    5. Molecular mechanisms of human thyrocyte dysfunction induced by low concentrations of polychlorinated biphenyl 118 through the Akt/FoxO3a/NIS pathway

      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.

    6. Different cytotoxicity responses to antimicrobial nanosilver coatings when comparing extract-based and direct-contact assays

      Eric M. Sussman, Brendan J. Casey, Debargh Dutta and Benita J. Dair

      Article first published online: 2 FEB 2015 | DOI: 10.1002/jat.3104

      Nanosilver (nAg) coatings are used as antimicrobial coatings on medical devices, but in spite of their intended benefit, there is concern over their potential toxicity. This study compares the response of cells to nAg in two formats of the cytotoxicity assay, an important component of biocompatibility evaluation. The results demonstrate cytotoxic responses to nAg coatings in the direct-contact but not the extract assay (100% reduction, P < 0.001), suggesting that nAg coatings in direct contact with cells and tissues could cause a cytotoxic response.

    7. Effects of cylindrospermopsin on the phagocytic cells of the common carp (Cyprinus carpio L.)

      Anna Sieroslawska, Anna Rymuszka and Łukasz Adaszek

      Article first published online: 29 JAN 2015 | DOI: 10.1002/jat.3118

      Cylindrospermopsin is a cyanotoxin with cytotoxic activity. In this study, we assessed the potential impact of cylindrospermopsin on the basic functions of phagocytic cells from common carp (Cyprinus carpio L.), including phagocytosis, reactive oxygen and nitrogen species production, and the structure of microfilaments and selected cytokine expression. The results indicated that the cyanotoxin cylindrospermopsin is able to modify basic features of carp phagocytic cells, which might result in adverse consequences for fish health.

    8. The relationship between Cd-induced autophagy and lysosomal activation in WRL-68 cells

      Su-Fang Meng, Wei-Ping Mao, Fang Wang, Xiao-Qian Liu and Luan-Luan Shao

      Article first published online: 29 JAN 2015 | DOI: 10.1002/jat.3114

      The present study shows the relationship between Cd-induced autophagy and lysosomal activation in WRL-68 cells. We found that the activation of lysosomal function was dependent on autophagosome and autophagosome–lysosome fusion. Autophagosome–lysosome fusion was inhibited by a rise of pH of acidic compartments. We also found that the intracellular Ca2+ did not markedly affect lysosomal pH, but lysosomal pH had a profound effect on the intracellular Ca2+. We infer that the intracellular Ca2+ channels or pumps are possibly pH-dependent in WRL-68 cells.

    9. Bisphenol A exposure induces metabolic disorders and enhances atherosclerosis in hyperlipidemic rabbits

      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.

    10. Effects of homocysteine on mesenchymal cell proliferation and differentiation during chondrogenesis on limb development

      Gilian Fernando Bourckhardt, Manuela Sozo Cecchini, Dib Ammar, Karoline Kobus-Bianchini, Yara Maria Rauh Müller and Evelise Maria Nazari

      Article first published online: 23 JAN 2015 | DOI: 10.1002/jat.3111

      We investigated whether homocysteine (Hcy) can affect cell cycle proteins and mesenchymal differentiation during limb development. An increase of p53, which can be activated by DNA damage and a decrease of PCNA and p21 in Hcy-treated embryos were observed. Additionally, Hcy induced an increase of Pax9 and Sox9 proteins. We have described impairments induced by Hcy, which does not change the morphology of the cartilage mold. These findings provide new insights to understand the cellular basis of Hcy toxicity.

    11. Quantitative evaluation of the pulmonary microdistribution of TiO2 nanoparticles using X-ray fluorescence microscopy after intratracheal administration with a microsprayer in rats

      Guihua Zhang, Naohide Shinohara, Hirokazu Kano, Hideki Senoh, Masaaki Suzuki, Takeshi Sasaki, Shoji Fukushima and Masashi Gamo

      Article first published online: 23 JAN 2015 | DOI: 10.1002/jat.3109

      The unevenness of pulmonary nanoparticle (NP) distribution, which hinders the establishment of an absolute dose-response relationship, has been described as one of the limitations of intratracheal administration techniques for toxicological assessment of inhaled NPs. Quantification of the NP microdistribution would facilitate the establishment of a concentration-response relationship in localized regions of the lung; however, such quantitative methods have not been reported. Here, we established a quantitative method for evaluating pulmonary TiO2 NP microdistribution in rats using X-ray fluorescence microscopy.

    12. Endocrine-disrupting potentials of equine estrogens equilin, equilenin, and their metabolites, in the medaka Oryzias latipes: in silico and DNA microarray studies

      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.

    13. Effects of lithium on growth, maturation, reproduction and gene expression in the nematode Caenorhabditis elegans

      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.

    14. Cytotoxicity of luteolin in primary rat hepatocytes: the role of CYP3A-mediated ortho-benzoquinone metabolite formation and glutathione depletion

      Fuguo Shi, Peng Zhao, Xiaobing Li, Hong Pan, Shiping Ma and Li Ding

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3106

      Luteolin, a well-known flavonoid, is widely distributed in the plant kingdom and present in many plant families. It can be found in diets, supplements and herbal medicines. The cytotoxicity of luteolin in hepatocytes was evaluated in this study. An electrophilic ortho-benzoquinone metabolite was identified by liquid chromatography coupled with tandem mass spectrometry in rat liver microsomes and primary rat hepatocytes. The CYP3A-mediated reactive metabolite formation was responsible for the cytotoxicity. Intracellular glutathione depletion by the ortho-benzoquinone metabolite was an initiating event in the cytotoxicity occurrence.

    15. Genomic and gene expression responses to genotoxic stress in PAC2 zebrafish embryonic cell line

      Maja Šrut, Jean-Paul Bourdineaud, Anamaria Štambuk and Göran I. V. Klobučar

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3113

      In this study, we assessed PAC2 cell line responses toward different forms of genotoxic stress by using the battery of tests: the Comet assay, quantitative random-amplified polymorphic DNA, amplified fragment length polymorphism and expression of several DNA repair, oxidative stress response and xenobiotic metabolism genes. PAC2 cell line exhibited genotoxic responses in all used test methods upon direct, and to a lower extent upon indirect acting genotoxicant.

    16. Toxicity of cobalt–chromium nanoparticles released from a resurfacing hip implant and cobalt ions on primary human lymphocytes in vitro

      Olga M. Posada, R. J. Tate and M. H. Grant

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3100

      In implant-related adverse reactions T-lymphocytes play a prominent role in sustaining the chronic inflammatory response. Primary human lymphocytes were isolated and treated with cobalt–chromium (CoCr) wear debris and Co ions, individually, and in combination, for 24, 48 and 120 h. Prolonged exposure to metal debris induced lymphocyte proliferation, suggesting that activation of resting lymphocytes may have occurred. Furthermore, cobalt toxicity may modulate interleukin-2 (IL-2) secretion, which may contribute to the impairment of immune regulation in vivo in patients with metal-to-metal (MoM) implants.

    17. Cobalt oxide nanoparticles induced oxidative stress linked to activation of TNF-α/caspase-8/p38-MAPK signaling in human leukemia cells

      Sourav Chattopadhyay, Sandeep Kumar Dash, Satyajit Tripathy, Balaram Das, Santanu Kar Mahapatra, Panchanan Pramanik and Somenath Roy

      Article first published online: 11 JAN 2015 | DOI: 10.1002/jat.3080

      The purpose of this study was to determine the intracellular signaling transduction pathways involved in oxidative stress induced by nanoparticles in cancer cells. Activation of reactive oxygen species (ROS) has some therapeutic benefits in arresting the growth of cancer cells. Cobalt oxide nanoparticles (CoO NPs) are an interesting compound for oxidative cancer therapy. Our results showed that CoO NPs elicited a significant (P <0.05) amount of ROS in cancer cells

    18. Quantitative toxicoproteomic analysis of zebrafish embryos exposed to a retinoid X receptor antagonist UVI3003

      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.

    19. The toxicity and distribution of iron oxide–zinc oxide core-shell nanoparticles in C57BL/6 mice after repeated subcutaneous administration

      Jun-Won Yun, Jung-Hee Yoon, Byeong-Cheol Kang, Nam-Hyuk Cho, Seung Hyeok Seok, Seung-Kee Min, Ji Hyun Min, Jeong-Hwan Che and Young Keun Kim

      Article first published online: 8 JAN 2015 | DOI: 10.1002/jat.3102

      Therapeutic cancer vaccines promote immune responses by delivering tumour-specific antigens. Recently, we developed iron oxide (Fe3O4)–zinc oxide (ZnO) core-shell nanoparticles (CSNPs) as carriers for antigen delivery into dendritic cells (DCs), and the CSNPs were injected subcutaneously into C57BL/6 mice to examine the systemic toxicity, tissue distribution and excretion of the CSNPs. The doses injected were 0, 4, 20 and 200 mg kg–1 weekly for 4 weeks. No significant changes were observed after the CSNPs administration with respect to mortality, clinical observations, body weight, food intake, water consumption, urinalysis, haematology, serum biochemistry,and organ weights.

    20. Enhanced QSAR models for drug-triggered inhibition of the main cardiac ion currents

      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.

    21. Tl(I) and Tl(III) alter the expression of EGF-dependent signals and cyclins required for pheochromocytoma (PC12) cell-cycle resumption and progression

      María T. L. Pino and Sandra V. Verstraeten

      Article first published online: 22 DEC 2014 | DOI: 10.1002/jat.3096

      The effects of thallium [Tl(I) and Tl(III)] (5–100 μM) on the PC12 cell cycle were evaluated without (EGF) or with (EGF+) media supplementation with epidermal growth factor (EGF). These cations did not activate EGF receptor (EGFR) in EGF cells, but induced ERK1/2 and Akt phosphorylation. Tl(I) promoted both EGF and EGF+ cell proliferation. In contrast, Tl(III) promoted EGF cell proliferation but delayed EGF+ cell-cycle resumption, which may be related to the toxic effects of this cation in PC12 cells.

    22. All-cause mortality increased by environmental cadmium exposure in the Japanese general population in cadmium non-polluted areas

      Yasushi Suwazono, Kazuhiro Nogawa, Yuko Morikawa, Muneko Nishijo, Etsuko Kobayashi, Teruhiko Kido, Hideaki Nakagawa and Koji Nogawa

      Article first published online: 22 DEC 2014 | DOI: 10.1002/jat.3077

      To evaluate the effect of environmental cadmium exposure on all-cause mortality, we conducted a 19-year cohort study in 1067 men and 1590 women aged 50 years or older who lived in three cadmium non-polluted areas in Japan. Continuous urinary cadmium and quartiles of urinary cadmium (Cd) were significantly related to the all-cause mortality in men and women. These results emphasized the necessity of further evaluation concerning the adoption of measures to protect the general population from environmental Cd exposure.

    23. Ginsenoside Re protects methamphetamine-induced mitochondrial burdens and proapoptosis via genetic inhibition of protein kinase C δ in human neuroblastoma dopaminergic SH-SY5Y cell lines

      Yunsung Nam, Myung Bok Wie, Eun-Joo Shin, Thuy-Ty Lan Nguyen, Seung-Yeol Nah, Sung Kwon Ko, Ji Hoon Jeong, Choon-Gon Jang and Hyoung-Chun Kim

      Article first published online: 18 DEC 2014 | DOI: 10.1002/jat.3093

      We examined the effects of dopaminergic protectant ginsenoside Re against methamphetamine toxicity using SH-SY5Y neuroblastoma cells. Re treatment exhibited significant protections against mitochondrial oxidative burdens, mitochondrial dysfunctions, mitochondrial translocation of PKCδ and apoptotic events induced by methamphetamine. These protective effects of Re were comparable to those of PKCδ antisense oligonucleotide. Re did not significantly provide additional effects on the protection mediated by PKCδ inhibition. The results suggest that PKCδ is a specific target for Re-mediated protective activity against methamphetamine toxicity.

    24. Combined exposure to lead, inorganic mercury and methylmercury shows deviation from additivity for cardiovascular toxicity in rats

      Tanja M. Wildemann, Lynn P. Weber and Steven D. Siciliano

      Article first published online: 18 DEC 2014 | DOI: 10.1002/jat.3092

      The cardiovascular effects of lead and mercury species and their mixtures were investigated in male rats. Exposure occurred for 28 days through the drinking water. A single exposure to methylmercury [MeHg(I)] increased blood pressure and decreased cardiac output, whereas mixtures reversed the effect (antagonism). A single exposure to lead [Pb(II)], mercury [Hg(II)] and MeHg(I) did not affect cardiac electrical activity, whereas co-exposure aggravated it (synergism). Single metal exposures cannot predict the adverse cardiovascular effects of Pb and Hg mixtures.

    25. HepaRG culture in tethered spheroids as an in vitro three-dimensional model for drug safety screening

      Zenan Wang, Xiaobei Luo, Chukwuemeka Anene-Nzelu, Yu Yu, Xin Hong, Nisha Hari Singh, Lei Xia, Side Liu and Hanry Yu

      Article first published online: 15 DEC 2014 | DOI: 10.1002/jat.3090

      We described the evaluation of HepaRG-tethered spheroids as an in vitro three-dimensional culture system for drug safety testing. The liver specific gene expression level and drug metabolizing enzyme activities in HepaRG tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of seven days. The inducibility of three major cytochrome P450 enzymes was improved in tethered spheroids. Its potential for high throughput drug safety screening could be in favor of by the pharmaceutical industry.

    26. Maternal exposure to 3,3’-iminodipropionitrile targets late-stage differentiation of hippocampal granule cell lineages to affect brain-derived neurotrophic factor signaling and interneuron subpopulations in rat offspring

      Megu Itahashi, Hajime Abe, Takeshi Tanaka, Sayaka Mizukami, Yoh Kikuchihara, Toshinori Yoshida and Makoto Shibutani

      Article first published online: 25 NOV 2014 | DOI: 10.1002/jat.3086

      This study investigated the maternal 3,3’-iminodipropionitrile (IDPN) exposure effect on hippocampal neurogenesis in rat offspring. Pregnant rats were supplemented with IDPN in drinking water during gestation and lactation. Female offspring subjected to analysis had decreased parvalbumin+, reelin+ and phospho-TrkB+ interneurons in the dentate hilus at 200 ppm and increased Arc+ and c-Fos+ granule cells at ≥ 67 ppm. The results suggest that IDPN targets neuronal plasticity of granule cell lineages to cause BDNF downregulation resulting in reduction in GABAergic interneurons.

    27. Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro

      Peter C. J. Schmeits, Jia Shao, Danique A. van der Krieken, Oscar L. Volger, Henk van Loveren, Ad. A. C. M. Peijnenburg and Peter J. M. Hendriksen

      Article first published online: 25 NOV 2014 | DOI: 10.1002/jat.3079

      Genomic biomarkers for direct immunotoxicity that were previously identified in human Jurkat T cells were tested using new compounds and compound classes. RNA isolated from exposures of Jurkat cells with subcytotoxic concentrations of compounds were subjected to Fluidigm high throughput analysis. The sensitivity (100%), specificity (80%) and accuracy (93%) were all higher than before. This Jurkat screening assay holds great promise to be applied in an animal-free testing strategy for human immunotoxicity.

    28. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues

      Anders Lundby, Pernille Bolvig, Anne Charlotte Hegelund, Bo F. Hansen, Jesper Worm, Anne Lützen, Nils Billestrup, Christine Bonnesen and Martin B. Oleksiewicz

      Article first published online: 21 NOV 2014 | DOI: 10.1002/jat.3082

      In a panel of five cell lines, we investigated correlations between surface expression levels of insulin receptors, IGF-I receptors and hybrid receptors and the mitogenic potency of insulin, the hyper-mitogenic insulin X10 and IGF-I. Mitogenicity modes of action were explored by siRNA-mediated receptor knockdown. Our results show that the insulin receptors (IR) as well as insulin-like growth factor 1 receptor (IGF-IR) may contribute to the mitogenic effects of insulin. These results are relevant for preclinical carcinogenicity safety assessment of developmental insulin analogues.

    29. Tributyltin alters secretion of interleukin 1 beta from human immune cells

      Shyretha Brown and Margaret Whalen

      Article first published online: 7 NOV 2014 | DOI: 10.1002/jat.3087

      Tributyltin (TBT) has been used as a biocide in industrial applications such as wood preservation, antifouling paint and antifungal agents. Owing to its many uses, it contaminates the environment and has been found in human blood samples. Interleukin-1 beta (IL-1β) is a pro-inflammatory cytokine that promotes cell growth, tissue repair and immune response regulation. Produced predominately by both monocytes and macrophages, IL-1β appears to increase the invasiveness of certain tumors.

    30. 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin induces premature senescence of astrocytes via WNT/β-catenin signaling and ROS production

      Xiaoke Nie, Lingwei Liang, Hanqing Xi, Shengyang Jiang, Junkang Jiang, Cuiying Tang, Xipeng Liu, Suyi Liu, Chunhua Wan, Jianya Zhao and Jianbin Yang

      Article first published online: 7 NOV 2014 | DOI: 10.1002/jat.3084

      2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that could exert significant neurotoxicity in the human nervous system. Nevertheless, the molecular mechanism underlying TCDD-mediated neurotoxicity has not been clarified clearly. Herein, we investigated the potential role of TCDD in facilitating premature senescence in astrocytes and the underlying molecular mechanisms.

    31. Acute toxicity of 50 metals to Daphnia magna

      Akira Okamoto, Masumi Yamamuro and Norihisa Tatarazako

      Article first published online: 7 NOV 2014 | DOI: 10.1002/jat.3078

      In this study, we conducted acute toxicity testing of 50 metals in Daphnia magna. The acute toxicity results of 40 elements, obtained in this study, were not correlated with electronegativity. Similarly, the acute toxicity results of metals including the rare metals were also not correlated with other physicochemical constants, and the metal toxicity was not able to be explained by some parameters. In the future, our data will be required in judging with metal toxicity in environment.

    32. RNA-Seq-based toxicogenomic assessment of fresh frozen and formalin-fixed tissues yields similar mechanistic insights

      Scott S. Auerbach, Dhiral P. Phadke, Deepak Mav, Stephanie Holmgren, Yuan Gao, Bin Xie, Joo Heon Shin, Ruchir R. Shah, B. Alex Merrick and Raymond R. Tice

      Article first published online: 6 NOV 2014 | DOI: 10.1002/jat.3068

      Formalin-fixed, paraffin-embedded (FFPE) pathology specimens represent a potentially vast resource for transcriptomic-based biomarker discovery. We present here a comparison of results from a whole transcriptome RNA-Seq analysis of RNA extracted from fresh frozen and FFPE rat liver samples exposed to aflatoxin B1. Overall, our results suggest that similar hypotheses about the biological mechanism of toxicity would be formulated from fresh frozen and FFPE samples.

    33. Impact of di-ethylhexylphthalate exposure on metabolic programming in P19 ECC-derived cardiomyocytes

      Kristina Schaedlich, Juliane-Susanne Schmidt, Wing Yee Kwong, Kevin D. Sinclair, Randy Kurz, Heinz-Georg Jahnke and Bernd Fischer

      Article first published online: 29 OCT 2014 | DOI: 10.1002/jat.3085

      Di(2-ethylhexyl)phthalate (DEHP) is a commonly used plasticizer in plastic devices of everyday use, primarily known to impair male gonadal development and fertility. Rising environmental pollution during the last centuries coincides with an increasing prevalence of cardiovascular and metabolic diseases. We have investigated the effects of early embryonic DEHP exposure on cardiomyogenesis in vitro, using the murine P19 embryonic carcinoma cell line (P19 ECC). Early DEHP exposure of P19 ECC altered the expression of genes associated with cellular metabolism and the functional features of cardiomyocytes.

    34. Cellular uptake and toxicity effects of silver nanoparticles in mammalian kidney cells

      Mirta Milić, Gerd Leitinger, Ivan Pavičić, Maja Zebić Avdičević, Slaven Dobrović, Walter Goessler and Ivana Vinković Vrček

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3081

      The rapid progress and early commercial acceptance of silver-based nanomaterials is owed to their biocidal activity. Besides embracing the antimicrobial potential of silver nanoparticles (AgNPs), it is imperative to give special attention to the potential adverse health effects of nanoparticles owing to prolonged exposure. Here, we report a detailed study on the in vitro interactions of citrate-coated AgNPs with porcine kidney (Pk15) cells. As uncertainty remains whether biological/cellular responses to AgNPs are solely as a result of the release of silver ions or whether the AgNPs themselves have toxic effects, we investigated the effects of Ag+ on Pk15 cells for comparison.

    35. Long-term exposures to di-n-butyl phthalate inhibit body growth and impair gonad development in juvenile Murray rainbowfish (Melanotaenia fluviatilis)

      Harpreet Bhatia, Anupama Kumar, John C. Chapman and Mike J. McLaughlin

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3076

      Juvenile Murray rainbowfish were exposed to 5-15 µg/L di-n-butyl phthalate for upto 90 days. Complete feminization of the gonad was noted in fish exposed to 5 µg/L for 90 days and to 15 and 50 µg/L of DnBP for 30 or 60 days. The E2/11-KT ratio was higher only after exposures to 5 µg/L for 90 days and to 50 µg/L for 30 days. Exposures to 5 µg/L DnBP for 30 days did not have profound effects on body growth and gonadal differentiation of fish.

    36. Organ-specific distribution of gold nanoparticles by their surface functionalization

      Jong Kwon Lee, Tae Sung Kim, Ji Young Bae, A. Young Jung, Sang Min Lee, Ji Hyun Seok, Hang Sik Roh, Chi Won Song, Mi Jin Choi, Jinyoung Jeong, Bong Hyun Chung, Yun-Geon Lee, Jayoung Jeong and Wan-Seob Cho

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3075

      To evaluate the role of surface charge on distribution of NPs, 15 nm-sized gold nanoparticles (AuNPs) having 3 different charges (AuNPPEG, AuNPCOOH, or AuNPNH2) were injected intravenously into mice and organ distribution were measured. The organ distribution showed the higher deposition rate depending on their functional groups: AuNPPEG for mesenteric lymph node, kidney, brain, and testis; AuNPCOOH for liver; AuNPNH2 for spleen, lung, and heart. This information is important for directing NPs or improving the kinetic properties of NPs.

    37. Assessment of temperature-induced hERG channel blockade variation by drugs

      Rahul R. Kauthale, Shruta S. Dadarkar, Raghib Husain, Vikas V. Karande and Madhumanjiri M. Gatne

      Article first published online: 28 OCT 2014 | DOI: 10.1002/jat.3074

      Prolongation of QT interval can be induced by drugs interacting with the cardiac potassium channel hERG. hERG channel blockade of certain drugs was evaluated at ambient and physiological temperatures. Amiodarone and β-estradiol showed a dose-dependent IKr blockade with higher blockade at 37°C. Whereas, ivermectin and frusemide showed a dose-dependent IKr blockade with lower blockade at 37°C. Gentamicin, enrofloxacin, xylazine and albendazole lacked effect. Thus, effect of temperature variation should be taken into consideration during the evaluation of hERG blockade potential.

    38. d-α-tocopheryl polyethylene glycol 1000 succinate-containing vehicles provide no detectable chemoprotection from oxidative damage

      Bethany R. Baumgart, Terry R. Van Vleet, Damir Simic, Theodora W. Salcedo, Kimberley Lentz, Michael Donegan, Marc H. Davies, Roderick T. Bunch, Thomas P. Sanderson and Robert W. Lange

      Article first published online: 27 OCT 2014 | DOI: 10.1002/jat.3072

      The objective of this study was to evaluate potential protective effects of vehicles containing d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), which may impact nonclinical safety assessments of oxidative processes. This was achieved by evaluating rat plasma, liver and adrenal gland concentrations of d-α-tocopheryl succinate (TS) and d-α-tocopherol as well as oxidative status of plasma following oral dosing of TPGS-containing vehicles, intraperitoneal (IP) dosing of TS or ex vivo treatment of blood with H2O2

    39. Comparison of the kinetics of various biomarkers of benzo[a]pyrene exposure following different routes of entry in rats

      Marjory Moreau and Michèle Bouchard

      Article first published online: 27 OCT 2014 | DOI: 10.1002/jat.3070

      This study provides insights on kinetic differences of biomarkers of exposure to carcinogenic polycyclic aromatic hydrocarbons and route-dependent variations in their excretion time courses based on experimental studies in rats. We confirmed the interest of measuring multiple metabolites due to route-to-route differences in the relative excretion of the different biomarkers and in the time courses of diolBaPs versus OHBaPs. Concentration ratios of the different metabolites may help indicate time and main route of exposure.

    40. Neurotoxic effects of ochratoxin A on the subventricular zone of adult mouse brain

      Sara Paradells, Brenda Rocamonde, Cristina Llinares, Vicente Herranz-Pérez, Misericordia Jimenez, Jose Manuel Garcia-Verdugo, Ivan Zipancic, Jose Miguel Soria and Ma. Angeles Garcia-Esparza

      Article first published online: 25 SEP 2014 | DOI: 10.1002/jat.3061

      Ochratoxin A (OTA) is a common contaminant in food and feedstuffs. In the present study we investigated, in vitro and in vivo, the effect of OTA exposure on the subventricular zone (SVZ) and on neural precursors obtained from this neurogenic niche in the adult brain. We demonstrate how OTA could be a threat to SVZ precursors and adult SVZ neurogenic niche through its impact in cell viability, proliferation and differentiation in a dose-dependent manner.

    41. Oral cadmium exposure during rat pregnancy: assessment of transplacental micronutrient transport and steroidogenesis at term

      Anja Mikolić, Martina Piasek, Antonija Sulimanec Grgec, Veda M. Varnai, Sandra Stasenko and Saša Kralik Oguić

      Article first published online: 25 SEP 2014 | DOI: 10.1002/jat.3055

      Biomarkers of Cd exposure, maternal and foetal micronutrients, and steroid hormones were evaluated after oral exposure to 50 mg Cd l–1 from pregnancy day 1 to 20. Non-pregnant rats were exposed under the same conditions. The Cd load was higher in pregnant rats. Progesterone and testosterone in placenta and serum were unchanged. Liver zinc increased in all exposed rats. Zinc decreased in maternal kidney and placenta, iron decreased in the maternal organs and foetus; hence micronutrient handover to the foetus was disrupted.

    42. Evaluation and refinement of a field-portable drinking water toxicity sensor utilizing electric cell–substrate impedance sensing and a fluidic biochip

      Mark W. Widder, Linda M. Brennan, Elizabeth A. Hanft, Mary E. Schrock, Ryan R. James and William H. van der Schalie

      Article first published online: 18 SEP 2014 | DOI: 10.1002/jat.3017

    43. Chronic trimethyltin chloride exposure and the development of kidney stones in rats

      Xuefeng Ren, Xin Wu, Gang Sui, Zhihong Gong, Emmanuel Yawson, Banghua Wu, Guanchao Lai, Xiaolin Ruan, Hongbin Gao, Feng Zhou, Bing Su, James R. Olson and Xiaojiang Tang

      Article first published online: 16 SEP 2014 | DOI: 10.1002/jat.3054

      We previously reported that occupational trimethyltin (TMT) exposure is a risk factor for developing kidney stones. Here we performed a 180-day animal study and showed that chronic TMT exposure can significantly inhibit the activity of renal H+/K+-ATPase and subsequently lead to an increase in urinary pH. We observed a dose-dependent increase in the incidence of kidney/urinary tract stones and the pathological changes in the kidneys of rats with TMT exposure compared with the rats in the control group.

    44. You have full text access to this OnlineOpen article
      Non-clinical safety evaluation of single and repeated intramuscular administrations of MAGE-A3 Cancer Immunotherapeutic in rabbits and cynomolgus monkeys

      Eric Destexhe, Emilie Grosdidier, Nathalie Baudson, Roy Forster, Catherine Gerard, Nathalie Garçon and Lawrence Segal

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3025

      We evaluated the potential local and systemic toxic effects induced by single (rabbits) or 25 repeated (monkeys) injections of MAGE-A3 Cancer Immunotherapeutic, compared with control saline. Immune responses were assessed in monkeys. Single and repeated (up to 4x at the same site) injections were well-tolerated. Following 5–7 repeated injections, limb circumferences increased up to 26% (5h post-injection), but returned to normal after 1–8 days. MAGE-A3 Cancer Immunotherapeutic induced MAGE-A3-specific antibody and T-cell responses in all monkeys.

    45. Exposure to MnCl2 · 4H2O during development induces activation of microglial and perivascular macrophage populations in the hippocampal dentate gyrus of rats

      Hajime Abe, Takumi Ohishi, Fumiyuki Nakane, Ayako Shiraki, Takeshi Tanaka, Toshinori Yoshida and Makoto Shibutani

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3059

      This study was performed to clarify whether Mn exposure during development causes proinflammatory responses in the hippocampal dentate gyrus of offspring, involving the Mn-induced disruption of neurogenesis. Pregnant rats were treated with dietary MnCl2 · 4H2O during gestation and lactation. Their offspring showed increased activated microglia and perivascular macrophages in the dentate hilus and increased proinflammatory cytokines in the hippocampal tissue after 800 ppm MnCl2 · 4H2O, probably involving the disruption of neurogenesis after 800 ppm exposure.

    46. Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 2: Evaluation of in vitro topical decontamination efficacy using undamaged skin

      Christopher H. Dalton, Charlotte A. Hall, Helen L. Lydon, J. K. Chipman, John S. Graham, John Jenner and Robert P. Chilcott

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3060

      There is a need to develop haemostatic products that can simultaneously arrest haemorrhage and decontaminate CW agents from within wounds. The purpose of this study was to evaluate a number of candidate haemostats for efficacy as skin decontaminants against three CW agents (soman, VX and sulphur mustard) using an in vitro diffusion cell containing undamaged pig skin. Two products were shown to be effective and will be subject to further assessment using damaged skin.

    47. Early chronic lead exposure reduces exploratory activity in young C57BL/6J mice

      Mayra Gisel Flores-Montoya and Christina Sobin

      Article first published online: 12 SEP 2014 | DOI: 10.1002/jat.3064

      Research has suggested that chronic low-level lead exposure diminishes children's neurocognitive function. Animal models are needed in order to understand how chronic low-level lead disrupts behavior and the brain. C57BL/6J mice (N = 61) were exposed chronically to low-level lead or sodium from birth until PND 28 and were tested behaviorally. As blood lead level increased, exploratory activity decreased. This is the first study to show behavioral effects of chronic low-level lead exposure in pre-adolescent C57BL/6J mice.

    48. Skin absorption of six performance amines used in metalworking fluids

      Lauriane N. Roux, James D. Brooks, James L. Yeatts and Ronald E. Baynes

      Article first published online: 4 SEP 2014 | DOI: 10.1002/jat.3056

      Every year, 10 million workers are exposed to metalworking fluids (MWFs) that may be toxic. There are four types of MWFs: neat oils and three water-based MWFs (soluble oil, semisynthetic and synthetic), which are diluted with water and whose composition varies according to the mineral oils ratio. MWFs also contain various additives. To determine the absorption of six amines used as corrosion inhibitors and biocides in MWFs, porcine skin flow-through diffusion cell experiments were conducted with hydrophilic ethanolamines (mono-, di- and triethanolamine, MEA, DEA and TEA respectively) and a mixture of lipophilic amines (dibutylethanolamine, dicyclohexylamine and diphenylamine).

    49. Reversible cholinesterase inhibitors as pre-treatment for exposure to organophosphates: assessment using azinphos-methyl

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

      Article first published online: 3 SEP 2014 | DOI: 10.1002/jat.3052

      Searching for a broad-range pre-treatment compound for organophosphate intoxication, the mortality-reducing efficacy of five reversible cholinesterase-inhibitors (pyridostigmine, physostigmine, ranitidine, tacrine and experimental oxime K-27) was assessed, when injected before exposure to the organophosphate cholinesterase-inhibitor azinphos-methyl. Best in vivo protection from azinphos-methyl-induced mortality was achieved by K-27 and physostigmine, reducing the relative risk (RR) of death to about 1/5. Prophylactic administration of an oxime, such as K-27, before exposure to organophosphorus compounds may be a promising option.

    50. Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells

      Qilong Gao, Huaimin Liu, Yamin Yao, Liang Geng, Xinfeng Zhang, Lifeng Jiang, Bian Shi and Feng Yang

      Article first published online: 1 SEP 2014 | DOI: 10.1002/jat.3049

      The therapeutic goal of cancer treatment is now geared towards triggering tumour-selective cell death with autophagic cell death being required for the chemotherapy of apoptosis-resistant cancer. In this study, Carnosic acid (CA), a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), significantly induced autophagic cell death in HepG2 cells. Ca treatment caused the formation of autophagic vacuoles produced an increasing ratio of LC3-II to LC3-I in a time- and dose-dependent manner but had no effect on the levels of autophagy-related protein ATG6 and ATG13 expression.

    51. Protective effects of ascorbic acid against the genetic and epigenetic alterations induced by 3,5-dimethylaminophenol in AA8 cells

      Ming-Wei Chao, P��nar Erkekoglu, Chia-Yi Tseng, Wenjie Ye, Laura J. Trudel, Paul L. Skipper, Steven R. Tannenbaum and Gerald N. Wogan

      Article first published online: 1 SEP 2014 | DOI: 10.1002/jat.3046

      Exposure to monocyclic aromatic alkylanilines and their metabolites were significantly and independently associated with ROS generation and bladder cancer incidence. Apropos to this knowledge and information, this study was designed to investigate the protective effects of Ascorbic acid on cytotoxicity, oxidant/antioxidant parameters, cell cyle arrest, Aprt mutation frequency, and epigenetic changes caused by 3,5-Dimethylaminophenol in Chinese Hamster Ovary (CHO) AA8 cells.

    52. Development of haemostatic decontaminants for the treatment of wounds contaminated with chemical warfare agents. 1: Evaluation of in vitro clotting efficacy in the presence of certain contaminants

      Charlotte A. Hall, Helen L. Lydon, Christopher H. Dalton, J. K. Chipman, John S. Graham and Robert P. Chilcott

      Article first published online: 15 AUG 2014 | DOI: 10.1002/jat.3019

      The treatment of battlefield injuries may be complicated by contamination with toxic chemicals. The aim of this study was to investigate the ex vivo haemostatic efficacy of seven commercially available haemostats in the presence of toxic chemicals (soman, VX, sulphur mustard, petrol, aviation fuel and motor oil). A number of commercial products which may have potential as haemostatic decontaminants were identified which warrant further investigation to establish their decontaminant efficacy.

    53. The relationship between chemical-induced kidney weight increases and kidney histopathology in rats

      Evisabel A. Craig, Zhongyu Yan and Q. Jay Zhao

      Article first published online: 4 AUG 2014 | DOI: 10.1002/jat.3036

      We examined the relationship between chemically-induced kidney weight changes and renal histopathological alterations in rats to better understand the utility of kidney weight measurements in predicting renal toxicity. We found that statistically significant increases in absolute, but not relative, kidney weight correlate well with renal histopathology irrespective of whether kidney weight changes reach 10% and independently of a chemical's effect on body weight. This suggests that absolute kidney weight measurements should be routinely analyzed to identify potential renal toxicants.

    54. In vitro evaluation of the effects of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) on IL-2 production in human T-cells

      Kristin Midgett, Margie M. Peden-Adams, Gary S. Gilkeson and Diane L. Kamen

      Article first published online: 23 JUL 2014 | DOI: 10.1002/jat.3037

      Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), have been shown to alter various immune functions suggesting they are immunotoxic. This study assessed the effects of PFOS and PFOA on interleukin (IL)-2 production in the human Jurkat T-cell line and PFOS in healthy human primary T cells. These data demonstrated that PFOA did not impact IL-2 production, but PFOS significantly suppressed IL-2 production in both cell types at dose levels within the high end of the human exposure range.

    55. Reactive oxygen species-dependent JNK downregulated olaquindox-induced autophagy in HepG2 cells

      Dongxu Zhao, Congcong Wang, Shusheng Tang, Chaoming Zhang, Shen Zhang, Yan Zhou and Xilong Xiao

      Article first published online: 18 JUL 2014 | DOI: 10.1002/jat.3022

      Olaquindox has been demonstrated to inhibit cell growth and induce cell death in a variety of cell lines. Recently, we reported that olaquindox can induce apoptosis of HepG2 cells in a mitochondria-dependent pathway. In this study, we demonstrated that olaquindox can induce autophagy. In addition, we also found that the autophagy inhibitor 3-MA enhances olaquindox-induced apoptotic cell death. Furthermore, ROS-dependent JNK activation may be involved in the negative regulation of olaquindox-induced autophagy in HepG2 cells.

    56. Renal cells exposed to cadmium in vitro and in vivo: normalizing gene expression data

      A. R. Nair, K. Smeets, E. Keunen, W.-K. Lee, F. Thévenod, E. Van Kerkhove and A. Cuypers

      Article first published online: 18 JUL 2014 | DOI: 10.1002/jat.3047

      The choice of reference genes for gene quantification is an important pre-requisite for carrying out new studies. A good normalization leads to biological relevant data interpretation as the detected variation in gene expression originates from biological rather than technical differences. The present study therefore serves as a baseline for renal cadmium (Cd) toxicity studies both in vitro and in vivo and the selected pool of reference genes that proved to be stable can be included in new experimental setups.


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