Journal of Applied Toxicology

Cover image for Vol. 36 Issue 9

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

Editor-in-Chief: Philip W. Harvey

Impact Factor: 2.722

ISI Journal Citation Reports © Ranking: 2015: 33/89 (Toxicology)

Online ISSN: 1099-1263


  1. 1 - 69
  1. Research articles

    1. Development of an in vivo anti-androgenic activity detection assay using fenitrothion in Japanese medaka (Oryzias latipes)

      Yoshifumi Horie, Haruna Watanabe, Hitomi Takanobu, Ayano Yagi, Takahiro Yamagishi, Taisen Iguchi and Norihisa Tatarazako

      Version of Record online: 27 JUL 2016 | DOI: 10.1002/jat.3365

      The purpose of this study was to establish a screening method for anti-androgenic activity utilizing the number of papillary processes in Japanese medaka (Oryzias latipes). After fenitrothion exposure, the number of papillary processes were significantly decreased in a dose-dependent manner in XY medaka. Our results indicate that the number of papillary processes can be used as an indicator of anti-androgenic activity and that this model may prove useful as a chemical screening method.

  2. Review articles

    1. Gender and geographical variability in the exposure pattern and metabolism of deoxynivalenol in humans: a review

      Liangkai Chen, Miao Yu, Qinghua Wu, Zhao Peng, Di Wang, Kamil Kuča, Ping Yao, Hong Yan, Andreas K. Nüssler, Liegang Liu and Wei Yang

      Version of Record online: 26 JUL 2016 | DOI: 10.1002/jat.3359

      Three kinds of conjugated products (DON-3-glucuronide, DON-15-glucuronide and DON-7-glucuronide) can be found as major metabolites in human urine. Females and males show different patterns of exposure levels, and human exposure to DON also shows some geographical differences because of different DON levels in cereal-based foods, food intake habits and UDP-glucuronosyltransferase expression. Specifically, the C12, 13-deepoxymetabolite was found predominantly in French adults but was rarely detected in UK adults.

  3. Research articles

    1. Effect of 4-week inhalation exposure to 1-bromopropane on blood pressure in rats

      Fen Huang, Sahoko Ichihara, Yuki Yamada, Shameema Banu and Gaku Ichihara

      Version of Record online: 25 JUL 2016 | DOI: 10.1002/jat.3364

      Short abstract

      The pathophysiology of hypertension is complex and multifactorial, and includes exposure to various chemical substances. Given that 1-bromopropane (1-BP) increased reactive oxygen species in the brain of rats, we hypothesized that 1-BP also has cardiovascular toxicity through increased oxidative stress. Our results indicate that subacute (4 week) inhalation exposure to 1-BP increases blood pressure and suggest that this cardiovascular toxic effect is due, at least in part, to increased oxidative stress mediated through activation of the NADPH oxidase pathway.

  4. Review articles

    1. You have full text access to this OnlineOpen article
      The C. elegans model in toxicity testing

      Piper Reid Hunt

      Version of Record online: 22 JUL 2016 | DOI: 10.1002/jat.3357

      Toxicity ranking screens in Caenorhabditis elegans have repeatedly been shown to be as predictive of rat LD50 ranking as mouse LD50 ranking. Additionally, many instances of conservation of mode of toxic action have been noted between C. elegans and mammals. These consistent correlations make the case for inclusion of C. elegans assays in early safety testing and as one component in tiered or integrated toxicity testing strategies. Good C. elegans culture practice (GCeCP) is essential for reliable results.

  5. Research articles

    1. Pulmonary persistence of graphene nanoplatelets may disturb physiological and immunological homeostasis

      Eun-Jung Park, Sang Jin Lee, Kyuhong Lee, Young Chul Choi, Byoung-Seok Lee, Gwang-Hee Lee and Dong-Wan Kim

      Version of Record online: 21 JUL 2016 | DOI: 10.1002/jat.3361

      In this study, we evaluated the local and systemic health effect after pulmonary persistence of graphene nanoplatelet (GNP) (1.25, 2.5 and 5 mg kg−1). In the lung of mice exposed to the highest dose, the total number of cells and the percentage of lymphocytes significantly increased in the lung with an increase in both the number of GNP-engulfed macrophages and the percentage of apoptotic cells. A Th1-shifted immune response, the elevated chemokine secretion and the enhanced expression of cytoskeletal-related genes were observed. Additionally, the number of white blood cells (WBC) and the percentage of macrophages and neutrophils clearly increased in the blood, whereas total protein, BUN and potassium levels significantly decreased. Therefore, we suggest that pulmonary persistence of GNP may cause adverse health effects by disturbing immunological- and physiological-homeostasis of our body.

    2. Hepatocytes cocultured with Sertoli cells in bioreactor favors Sertoli barrier tightness in rat

      P. Zeller, A. Legendre, S. Jacques, M. J. Fleury, F. Gilard, G. Tcherkez and E. Leclerc

      Version of Record online: 21 JUL 2016 | DOI: 10.1002/jat.3360

      The lack of a reliable in vitro system to assess reprotoxicity is an emerging problem. Here, we integrated hepatic metabolism and the blood–testis barrier using a culture insert within a dynamic microfluidic platform system (IIDMP). We demonstrate that permeability of the barrier is reduced by dynamic coculture. IIDMP seems to be well suited for (i) assessing the dose–response effect of chemicals within the rodent or human male reproductive tract, and (ii) improving the quality of reprotoxicological assays by including hepatic metabolism.

    3. In vitro toxicology studies of extracellular vesicles

      Sayantan Maji, Irene K. Yan, Mansi Parasramka, Swathi Mohankumar, Akiko Matsuda and Tushar Patel

      Version of Record online: 20 JUL 2016 | DOI: 10.1002/jat.3362

      The use of extracellular vesicles (EV) for therapeutic applications requires demonstration of their safety. We performed detailed toxicological studies on two types of EVs that may be used for this purpose. EV from human mesenchymal stem cells have a greater safety profile than those derived from bovine milk and are attractive for further development as disease therapeutics. Detailed safety and toxicological assessment will be necessary before the use of biologically derived EVs for in vivo studies or for clinical indications.

    4. Molecular docking reveals the potential of phthalate esters to inhibit the enzymes of the glucocorticoid biosynthesis pathway

      Shahzad Ahmad, Mohemmed Faraz Khan, Suhel Parvez, Mohammad Akhtar and Sheikh Raisuddin

      Version of Record online: 18 JUL 2016 | DOI: 10.1002/jat.3355

      Using in silico tools of Schrodinger Maestro 9.4, we performed molecular docking study of 32 ligands including PAEs of known endocrine disrupting potential with the selective enzymes of glucocorticoid biosynthesis pathway such as CYP11A1, CYP11B2, CYP19A1, CYP17A1, CYP21A2 and 3α/20β-HSD. Besides benzyl butyl benzene-1,2-dicarboxylate, bis(7-methylnonyl) benzene-1,2-dicarboxylate, and bis(2-ethylhexyl) benzene-1,2-dicarboxylate also showed comparable molecular interaction with enzymes. Interestingly, in silico study revealed that certain PAEs have more inhibitory potential against enzymes of glucocorticoid biosynthesis pathway than their respective known inhibitors.

    5. You have full text access to this OnlineOpen article
      Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage

      Francis S. Wolenski, Pooja Shah, Tomoya Sano, Tadahiro Shinozawa, Hugues Bernard, Matt J. Gallacher, Shylah D. Wyllie, Georgianna Varrone, Lisa A. Cicia, Mary E. Carsillo, Craig D. Fisher, Sean E. Ottinger, Erik Koenig and Patrick J. Kirby

      Version of Record online: 11 JUL 2016 | DOI: 10.1002/jat.3358

      MicroRNAs (miRNA) have great potential as novel safety biomarkers. Next-generation sequencing was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (acetaminophen or carbon tetrachloride). Cisplatin treatment caused an elevation of miR-378a in the urine, confirming the findings of other similar studies. Treatment with either acetaminophen or carbon tetrachloride caused a serum elevation of four liver-enriched miRNAs (miR-122, −802, −31a and −365).

  6. Review articles

    1. Anthophyllite asbestos: state of the science review

      Shannon H. Gaffney, Matthew Grespin, Lindsey Garnick, Derek A. Drechsel, Rebecca Hazan, Dennis J. Paustenbach and Brooke D. Simmons

      Version of Record online: 11 JUL 2016 | DOI: 10.1002/jat.3356

      Anthophyllite is an amphibole form of asbestos historically used in only a limited number of products. No published resource currently exists that offers a complete overview of anthophyllite toxicity or of its effects on exposed human populations. We performed a review focusing on how anthophyllite toxicity was understood over time by conducting a comprehensive search of publicly available documents that discussed the use, mining, properties, toxicity, exposure and potential health effects of anthophyllite. Over 200 documents were identified; 114 contained relevant and useful information which we present chronologically in this assessment.

  7. Research articles

    1. Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for skin sensitization

      Jeremy M. Fitzpatrick, David W. Roberts and Grace Patlewicz

      Version of Record online: 29 JUN 2016 | DOI: 10.1002/jat.3354

      A large dataset of substances that had been evaluated for their skin sensitization potential under the EU REACH regulation, together with available measured LogKow values was compiled. 1482 substances were identified with skin sensitization data and measured LogKow values. 525 substances had a measured LogKow ≤ 1, 100 of those were sensitizers. There was no significant difference in the incidence of sensitizers above and below a LogKow of 1. Reaction chemistry principles that had been established for lower MW and more hydrophobic substances were found to be still valid in rationalizing the skin sensitizers with a LogKow ≤ 0. The LogKow threshold arises from the widespread misconception that the ability to efficiently penetrate the stratum corneum is a key determinant of sensitization potential and potency.

    2. Toxicity of single-wall carbon nanotubes functionalized with polyethylene glycol in zebrafish (Danio rerio) embryos

      Felipe A. Girardi, Gisele E. Bruch, Carolina S. Peixoto, Lidiane Dal Bosco, Sangram K. Sahoo, Carla O. F. Gonçalves, Adelina P. Santos, Clascídia A. Furtado, Cristiano Fantini and Daniela M. Barros

      Version of Record online: 20 JUN 2016 | DOI: 10.1002/jat.3346

      Individual zebrafish embryos were exposed to the single-wall carbon nanotubes functionalized with 2 kDa polyethylene glycol. The sample was characterized by transmission electron microscopy, thermogravimetric analysis and Raman spectroscopy. The results demonstrate that single-wall carbon nanotube–polyethylene glycol have low toxicity in zebrafish embryos and were unable to reach the internal tissues of the animals. The presence of residual metals is possibly among the primary mechanisms responsible for the toxic effects observed.

    3. Cytotoxic effects of psychotropic benzofuran derivatives, N-methyl-5-(2-aminopropyl)benzofuran and its N-demethylated derivative, on isolated rat hepatocytes

      Yoshio Nakagawa, Toshinari Suzuki, Yukie Tada and Akiko Inomata

      Version of Record online: 13 JUN 2016 | DOI: 10.1002/jat.3351

      The novel psychoactive compounds derived from amphetamine have been illegally abused as recreational drugs, some of which are known to be hepatotoxic in humans and experimental animals. The cytotoxic effects and mechanisms of 5-(2-aminopropyl)benzofuran (5-APB) and N-methyl-5-(2-aminopropyl)benzofuran (5-MAPB), both of which are benzofuran analogues of amphetamine, and 3,4-methylenedioxy-N-methamphetamine (MDMA) were studied in freshly isolated rat hepatocytes. 5-MAPB caused not only concentration-dependent (0–4.0mM) and time-dependent (0–3 h) cell death accompanied by the depletion of cellular ATP and reduced glutathione and protein thiol levels, but also accumulation of oxidized glutathione. Of the other analogues examined at a concentration of 4mM, 5-MAPB/5-APB-induced cytotoxicity with the production of reactive oxygen species and loss of mitochondrial membrane potential was greater than that induced by MDMA.

    4. Detection of exposure effects of mixtures of heavy polycyclic aromatic hydrocarbons in zebrafish embryos

      Alejandro Barranco, Laura Escudero, Jon Sanz Landaluze and Sandra Rainieri

      Version of Record online: 10 JUN 2016 | DOI: 10.1002/jat.3353

      Our objective was to detect in a realistic and accurate manner the effects of mixtures of heavy polycyclic aromatic hydrocarbons (PAHs) in zebrafish embryos. Assays were performed in the darkness, supplementing the exposure solution with dimethyl sulfoxide and Tween 20. PAHs did not bioaccumulate in zebrafish embryos; however, genes were induced already after 6 h of exposure indicating that the exposure effects are due to PAH metabolites formed shortly after uptake. Benzo[k]fluoranthene was responsible for the induction of cyp1a1 in the mixture at low concentration, but not at the high concentration tested.

    5. What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut-off: An updated analysis

      Jeremy M. Fitzpatrick, David W. Roberts and Grace Patlewicz

      Version of Record online: 10 JUN 2016 | DOI: 10.1002/jat.3348

      This updated analysis systematically interrogated a large repository of sensitization information collected under the EU REACH regulation. A data set of 2904 substances that had been tested for skin sensitization, using guinea pigs and/or mice were collected. The data set contained 197 substances with a MW > 500; 33 of these were skin sensitizers. Metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitizers substantiated the original findings.

    6. Comparative oral dose toxicokinetics of sodium selenite and selenomethionine

      T. Zane Davis, Asheesh K. Tiwary, Bryan L. Stegelmeier, James A. Pfister, Kip E. Panter and Jeffery O. Hall

      Version of Record online: 10 JUN 2016 | DOI: 10.1002/jat.3350

      Selenium (Se) poisoning by different forms of Se occurs in the United States. However, the toxicokinetics of different selenocompounds after oral ingestion is not well documented. In this study the toxicokinetics of Se absorption, distribution and elimination were determined in serum and whole blood of lambs that were orally dosed with increasing doses of Se as sodium selenite (inorganic Se) or selenomethionine (SeMet, organic Se).

    7. You have full text access to this OnlineOpen article
      Does industry take the susceptible subpopulation of asthmatic individuals into consideration when setting derived no-effect levels?

      Mia K. V. Johansson, Gunnar Johanson, Mattias Öberg and Linda Schenk

      Version of Record online: 9 JUN 2016 | DOI: 10.1002/jat.3352

      We investigate the extent to which experimental observations on asthmatic subjects are taken into consideration by REACH registrants and determine whether asthmatics are provided adequate protection by the acute inhalation Derived No-Effect Levels. Of 114 studies concerning 14 substances fulfilling our inclusion criteria, 63 studies, involving nine substances, were cited by the REACH registrants. However, only 17 of the 114 studies, involving four substances, were regarded as key studies. Furthermore, many of the Derived No-Effect Levels were higher than Lowest- or No-Observed Adverse Effect Concentrations values from these studies.

  8. Review articles

    1. Pluripotent stem cells: An in vitro model for nanotoxicity assessments

      Harish K. Handral, Huei Jinn Tong, Intekhab Islam, Gopu Sriram, Vinicus Rosa and Tong Cao

      Version of Record online: 30 MAY 2016 | DOI: 10.1002/jat.3347

      Pluripotent stem cells (PSCs) are viable source of cells that are capable of developing into specialized cells of the human body. PSCs can be efficiently used to screen new biomaterials/drugs and are potential candidates for studying impairments of biophysical morphology at both the cellular and tissue levels during interactions with nanomaterials and for diagnosing toxicity. Three-dimensional in vitro models obtained using PSC-derived cells would provide a realistic, patient-specific platform for toxicity assessments and in drug screening applications. The current review focuses on PSCs as an alternative in vitro platform for assessing the hazardous effects of nanomaterials on health systems and highlights the importance of PSC-derived in vitro platforms.

  9. Research articles

    1. Development of the Larval Amphibian Growth and Development Assay: Effects of benzophenone-2 exposure in Xenopus laevis from embryo to juvenile

      Jonathan T. Haselman, Maki Sakurai, Naoko Watanabe, Yasushi Goto, Yuta Onishi, Yuki Ito, Yu Onoda, Patricia A. Kosian, Joseph J. Korte, Rodney D. Johnson, Taisen Iguchi and Sigmund J. Degitz

      Version of Record online: 30 MAY 2016 | DOI: 10.1002/jat.3336

      The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized chemical testing guideline used to generate apical effect data for ecological risk assessment. Benzophenone-2 (BP-2) was tested using the LAGDA by exposing Xenopus laevis embryos until two months post-metamorphosis. BP-2 caused thyroid gland pathology in larvae. Liver and kidney pathologies were present in exposed juveniles, likely due to accumulations of estrogen-responsive yolk proteins. All genetic males int the 3.0 and 6.0 mg l−1 treatments were sex-reversed phenotypic females.

    2. Preclinical safety study of a recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant

      Harm HogenEsch, Anisa Dunham, Elodie Burlet, Fangjia Lu, Yung-Yi C. Mosley and Garry Morefield

      Version of Record online: 30 MAY 2016 | DOI: 10.1002/jat.3349

      The safety and local reactogenicity of a recombinant vaccine against Streptococcus pyogenes formulated with aluminum hydroxide adjuvant was evaluated in preclinical studies. The vaccine did not cause clinical evidence of systemic toxicity in mice or rabbits. The concentrations of serum amyloid A and haptoglobin were significantly increased 1 day after injection of the vaccine in mice. Treatment-related pathology was limited to inflammation at the injection site and accumulation of adjuvant-containing macrophages in draining lymph nodes.

    3. Lithium limits trimethyltin-induced cytotoxicity and proinflammatory response in microglia without affecting the concurrent autophagy impairment

      Cinzia Fabrizi, Elena Pompili, Francesca Somma, Stefania De Vito, Viviana Ciraci, Marco Artico, Paola Lenzi, Francesco Fornai and Lorenzo Fumagalli

      Version of Record online: 25 MAY 2016 | DOI: 10.1002/jat.3344

      Trimethyltin (TMT) is a highly toxic molecule present as an environmental contaminant causing neurodegeneration particularly of the limbic systemboth in humans and in rodents. We recently described the occurrence of impairment in the late stages of autophagy in TMT-intoxicated astrocytes. Here we show that similarly to astrocytes also in microglia, TMT induces the precocious block of autophagy indicated by the accumulation of the autophagosome marker, microtubule associated protein light chain 3.

    4. Toxic effects of chemical dispersant Corexit 9500 on water flea Daphnia magna

      Kenji Toyota, Nicole A. McNabb, Demetri D. Spyropoulos, Taisen Iguchi and Satomi Kohno

      Version of Record online: 25 MAY 2016 | DOI: 10.1002/jat.3343

      To understand the toxic effects of chemical dispersant, Corexit 9500, on freshwater zooplankton, we conducted the acute and chronic toxicity tests using Daphnia magna. Our results indicate that it has toxic effects on daphnids, particularly during the neonatal developmental stage, which is consistent with marine zooplankton results. Therefore, our findings of its adverse effects on daphnids suggest that application of this type of chemical dispersant may have catastrophic impacts on freshwater ecosystems by disrupting the key food chain network.

    5. Cytotoxic and inflammatory responses of TiO2 nanoparticles on human peripheral blood mononuclear cells

      Supunsa Kongseng, Krongtong Yoovathaworn, Kanokpan Wongprasert, Rodjana Chunhabundit, Patinya Sukwong and Dakrong Pissuwan

      Version of Record online: 25 MAY 2016 | DOI: 10.1002/jat.3342

      The effect of commercial titanium dioxide nanoparticles (TiO2-NPs) on induction of cytotoxic effect in human peripheral blood mononuclear cells (PBMCs) was investigated in serum-free medium. We assessed how TiO2-NPs affect cell viability, cell apoptosis, reactive oxygen species production and proinflammatory cytokine secretion of PBMCs. Our results suggest that the used concentration of TiO2-NPs has a significant impact on toxic induction of PBMCs.

    6. Integrated approach to testing and assessment for predicting rodent genotoxic carcinogenicity

      Petko I. Petkov, Terry W. Schultz, E. Maria Donner, Masamitsu Honma, Takeshi Morita, Shuichi Hamada, Akihiro Wakata, Masayuki Mishima, Jiro Maniwa, Milen Todorov, Elena Kaloyanova, Stefan Kotov and Ovanes G. Mekenyan

      Version of Record online: 25 MAY 2016 | DOI: 10.1002/jat.3338

      The performance of an integrated approach to testing and assessment (IATA) is investigated, covering different genotoxic mechanisms causing cancer and to replicate measured carcinogenicity data included in a new consolidated database. The IATA is docked to the OECD Toolbox and uses measured data for different genotoxicity endpoints when available. Alternatively, the system automatically provides predictions from structure–activity relationship genotoxicity models. When assigned only within the models' domains, performance of the IATA was high, with sensitivity of 74% and specificity of 83%.

    7. Investigation on the mechanism of non-photocatalytically TiO2-induced reactive oxygen species and its significance on cell cycle and morphology

      Nirmal Kumar Gali, Zhi Ning, Walid Daoud and Peter Brimblecombe

      Version of Record online: 18 MAY 2016 | DOI: 10.1002/jat.3341

      Titanium dioxide nanoparticles are widely used in daily activities of human life. However its toxic effects are not fully understood. In this study, a new mechanism of TiO2 catalytic action was discussed to understand its long-term cytotoxic effects, where cytoskeletal rearrangement was hypothesized to be induced by particle mediated-cellular ROS. The study was further extended in identifying dissolved oxygen as the driving agent in TiO2 catalytic activity in dark environment.

    8. Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment

      Xiaoqing Guo, Melanie Dumas, Bonnie L. Robinson, Syed F. Ali, Merle G. Paule, Qiang Gu and Jyotshna Kanungo

      Version of Record online: 18 MAY 2016 | DOI: 10.1002/jat.3340

      Acetyl l-carnitine prevents toxicities induced by ketamine and verapamil in the zebrafish embryos. In vivo assessment using various inhibitors of specific signaling pathways indicates that adenosine triphosphate synthase mediates acetyl L-carnitine's effects and potentially acts downstream of Ca2+ as an effector molecule in reversing adverse effects induced by ketamine and verapamil, alone or in combination, on the overall development and heart rate.

    9. Dibutyltin-induced alterations of interleukin 1beta secretion from human immune cells

      Shyretha Brown, Shahin Tehrani and Margaret M. Whalen

      Version of Record online: 17 MAY 2016 | DOI: 10.1002/jat.3339

      This study reveals that exposures to DBT (24 h, 48 h, and 6 day) modify the secretion of IL-1β from increasingly reconstituted preparations of human immune cells (highly enriched human natural killer (NK) cells, monocyte-depleted (MD) peripheral blood mononuclear cells (MD-PBMCs), PBMCs, granulocytes, and a preparation combining both PBMCs and granulocytes (PBMCs+granulocytes)). DBT altered IL-1β secretion from all cell preparations. Higher concentrations of DBT (5 and 2.5 μM) decreased the secretion of IL-1β, while lower concentrations of DBT (0.1 and 0.05 μM) increased the secretion of IL-1β. Selected signaling pathways were examined in MD-PBMCs to determine if they play a role in DBT-induced elevations of IL-1β secretion.

  10. Hypothesis reviews

    1. Revision of the affinity constant for perchlorate binding to the sodium-iodide symporter based on in vitro and human in vivo data

      Paul M. Schlosser

      Version of Record online: 13 MAY 2016 | DOI: 10.1002/jat.3337

      Short abstract

      Published physiologically based pharmacokinetic models describe inhibition of thyroidal iodide uptake by perchlorate, via competitive inhibition of the sodium-iodide symporter (NIS). A key parameter is the affinity (1/Km) of perchlorate for the NIS. However, the models underpredicted human radio-iodide uptake inhibition data at ≥20 μg kg−1 day−1 perchlorate. Re-analysis of published in vitro data for perchlorate-induced NIS inhibition yielded a 60% lower Km (higher affinity). The revised Km significantly improved the physiologically based pharmacokinetic model agreement with human radio-iodide uptake inhibition data.

  11. Research articles

    1. Non-clinical safety assessment of single and repeated administration of gE/AS01 zoster vaccine in rabbits

      Giulia Giordano, Lawrence Segal, Menk Prinsen, Marcel V. W. Wijnands, Nathalie Garçon and Eric Destexhe

      Version of Record online: 12 MAY 2016 | DOI: 10.1002/jat.3329

      HZ/su is an investigational recombinant subunit vaccine for the prevention of shingles, a disease resulting from reactivation of the varicella zoster virus. The vaccine is composed of recombinant varicella zoster virus glycoprotein E (gE), and liposome-based adjuvant system AS01. We evaluated the potential local and systemic effects of this vaccine in rabbits and observed that single and repeated SC and IM administration of the gE/AS01 vaccine were locally and systemically well-tolerated, which support the clinical development of the vaccine.

    2. 4-Nitrophenol exposure alters the AhR signaling pathway and related gene expression in the rat liver

      Ruonan Li, Meiyan Song, Zhi Li, Yansen Li, Gen Watanabe, Kentaro Nagaoka, Kazuyoshi Taya and Chunmei Li

      Version of Record online: 12 MAY 2016 | DOI: 10.1002/jat.3332

      4-Nitrophenol (PNP) is an environmental endocrine disruptor. The aim of this study was to clarify the mechanism of PNP-induced liver damage. 28-day-old male Wistar-Imamichi rats were randomly divided into control (vehicle) and PNP (200 mg·body-1 weight) groups, which consisted of 1- and 3-day exposure (1 DE and 3 DE, respectively) and 3-day exposure followed by 3-day recovery (3 DE + 3 DR), groups. The body and liver weight were significantly decreased in the 3 DE group. The mRNA expression levels of estrogen receptor-α (ERα), glutathione S-transferase (GST), and aryl hydrocarbon receptor (AhR) exhibited a significant increase in the 1 DE group while cytochrome P450 (CYP) 1A1 decreased significantly in the 3 DE +3 DR group. AhR and CYP1A1 proteins were detected in the cytoplasm of hepatocytes of the 1 DE and 3 DE +3 DR groups while the ERα protein was found in the hepatocyte nuclei of the 1 DE and 3 DE groups. The present study demonstrates that PNP activated the AhR signaling pathway and regulated related CYP1A1 and GST gene expression in the liver.

    3. Lack of genotoxic mechanisms in early-stage furan-induced hepatocellular tumorigenesis in gpt delta rats

      Daisuke Hibi, Yu Yokoo, Yuta Suzuki, Yuji Ishii, Meilan Jin, Aki Kijima, Takehiko Nohmi, Akiyoshi Nishikawa and Takashi Umemura

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/jat.3331

      Furan is shown to contaminate various foods and hepatocarcinogen in rodents. To elucidate furan-induced hepatocarcinogenic mechanisms, comprehensive medium-term analysis was conducted using gpt delta rats treated with furan at carcinogenic doses for 13 weeks. The reporter gene mutant frequencies in the liver were significantly increased. But, the number and area of glutathione S-transferase placental form-positive foci, and cell proliferation activity were significantly increased. Thus, it is highly probable that cell proliferation, but not genotoxic mechanisms, contribute to early-stage furan-induced hepatocarcinogenesis.

    4. Development of the Larval Amphibian Growth and Development Assay: effects of chronic 4-tert-octylphenol or 17β-trenbolone exposure in Xenopus laevis from embryo to juvenile

      Jonathan T. Haselman, Patricia A. Kosian, Joseph J. Korte, Allen W. Olmstead, Taisen Iguchi, Rodney D. Johnson and Sigmund J. Degitz

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/jat.3330

      The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized test guideline designed to evaluate apical effects of chronic chemical exposure with emphasis on endocrine disruption. Xenoestrogen, 4-tert-octylphenol, and xenoandrogen, 17β-trenbolone, were tested to evaluate the performance of the assay. Chemical-specific effects on thyroid homeostasis and reproductive development were identified. Notably, Müllerian duct development was the most sensitive endpoint affected by both chemicals. The LAGDA performed adequately to evaluate apical effects of chronic exposure to two endocrine-active compounds.

    5. Characterization of three human cell line models for high-throughput neuronal cytotoxicity screening

      Zhi-Bin Tong, Helena Hogberg, David Kuo, Srilatha Sakamuru, Menghang Xia, Lena Smirnova, Thomas Hartung and David Gerhold

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/jat.3334

      Three human neuronal cell lines were evaluated as high throughput screening models for neuronal cytotoxicity: SH-SY5Y neuroblastoma cells, LUHMES conditionally-immortalized dopaminergic neurons, and Neural Stem Cells. After 7 days of differentiation, LUHMES expressed the highest levels of neuronal markers. Differentiated LUHMES cells exhibited greater cytotoxic sensitivity to most of 32 suspected or known neurotoxicants than differentiated SH-SY5Y or NSCs, and greater cytotoxic sensitivity to 11 compounds compared to undifferentiated LUHMES cells.

    6. Regucalcin counteracts tert-butyl hydroperoxide and cadmium-induced oxidative stress in rat testis

      Sara Correia, Cátia V. Vaz, Ana M. S. Silva, José E. Cavaco and Sílvia Socorro

      Version of Record online: 25 APR 2016 | DOI: 10.1002/jat.3333

      To analyze the role of regucalcin (RGN)-modulating testicular oxidative stress, seminiferous tubules (SeT) from transgenic rats overexpressing RGN (Tg-RGN) and wild-type (WT) controls were cultured ex vivo in the presence/absence of pro-oxidant stimuli, tert-butyl hydroperoxide and cadmium chloride. The SeT of Tg-RGN animals displayed lower levels of oxidative stress and increased antioxidant defenses, underpinned by diminished rates of apoptosis. These findings support the antioxidant role of RGN in spermatogenesis.

    7. Biodistribution of polyacrylic acid-coated iron oxide nanoparticles is associated with proinflammatory activation and liver toxicity

      Diana Couto, Marisa Freitas, Vera Marisa Costa, Renan Campos Chisté, Agostinho Almeida, M. Arturo Lopez-Quintela, José Rivas, Paulo Freitas, Paula Silva, Félix Carvalho and Eduarda Fernandes

      Version of Record online: 22 APR 2016 | DOI: 10.1002/jat.3323

      Iron oxide nanoparticles (IONs) have physical and chemical properties that render them useful for several new biomedical applications. Still, so far, in vivo safety studies of IONs with coatings of biomedical interest are still scarce. The aimof this study, therefore, was to clarify the acute biological effects of polyacrylic acid (PAA)-coated IONs, by determining their biodistribution and their potential proinflammatory and toxic effects in CD-1 mice.

    8. Neuroglial alterations in the zebrafish brain exposed to cadmium chloride

      Antonio Monaco, Maria C. Grimaldi and Ida Ferrandino

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3328

      The effects of cadmium chloride on zebrafish brain were analysed by detecting the GFAP expression and mRNA levels of mbp, mpz and plp1 in specimens exposed to cadmium for 2, 7 and 16 days. A significant decrease in GFAP protein was observed already after 2 days reaching 50% after 16 days. This reduction was observed around ventricle areas and at the pial surface. Alterations in myelin were observed with upregulation of mpz mRNA levels. These data confirm the neurotoxic action of cadmium.

    9. Impact of silver nanoparticles on marine diatom Skeletonema costatum

      Jun Huang, Jinping Cheng and Jun Yi

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3325

      Exposure to AgNPs induces excess intracellular reactive oxygen species, reduces chlorophyll a content and cell viability, inhibits the conversion of light energy into photosynthetic electron transport, and down-regulate the expression of the genes of the photosystem II reaction center protein in the exposed marine diatom. Scanning electron microscopy observation reveals that AgNPs obstruct the light absorption of algae. This study implies AgNPs might have serious consequences on the succession of the phytoplankton communities and aquatic ecosystem equilibrium.

    10. Accounting for data variability, a key factor in in vivo/in vitro relationships: application to the skin sensitization potency (in vivo LLNA versus in vitro DPRA) example

      S. Dimitrov, A. Detroyer, C. Piroird, C. Gomes, J. Eilstein, T. Pauloin, C. Kuseva, H. Ivanova, I. Popova, Y. Karakolev, S. Ringeissen and O. Mekenyan

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3318

      A general methodology to analyze and integrate data variability when rescaling from one test to another is proposed. The methodology is demonstrated through the case study of rescaling in vitro DPRA reactivity to the in vivo LLNA skin sensitization potency classifications. A comprehensive statistical analysis evaluating the reliability and variability of LLNA and DPRA data a concept of grey zones around the thresholds and confidence probability have been introduced. The presented methodology is not restricted to skin sensitization only.

    11. A 28-year observational study of urinary cadmium and β2-microglobulin concentrations in inhabitants in cadmium-polluted areas in Japan

      Hoang Duc Phuc, Teruhiko Kido, Ho Dung Manh, Le Thai Anh, Nguyen Thi Phuong Oanh, Rie Okamoto, Akie Ichimori, Kazuhiro Nogawa, Yasushi Suwazono and Hideaki Nakagawa

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3327

      A follow-up study was conducted over 28 years (1986–2014) to clarify the relationship between urinary cadmium (Cd) and β2-microglobulin (β2-MG) concentration in 28 inhabitants who lived in a previously Cd-polluted region in Japan. Urinary Cd concentration decreased by nearly half in both sexes between 1986 and 2008. However, it increased significantly from 2008 to 2014 in males. Urinary β2-MG concentrations tended to increase during the study. Age is more strongly associated with urinary β2-MG concentration than recent Cd body burden.

    12. Airborne nanoparticles (PM0.1) induce autophagic cell death of human neuronal cells

      Yu-Mi Jeon and Mi-Young Lee

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3324

      Exposure to airborne nanoparticles PM0.1 (<100 nm in diameter) resulted in cell viability decrease and oxidative DNA damage. PM0.1-induced autophagic cell death occurred with increase in the expression of autophagy-related proteins. Moreover, 14 proteins were significantly changed upon exposure to PM0.1. Taken together, PM0.1-induced oxidative stress via ROS generation might play a key role in autophagic cell death and differential protein expressions in SH-SY5Y cells.

    13. You have full text access to this OnlineOpen article
      MicroRNA profiles in a monkey testicular injury model induced by testicular hyperthermia

      Ken Sakurai, Kei Mikamoto, Makoto Shirai, Takuma Iguchi, Kazumi Ito, Wataru Takasaki and Kazuhiko Mori

      Version of Record online: 12 APR 2016 | DOI: 10.1002/jat.3326

      In this study, we identified 4 testicular-specific miRNAs, miR-34c-5p, miR-202-5p, miR-449a, and miR-508-3p based on next-generation sequencing of miRNAs from representative organs obtained from naïve mature cynomolgus monkeys. Next, miRNAs were profiled in a model of testicular injury induced by testicular hyperthermia. Microarray and PCR analyses revealed down-regulation of miR-34c-5p in the testis, which is enriched in meiotic cells, reflecting decreased numbers of pachytene spermatocytes and spermatids by the treatment.

    14. Accessing the molecular interactions of phthalates and their primary metabolites with the human pregnane X receptor using in silico profiling

      M. K. Sarath Josh, S. Pradeep, Aparna K. Balan, M. N. Sreejith and Sailas Benjamin

      Version of Record online: 12 APR 2016 | DOI: 10.1002/jat.3321

      This molecular docking study using Glide evaluates a variety of molecular interactions of 12 commonly used diphthalates (generally reported as hazardous) and respective monophthalates with the ligand binding domain of the human pregnane X receptor (hPXR). Diisodecyl phthalate showed more affinity towards hPXR; whereas diisononyl phthalate and di(2-ethyhexyl)phthalate, the predominant plasticizers found in a variety of plastics and allied products, showed moderate binding. A higher affinity of certain phthalates to hPXR than its natural ligands and BPA (a proven endocrine disruptor) is alarming.

    15. Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

      Yun Zhang, Hongli Guo, Hozeifa M. Hassan, Ping-ping Ding, Yijing Su, Yuming Song, Tao Wang, Lixin Sun, Luyong Zhang and Zhenzhou Jiang

      Version of Record online: 12 APR 2016 | DOI: 10.1002/jat.3319

      In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L-Fabp, Lpl, Cpt-1b, Acaa1, Apo-A1 and Me1 in this process. We found PZA induced the liver lipid metabolismdisorder and PPARα expression was down-regulated which had a significant inverse correlation with liver injury degree.

    16. Polymatin A from Smallanthus macroscyphus leaves: A safe and promising antidiabetic compound

      Carolina Serra-Barcellona, Stella M Honoré, Wilfredo M Cabrera, Natalia C Habib, Susana B Genta and Sara S Sánchez

      Version of Record online: 7 APR 2016 | DOI: 10.1002/jat.3312

      Smallanthus macroscyphus is an herb native to South America whose leaves are a source of anti-diabetic compounds, although complete information about their safe use is not available yet. This study was developed to evaluate the toxicity profile of both 10% decoction and the sesquiterpene lactone polymatin A from S. macroscyphus leaves through in vitro cytotoxicity assays and in vivo subchronic oral toxicity.

    17. Perfluorooctane sulfonate (PFOS) impairs the proliferation of C17.2 neural stem cells via the downregulation of GSK-3β/β-catenin signaling

      Xuan Dong, Jianbin Yang, Xiaoke Nie, Jing Xiao and Shengyang Jiang

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/jat.3320

      PFOS has been recently documented to cause significant adverse effects on nervous system. We herein reported that PFOS exposure led to the downregulation of GSK-3β/β-catenin in C17.2 neural stem cells at a dose range of 25-200 nM, which is correlated with impaired proliferation of C17.2 cells. Our findings may help gain a better insight into the molecular mechanisms underlying PFOS-induced neurological deficits.

    18. Arsenic inhibits mast cell degranulation via suppression of early tyrosine phosphorylation events

      Juyoung Shim, Rachel H. Kennedy, Lisa M. Weatherly, Lee M. Hutchinson, Jonathan H. Pelletier, Hina N. Hashmi, Kayla Blais, Alejandro Velez and Julie A. Gosse

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/jat.3300

      Arsenite inhibits IgE-mediated degranulation of RBL-2H3 mast cells. Mast cells serve vital roles in many physiological processes and diseases. Upon activation, mast cells secrete mediators from cytoplasmic granules, in degranulation. Here, we report that arsenic does not affect degranulation stimulated by Ca2+ ionophore A23187, thapsigargin, or the G-protein activator compound 48/80, all of which bypass early signaling events. However, arsenic inhibits the Ca2+ influx into antigen-activated mast cells. Syk and phosphoinositide 3-kinase enzyme-linked immunosorbent assay data show that arsenic inhibits early phosphorylation events.

    19. Danio rerio ABC transporter genes abcb3 and abcb7 play a protecting role against metal contamination

      Adélaïde Lerebours, Van Vinh To and Jean-Paul Bourdineaud

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/jat.3313

      The involvement of two zebrafish ABC transporters in cadmium, zinc and mercury detoxification was characterized in a metal hypersensitive mutant of Escherichia coli. The E. coli tolC mutant expressing ABCB3 or ABCB7 transporters exhibited higher survival ratios and lower metal accumulation under a metal exposure condition than the controls.

  12. Short communications

    1. Triclosan is a mitochondrial uncoupler in live zebrafish

      Juyoung Shim, Lisa M. Weatherly, Richard H. Luc, Maxwell T. Dorman, Andy Neilson, Ryan Ng, Carol H. Kim, Paul J. Millard and Julie A. Gosse

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/jat.3311

      Antimicrobial agent triclosan (TCS) is a mitochondrial uncoupler in multiple cell types. Here, we present data, obtained with a Seahorse Bioscience XFe 96 Extracellular Flux Analyzer, indicating that TCS is also a mitochondrial uncoupler in living zebrafish [24 hour post-fertilization (hpf); 1 embryo per well]. TCS increases the oxygen consumption rate and proton leak and decreases ATP-linked respiration and spare respiratory capacity without affecting survival or heartbeat rate. These data indicate, for the first time, that TCS is a mitochondrial uncoupler in vivo.

  13. Research articles

    1. The neurotoxicity of DE-71: effects on neural development and impairment of serotonergic signaling in zebrafish larvae

      Xianfeng Wang, Lihua Yang, Qiangwei Wang, Yongyong Guo, Na Li, Mei Ma and Bingsheng Zhou

      Version of Record online: 22 MAR 2016 | DOI: 10.1002/jat.3322

      Polybrominated diphenyl ethers have been proven to damage the central nervous system and affect neurobehavior in animals, but the underlying mechanism is still not clear. In our study, it was suggested that DE-71 exposure could cause impairment of the neural development and secondary effects on serotonergic system, and these lesions might be involved in the altered locomotor behavior in zebrafish larvae.

    2. Let-7a modulates particulate matter (≤ 2.5 μm)-induced oxidative stress and injury in human airway epithelial cells by targeting arginase 2

      Lei Song, Dan Li, Yue Gu, Xiaoping Li and Liping Peng

      Version of Record online: 15 MAR 2016 | DOI: 10.1002/jat.3309


      Let-7a level was decreased in B2B cells after particulate matter (≤ 2.5 μm; PM2.5) exposure. Overexpression of let-7a decreased intracellular reactive oxygen species levels and the percentage of apoptotic cells after PM2.5 exposure. Arginase 2 (ARG2) was identified as a direct target of let-7a. Knockdown of ARG2 remarkably reduced oxidative stress and cellular injury. Restoration of ARG2 abrogated the protective effects of let-7a against PM2.5-induced injury. These data suggested that let-7a modulated PM2.5-induced oxidative stress and injury in human airway epithelial cells by targeting ARG2. The let-7a/ARG2 axis could be a therapeutic target for PM2.5-induced airway epithelial injury.

    3. Different mechanisms of action of 2, 2’, 4, 4’-tetrabromodiphenyl ether (BDE-47) and its metabolites (5-OH-BDE-47 and 6-OH-BDE-47) on cell proliferation in OVCAR-3 ovarian cancer cells and MCF-7 breast cancer cells

      Anna Karpeta, Anna Maniecka and Ewa Łucja Gregoraszczuk

      Version of Record online: 14 MAR 2016 | DOI: 10.1002/jat.3316

      In present study, we investigated the influence of BDE-47 and its metabolites on proliferation in OVCAR-3 ovarian and MCF-7 breast cancer cells by examining their effects on cell-cycle regulation, oestrogen receptors expression and activation of ERK1/2 and PKCα phosphorylation. The results clearly show a tissue-dependent mechanism of BDE-47 action. BDE-47 increased cell-cycle genes and proteins expression in OVCAR-3, but not in MCF-7 cells. Hydroxylated metabolites in both cell lines acted on ERs expression and ERK1/2 and PKCα phosphorylation.

    4. 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure influence the expression of glutamate transporter GLT-1 in C6 glioma cells via the Ca2+/protein kinase C pathway

      Jianya Zhao, Yan Zhang, Jianmei Zhao, Cheng Wang, Jiamin Mao, Ting Li, Xiaoke Wang, Xiaoke Nie, Shengyang Jiang and Qiyun Wu

      Version of Record online: 14 MAR 2016 | DOI: 10.1002/jat.3294

      In this study, we investigated the role of TCDD in regulating the expression of glutamate transporter GLT-1 in astrocytes. TCDD, at concentrations of 0.1–100 nM, had no significantly harmful effect on the viability of C6 glioma cells. However, the expression of GLT-1 in C6 glioma cells was downregulated in a dose-and time-dependent manner. TCDD also caused activation of protein kinase C (PKC), as TCDD induced translocation of the PKC from the cytoplasmor perinuclear to the membrane.

    5. Neuropathy target esterase in mouse whole blood as a biomarker of exposure to neuropathic organophosphorus compounds

      Galina F. Makhaeva, Elena V. Rudakova, Larisa V. Sigolaeva, Ilya N. Kurochkin and Rudy J. Richardson

      Version of Record online: 11 MAR 2016 | DOI: 10.1002/jat.3305

      The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organophosphorus compound-induced delayed neurotoxicity (OPIDN). Recently, we developed a mouse model for the biochemical assessment of the neuropathic potential of OP compounds based on brain neuropathy target esterase (NTE) and acetylcholinesterase (AChE) inhibition. The present work represents further development of the mouse model aimed at using whole blood NTE as a biomarker of exposure to neuropathic OP compounds and predicting OPIDN risk in susceptible species by comparing blood NTE and AChE inhibition.

    6. Silver nanoparticles induce pro-inflammatory gene expression and inflammasome activation in human monocytes

      A. Murphy, A. Casey, G. Byrne, G. Chambers and O. Howe

      Version of Record online: 10 MAR 2016 | DOI: 10.1002/jat.3315

      As a result of the increasing incidence of silver nanoparticle (AgNP) exposure, it is vital to determine their effect on the immune response. This study clearly demonstrates proinflammatory cytokine up-regulation after AgNP exposure to both a THP-1 monocyte cell line and primary human monocytes and the synergistic effect of combined exposure to AgNP and LPS. In addition, the release of IL-1β by THP-1 cells indicates inflammasome involvement. These results demonstrate the important immunological influence of AgNP.

    7. You have full text access to this OnlineOpen article
      Optimization of an air–liquid interface exposure system for assessing toxicity of airborne nanoparticles

      Siiri Latvala, Jonas Hedberg, Lennart Möller, Inger Odnevall Wallinder, Hanna L. Karlsson and Karine Elihn

      Version of Record online: 3 MAR 2016 | DOI: 10.1002/jat.3304

      An electrostatic airliquid interface exposure system was developed to assess the effects of pulmonary exposure to airborne nanoparticles. An applied electrostatic field strength and aerosol flow rate can be adjusted for achieving different particle doses. The highest amount of deposited particles was 2.2 μg cm2. Silver nanoparticles were found to cause cytotoxicity after 2 h exposure to 0.45 and 0.74 μg(Ag+)/cm2.

    8. Evaluation of the effects of deltamethrin on the fetal rat testis

      Anne-Marie Saillenfait, Dieynaba Ndiaye, Jean-Philippe Sabaté, Flavien Denis, Guillaume Antoine, Alain Robert, Virginie Rouiller-Fabre and Delphine Moison

      Version of Record online: 2 MAR 2016 | DOI: 10.1002/jat.3310

      Pregnant Sprague–Dawley rats were administered deltamethrin, at a broad range of doses (0.1–10 mg kg−1 day−1), or di-n-hexyl phthalate (250 mg kg−1 day−1), by gavage, from gestational day 13 to 19. Unlike di-n-hexyl phthalate, deltamethrin had no significant effect on ex vivo testosterone production by gestational day 19.5 fetal testis or on the expression of several genes and proteins involved in the steroid synthesis pathway (SRB1, StAR, P450scc, 3βHSD, P450c17 and/or 17βHSD), up to the maternal toxic dose of 10 mg kg−1 day−1.

    9. Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice

      Laura K. Schnackenberg, Lisa Pence, Vikrant Vijay, Carrie L. Moland, Nysia George, Zhijun Cao, Li-Rong Yu, James C. Fuscoe, Richard D. Beger and Varsha G. Desai

      Version of Record online: 2 MAR 2016 | DOI: 10.1002/jat.3307

      Metabolomics analyses of plasma and heart tissue from male B6C3F1 mice dosed weekly with 3 mg kg−1 doxorubicin or saline for 2, 3, 4, 6 or 8 weeks (cumulative doses of 6, 9, 12, 18 and 24 mg kg−1, respectively) identified potential early stage injury biomarkers of doxorubicin-induced cardiotoxicity. Select metabolites were altered after the 6 mg kg−1 cumulative dose whereas myocardial injury and cardiac pathology were not noted until after the 18 and 24 mg kg−1 cumulative doses, respectively.

    10. Involvement of calcium/calmodulin-dependent protein kinase II in methamphetamine-induced neural damage

      Xufeng Chen, Jingjing Xing, Lei Jiang, Wenyi Qian, Yixin Wang, Hao Sun, Yu Wang, Hang Xiao, Jun Wang and Jinsong Zhang

      Version of Record online: 29 FEB 2016 | DOI: 10.1002/jat.3301

      Mounting evidence shows that METH exposure contributes to neurotoxicity, especially for the monoaminergic neurons. However, only a few studies have tried to unravel the mechanisms involved in METH-induced non-monoaminergic neural damage. Therefore, in the present study, we tried to explore the mechanisms for METH-induced neural damage in cortical neurons. Our results showed that METH significantly increased intracellular [Ca2+]i and up-regulated calmodulin (CaM) expression and activated calmodulin-dependent protein kinase II (CaMK II). Noteworthily, METH-induced neural damage can be partially retarded by CaM antagonist W7, CaMK II blocker KN93 and L-type Ca2+ channel specific inhibitor nifedipine. Collectively, our results suggest that Ca2+-CaM-CaMKII is involved in METH-mediated neurotoxicity, and it might suggest a potential target for the development of therapeutic strategies for METH abuse.

    11. Oxidative stress and lung pathology following geogenic dust exposure

      M. Leetham, J. DeWitt, B. Buck, D. Goossens, Y. Teng, J. Pollard, B. McLaurin, R. Gerads and D. Keil

      Version of Record online: 29 FEB 2016 | DOI: 10.1002/jat.3297

      This study was designed to evaluate markers of systemic oxidative stress and lung histopathology following subacute exposure to geogenic dust with varying heavy metal content collected from a natural setting prone to wind erosion and used heavily for off-road vehicle recreation.

    12. Low-dose benzo[a]pyrene aggravates allergic airway inflammation in mice

      Rie Yanagisawa, Eiko Koike, Tin-Tin Win-Shwe, Takamichi Ichinose and Hirohisa Takano

      Version of Record online: 25 FEB 2016 | DOI: 10.1002/jat.3308

      We examined to determine the effects of low dose BaP intratracheal administration on allergic airway inflammation and mediastinal lymph node (MLN) cell activation/proliferation in male C3H/HeJ mice. This study revealed that real-world exposure levels of BaP can, at least in part, enhance allergic airway inflammation by facilitating Th2 responses and activating MLN cells. In addition, high dose of BaP may contribute in activating both Th1 and Th2 responses.

    13. Differential cytotoxicity of copper ferrite nanoparticles in different human cells

      Javed Ahmad, Hisham A. Alhadlaq, Aws Alshamsan, Maqsood A. Siddiqui, Quaiser Saquib, Shams T. Khan, Rizwan Wahab, Abdulaziz A. Al-Khedhairy, Javed Musarrat, Mohd Javed Akhtar and Maqusood Ahamed

      Version of Record online: 25 FEB 2016 | DOI: 10.1002/jat.3299

      Copper ferrite nanoparticles (NPs) have the potential to be applied in biomedical fields such as cell labeling and hyperthermia. However, there is a lack of information concerning the toxicity of copper ferrite NPs. We explored the cytotoxic potential of copper ferrite NPs in human lung (A549) and liver (HepG2) cells. Copper ferrite NPs were crystalline and almost spherically shaped with an average diameter of 35nm. Copper ferrite NPs induced dose-dependent cytotoxicity in both types of cells, evident by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide and neutral red uptake assays.

    14. Neverland regulates embryonic moltings through the regulation of ecdysteroid synthesis in the water flea Daphnia magna, and may thus act as a target for chemical disruption of molting

      Eri Sumiya, Yukiko Ogino, Kenji Toyota, Hitoshi Miyakawa, Shinichi Miyagawa and Taisen Iguchi

      Version of Record online: 22 FEB 2016 | DOI: 10.1002/jat.3306

      To understand the physiological roles of ecdysteroids in Daphnia magna embryos, we analyzed the genes for ecdysteroid synthesis or degradation. The innate ecdysteroids titer during the embryogenesis showed two peaks after which embryonic moltings occur. Expression of neverland1 and shade increased before the first peak. Knocking-down neverland1 or shade inhibited embryonic moltings. Neverland1-knowckdown embryos showed lowered ecdysteroids titer. In situ hybridization revealed neverland1 was expressed in embryonic gut epithelium suggesting the site for an initial step of ecdysteroid synthesis.

    15. Cytotoxicity of various chemicals and mycotoxins in fresh primary duck embryonic fibroblasts: a comparison to HepG2 cells

      Xi Chen, Rhonda Murdoch, Daniel J. Shafer, Kolapo M. Ajuwon and Todd J. Applegate

      Version of Record online: 18 FEB 2016 | DOI: 10.1002/jat.3298

      To cost-effectively screen the overall toxicity of a sample, especially in the case of food and feed ingredient quality control, a sensitive bioassay is necessary. Cell viability of fresh primary duck embryonic fibroblasts (DEF) in response to various chemicals and mycotoxins were determined. Results suggest that primary DEF are more sensitive to cytotoxins and mycotoxins compared to HepG2, and has great potential as an effective tool for in vitro cytotoxicity assessment.

    16. Cannabis effects on driving longitudinal control with and without alcohol

      Rebecca L. Hartman, Timothy L. Brown, Gary Milavetz, Andrew Spurgin, Russell S. Pierce, David A. Gorelick, Gary Gaffney and Marilyn A. Huestis

      Version of Record online: 18 FEB 2016 | DOI: 10.1002/jat.3295

      Cannabis’ effects with/without alcohol on driving longitudinal control were evaluated against blood ∆9-tetrahydrocannabinol (THC) and breath alcohol concentrations (BrAC) in 18 drivers at the National Advanced Driving Simulator, University of Iowa. THC was associated with decreased speed, increased driving time >10% below the speed limit, and increased following distance during headway maintenance; BrAC, with increased standard deviation (SD) speed and increased time >10% above the speed limit. Cannabis’ association with slower driving and greater headway may suggest awareness of impairment, attempt to compensate.

    17. Quantitative evaluation of local pulmonary distribution of TiO2 in rats following single or multiple intratracheal administrations of TiO2 nanoparticles using X-ray fluorescence microscopy

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

      Version of Record online: 16 FEB 2016 | DOI: 10.1002/jat.3287

      We quantitatively evaluated the pulmonary microdistribution (per mesh: 100 μm × 100 μm) of TiO2 in lung sections from rats following one, two, three, or four doses of TiO2 NPs at a same total dosage of 10 mg kg−1 using X-ray fluorescence microscopy. The evidence suggests that multiple-dose administrations do not offer remarkable advantages over single-dose administration on the pulmonary NP microdistribution, although multiple-dose administrations may reduce the variations in TiO2 content for each lung lobe.

    18. Gene expression analyses of vitellogenin, choriogenin and estrogen receptor subtypes in the livers of male medaka (Oryzias latipes) exposed to equine estrogens

      Hiroshi Ishibashi, Masaya Uchida, Akiko Koyanagi, Yoshihiro Kagami, Teruhiko Kusano, Ayami Nakao, Ryoko Yamamoto, Nobuhiro Ichikawa, Nobuaki Tominaga, Yasuhiro Ishibashi and Koji Arizono

      Version of Record online: 11 FEB 2016 | DOI: 10.1002/jat.3292

      No comprehensive data are yet available regarding the estrogenic potentials and risks of equine estrogens to aquatic organisms. We carried out expression analyses on estrogen-responsive genes in the livers of male medaka (Oryzias latipes) that were exposed to the equine estrogens for 3 days. Our qRT-PCR analyses revealed that the expression levels of hepatic estrogen-responsive genes in male medaka responded to various types and concentrations of equine estrogens. This is the first report describing the comprehensive analyses of in vivo estrogenicity of the equine estrogens in male medaka.

    19. Gelucire and Gelucire-PEG400 formulations; tolerability in species used for non-clinical safety testing after oral (gavage) dosing

      Mikael Elander, Jette B. Boll, Anne S. Hojman and Allan D. Rasmussen

      Version of Record online: 5 FEB 2016 | DOI: 10.1002/jat.3296

      A series of oral tolerability studies were conducted with Gelucire and Gelucire:PEG400 formulations in rats, dogs and minipigs in order to determine tolerable daily dose volumes in these species. It was concluded that Gelucire:PEG400 (90:10) was tolerated in Beagle dogs when administered at 1 ml kg–1 once daily for 39 weeks, and 100% Gelucire was tolerated in the rat and the minipig when administered once daily at 5 ml kg–1 for 5 days.

    20. Nanosuspension formulations of poorly water-soluble compounds for intravenous administration in exploratory toxicity studies: in vitro and in vivo evaluation

      Hisako Fujimura, Takao Komasaka, Taizo Tomari, Yasunori Kitano and Kouji Takekawa

      Version of Record online: 5 FEB 2016 | DOI: 10.1002/jat.3280

      Nanosuspensions for intravenous injections were prepared using a mixer mill and zirconia beads with a vehicle of 2% (w/v) poloxamer 338, which was confirmed to induce no histamine release in dogs. Sterilized nanosuspensions were obtained by milling for 30 min, followed by autoclaving for 20 min at 121 °C and milling for 30 min (mill–autoclave–mill method). The enhancing effect of a nanosuspension on exposure in dogs and the versatility of the method were demonstrated.


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