Journal of Applied Toxicology

Cover image for Vol. 35 Issue 5

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

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  1. 1 - 75
  1. Research Articles

    1. Augmenting effects of gestational arsenite exposure of C3H mice on the hepatic tumors of the F2 male offspring via the F1 male offspring

      Keiko Nohara, Kazuyuki Okamura, Takehiro Suzuki, Hikari Murai, Takaaki Ito, Keiko Shinjo, Shota Takumi, Takehiro Michikawa, Yutaka Kondo and Kenichiro Hata

      Article first published online: 30 MAR 2015 | DOI: 10.1002/jat.3149

      Gestational exposure can affect the F2 generation through exposure of F1 germ cells. We assessed tumor incidence in the F2 males obtained by reciprocal crossing between the control and gestationally arsenite-exposed F1 males and females in C3H mice. The results demonstrated that the F2 males born to arsenite-F1 males developed tumors at a significantly higher rate than the F2 males born to the control F1 males. We also characterized gene expression of several hepatocellular carcinoma markers in the F2 tumors.

    2. Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism

      Ayako Shiraki, Fumiyo Saito, Hirotoshi Akane, Yumi Akahori, Nobuya Imatanaka, Megu Itahashi, Toshinori Yoshida and Makoto Shibutani

      Article first published online: 30 MAR 2015 | DOI: 10.1002/jat.3140

      Global gene expression profiling was performed in four brain regions in 6-propyl-2-thiouracil (PTU)-administered young adult rats with hypothyroidism. Among the brain regions, gene expression alterations related to neural development and myelination were most profound in the hippocampal dentate gyrus. Because the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects.

    3. You have full text access to this OnlineOpen article
      Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment

      Daniele Wikoff, Chad Thompson, Camarie Perry, Matthew White, Susan Borghoff, Lauren Fitzgerald and Laurie C. Haws

      Article first published online: 30 MAR 2015 | DOI: 10.1002/jat.3132

      Data from the National Toxicology Program (NTP) were utilized to develop an oral reference dose (RfD) and oral cancer slope factor (OSF) for tetrabromobisphenol A (TBBPA). Comparison of exposure estimates based on breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion, resulted in margins of exposure > 800 000 in infants, young children, older children and adults. These data collectively indicate a low level of health concern associated with exposures to TBBPA.

    4. Evaluation of combinations of in vitro sensitization test descriptors for the artificial neural network-based risk assessment model of skin sensitization

      Morihiko Hirota, Shiho Fukui, Kenji Okamoto, Satoru Kurotani, Noriyasu Imai, Miyuki Fujishiro, Daiki Kyotani, Yoshinao Kato, Toshihiko Kasahara, Masaharu Fujita, Akemi Toyoda, Daisuke Sekiya, Shinichi Watanabe, Hirokazu Seto, Osamu Takenouchi, Takao Ashikaga and Masaaki Miyazawa

      Article first published online: 30 MAR 2015 | DOI: 10.1002/jat.3105

      The skin sensitization potential of chemicals has been determined with the use of the murine local lymph node assay (LLNA). However, in recent years public concern about animal welfare has led to a requirement for non-animal risk assessment systems for the prediction of skin sensitization potential, to replace LLNA. Selection of an appropriate in vitro test or in silico model descriptors is critical to obtain good predictive performance

    5. Test battery with the human cell line activation test, direct peptide reactivity assay and DEREK based on a 139 chemical data set for predicting skin sensitizing potential and potency of chemicals

      Osamu Takenouchi, Shiho Fukui, Kenji Okamoto, Satoru Kurotani, Noriyasu Imai, Miyuki Fujishiro, Daiki Kyotani, Yoshinao Kato, Toshihiko Kasahara, Masaharu Fujita, Akemi Toyoda, Daisuke Sekiya, Shinichi Watanabe, Hirokazu Seto, Morihiko Hirota, Takao Ashikaga and Masaaki Miyazawa

      Article first published online: 29 MAR 2015 | DOI: 10.1002/jat.3127

      To develop a testing strategy incorporating the human cell line activation test (h-CLAT), direct peptide reactivity assay (DPRA) and DEREK, we created an expanded data set of 139 chemicals (102 sensitizers and 37 non-sensitizers) by combining the existing data set of 101 chemicals through the collaborative projects of Japan Cosmetic Industry Association. Of the additional 38 chemicals, 15 chemicals with relatively low water solubility (log Kow > 3.5) were selected to clarify the limitation of testing strategies regarding the lipophilic chemicals.

    6. A novel in chemico method to detect skin sensitizers in highly diluted reaction conditions

      Yusuke Yamamoto, Haruna Tahara, Ryota Usami, Toshihiko Kasahara, Yoshihiro Jimbo, Takanori Hioki and Masaharu Fujita

      Article first published online: 25 MAR 2015 | DOI: 10.1002/jat.3139

      We modified the ADRA (amino acid derivative reactivity assay) method by reducing the test chemical concentration in the solution 100-fold. We investigated the accuracy of skin sensitization predictions made using this modified method, which was designated the ADRA-dilutional method (ADRA-DM). The predictive accuracy of the ADRA-DM for skin sensitization was 90% for 82 test chemicals, and no precipitation of test compounds was observed. These results show that the ADRA-DM is a versatile and useful method to predict skin sensitization.

    7. Particle uptake efficiency is significantly affected by type of capping agent and cell line

      Fan Zhang, Phillip Durham, Christie M. Sayes, Boris L. T. Lau and Erica D. Bruce

      Article first published online: 24 MAR 2015 | DOI: 10.1002/jat.3138

      Silver nanoparticles (AgNPs) capped with citrate, polyvinylpyrrolidone (PVP) and tannic acid were studied with human bronchoalveolar carcinoma and human colon adenocarcinoma cell lines to investigate the contribution of capping agents to their observed health impacts at realistic dose ranges. Results showed higher cellular uptake and rate from tannic acid capped AgNPs in both cell lines, and no observed toxicity from any type of the AgNPs treatment. Similar doses of silver ions, however, significantly altered cellular functionality.

    8. Comparative effects of sulfhydryl compounds on target organellae, nuclei and mitochondria, of hydroxylated fullerene-induced cytotoxicity in isolated rat hepatocytes

      Yoshio Nakagawa, Akiko Inomata, Akio Ogata and Dai Nakae

      Article first published online: 23 MAR 2015 | DOI: 10.1002/jat.3137

      The exposure of rat hepatocytes to C60(OH)24 caused cell death accompanied by the formation of plasma membrane blebs, the loss of cellular levels of ATP and GSH, and the induction of DNA fragmentation and reactive oxygen species. C60(OH)24-induced DNA damage and mitochondrial dysfunction were effectively prevented by pretreatment with sulfhydryl compounds, NAC, L-cysteine, and L-methionine. These results suggest that the onset of toxic effects is at least partially attributable to a thiol redox-state imbalance caused by the fullerenol.

  2. Review Articles

    1. Metals in cosmetics: implications for human health

      Sylwia Borowska and Malgorzata M. Brzóska

      Article first published online: 23 MAR 2015 | DOI: 10.1002/jat.3129

      Cosmetics should be completely safe to human health; however, their use is sometimes related to the occurrence of unfavourable effects resulting from the presence of chemical substances, including metals. This review article is focused on problems related to heavy metals and aluminium presence in cosmetics, including their sources, concentrations, allowed limits of occurrence and danger for the health of users of these products. Owing to the growing usage of cosmetics it is necessary to pay special attention to these problems.

  3. Research Articles

    1. Meloxicam inhibits fipronil-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells

      Jae Hyeon Park, Youn Sun Park, Je-Bong Lee, Kyung-Hun Park, Min-kyoung Paik, Mihye Jeong and Hyun Chul Koh

      Article first published online: 13 MAR 2015 | DOI: 10.1002/jat.3136

      Oxidative stress and inflammatory responses have been identified as key elements of neuronal cell apoptosis. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in human neuroblastoma SH-SY5Y cells treated with fipronil (FPN). Based on the cytotoxic mechanism of FPN, we examined the neuroprotective effects of meloxicam against FPN-induced neuronal cell death.

    2. Investigation on cobalt-oxide nanoparticles cyto-genotoxicity and inflammatory response in two types of respiratory cells

      Delia Cavallo, Aureliano Ciervo, Anna Maria Fresegna, Raffaele Maiello, Paola Tassone, Giuliana Buresti, Stefano Casciardi, Sergio Iavicoli and Cinzia Lucia Ursini

      Article first published online: 13 MAR 2015 | DOI: 10.1002/jat.3133

      The increasing use of Co3O4 nanoparticles and the suggested genotoxicity highlight the need of further investigation. We evaluated cyto-genotoxic and inflammatory effects of Co3O4-NPs in human alveolar and bronchial cells. In alveolar cells direct and oxidative DNA damage were detected. In bronchial cells moderate cytotoxicity, direct DNA damage only at the highest concentration, and significant oxidative-inflammatory effects at lower concentrations were detected. The findings confirm the genotoxic-oxidative potential of Co3O4-NPs and the greater sensitivity of bronchial cells to cytotoxic-inflammatory effects.

    3. Cellular localization of uranium in the renal proximal tubules during acute renal uranium toxicity

      Shino Homma-Takeda, Keisuke Kitahara, Kyoko Suzuki, Benjamin J. Blyth, Noriyoshi Suya, Teruaki Konishi, Yasuko Terada and Yoshiya Shimada

      Article first published online: 13 MAR 2015 | DOI: 10.1002/jat.3126

      To investigate cellular dynamics and localization of uranium in the renal proximal tubules, high-resolution quantitative in situ measurements by high-energy synchrotron radiation X-ray fluorescence analysis was performed for renal sections from a rat model of uranium-induced acute renal toxicity. Our findings suggest that site-specific accumulation of uranium in micro-regions of the S3 segment of the proximal tubules and retention of uranium in concentrated areas during recovery are characteristics of uranium behavior in the kidney.

    4. Time profiles and toxicokinetic parameters of key biomarkers of exposure to cypermethrin in orally exposed volunteers compared with previously available kinetic data following permethrin exposure

      Mylène Ratelle, Jonathan Coté and Michèle Bouchard

      Article first published online: 13 MAR 2015 | DOI: 10.1002/jat.3124

      Time profiles and toxicokinetic parameters of key biomarkers of exposure to cypermethrin pyrethroid were documented in 6 orally exposed volunteers and compared with previously available kinetic data following permethrin dosing. Blood and urine samples were collected over 72 h postdosing. Trans-DCCA, cis-DCCA and 3-PBA metabolites were quantified. Urinary rate time courses of metabolites showed apparent elimination t1/2 circa 6.4 h. These data confirm that the kinetics of cypermethrin is similar to that of permethrin in humans.

    5. Non-clinical safety assessment of single and repeated intramuscular administration of a human papillomavirus-16/18 vaccine in rabbits and rats

      Lawrence Segal, Danielle Morelle, Kari Kaaber, Eric Destexhe and Nathalie Garçon

      Article first published online: 6 MAR 2015 | DOI: 10.1002/jat.3131

      The human papillomavirus vaccine Cervarix® is for the prevention of cervical cancer. It contains recombinant virus-like particles and AS04 (MPL and aluminium salt). Local and systemic toxic effects of Cervarix® or AS04 were evaluated in repeated-dose studies in rabbits and rats. Treatment-related changes included a slight transient increase in circulating neutrophils and injection site inflammation. Thirteen weeks post-fourth dose, recovery at the injection site was near complete. Therefore in these non-clinical models, Cervarix® and AS04 alone were safe and well tolerated.

    6. Comparative toxicity of silicon dioxide, silver and iron oxide nanoparticles after repeated oral administration to rats

      Jun-Won Yun, Seung-Hyun Kim, Ji-Ran You, Woo Ho Kim, Ja-June Jang, Seung-Kee Min, Hee Chan Kim, Doo Hyun Chung, Jayoung Jeong, Byeong-Cheol Kang and Jeong-Hwan Che

      Article first published online: 6 MAR 2015 | DOI: 10.1002/jat.3125

      Although silicon dioxide (SiO2), silver (Ag) and iron oxide (Fe2O3) nanoparticles are widely used in diverse applications from food to biomedicine, in vivo toxicities of these nanoparticles exposed via the oral route remain highly controversial. To examine the systemic toxicity of these nanoparticles, well-dispersed nanoparticles were orally administered to Sprague–Dawley rats daily over a 13-week period

    7. Potential of biofluid components to modify silver nanoparticle toxicity

      Anna Murphy, Kate Sheehy, Alan Casey and Gordon Chambers

      Article first published online: 6 MAR 2015 | DOI: 10.1002/jat.3123

      Silver nanoparticle (AgNP) interaction with biofluids upon entry to the body is important for accurate toxicological investigation. A number of toxicological tests were performed and demonstrated modification of AgNP toxicity by the chosen biofluid components cholic acid, deoxycholic acid and ursodeoxycholic acid. It is concluded that the influence on AgNP toxicity by biofluid components is dependent on the biofluid component itself and the location where it acts.

  4. Review Articles

    1. T-helper cell-mediated factors in drug-induced liver injury

      Xinzhi Wang, Luyong Zhang and Zhenzhou Jiang

      Article first published online: 6 MAR 2015 | DOI: 10.1002/jat.3115

      T-helper cell-mediated immune responses can contribute to drug-induced liver injury (DILI). This review summarizes recent advances in the T-helper cell-mediated factors in DILI and potential mechanisms, which may lead to a better understanding of DILI.

  5. 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.

  6. 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.

  7. 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.

    7. 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.

    8. 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.

    9. 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.

    10. 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.

    11. 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.

    12. 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.

    13. 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.

    14. 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.

    15. 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.

    16. 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.

    17. 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.

    18. 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.

    19. 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.

    20. 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.

    21. 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.

    22. 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.

    23. 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

    24. 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.

    25. 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.

    26. 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.

    27. 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.

    28. 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.

    29. 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.

    30. 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.

    31. 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.

    32. 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.

    33. 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.

    34. 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.

    35. 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.

    36. 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.

    37. 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.

    38. 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.

    39. 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.

    40. 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.

    41. 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.

    42. 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.

    43. 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.

    44. 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

    45. 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.

    46. 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.

    47. 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

    48. 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.

    49. 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.

    50. 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.

    51. 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.

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