Journal of Applied Toxicology

Cover image for Vol. 35 Issue 10

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

Editor-in-Chief: Philip W. Harvey

Impact Factor: 2.982

ISI Journal Citation Reports © Ranking: 2014: 27/87 (Toxicology)

Online ISSN: 1099-1263

  1. Research Articles

    1. Onset of hepatocarcinogen-specific cell proliferation and cell cycle aberration during the early stage of repeated hepatocarcinogen administration in rats

      Masayuki Kimura, Hajime Abe, Sayaka Mizukami, Takeshi Tanaka, Megu Itahashi, Nobuhiko Onda, Toshinori Yoshida and Makoto Shibutani

      Article first published online: 22 MAY 2015 | DOI: 10.1002/jat.3163

      This study aimed to determine the onset time of hepatocarcinogen-specific cellular responses. Rats were treated orally with hepatocarcinogens for 3, 7 or 28 days. For comparison, some animals were subjected to partial hepatectomy or treated with noncarcinogenic hepatotoxicants. Obtained results suggest that it may take 28 days to induce hepatocarcinogen-specific disruption of G1/S checkpoint function, early withdrawal of proliferating cells from M phase due to disruptive spindle checkpoint function and aberrant p21Cip1 activation to cause apoptosis reflecting DNA damage accumulation.

    2. RNA sequencing provides insights into the toxicogenomic response of ZF4 cells to methyl methanesulfonate

      Zhouquan Li, Yong Long, Liqiao Zhong, Guili Song, Xiaohua Zhang, Li Yuan, Zongbin Cui and Heping Dai

      Article first published online: 22 MAY 2015 | DOI: 10.1002/jat.3147

      RNA-seq identified 6,637 differentially expressed genes (DEGs). GO enrichment revealed that RNA-associated processes were the most up-regulated, while cell cycle and adhesion were the most repressed, neuron-related processes were the most down-regulated developmental process. KEGG pathway enrichment identified DNA damage repair, cell cycle, apoptosis and spliceosome overrepresented. There were 1,156 AS DEGs specifically expressed after MMS treatment, many of which belonged to metabolism and catabolic process. Cluster analysis of orthologs was able to extrapolate toxicotranscriptomics data between zebrafish and yeast.

    3. A method for estimating the glomerular filtration rate in conscious monkeys

      Hiroshi Satoh, Nana Nomiya, Daiki Imai, Shigeru Sato, Ken Sakurai, Kiyoshi Takasuna and Kazuhisa Furuhama

      Article first published online: 21 MAY 2015 | DOI: 10.1002/jat.3178

      To establish a method for estimating the GFR in monkeys, the radiographic contrast medium iodixanol was administered as tracers to monkeys as a bolus injection; blood was collected after 60, 90 and 120 min. An equation based on a single-blood-sample method derived from Jacobsson's formula was prepared using the data from healthy and gentamicin-treated monkeys by a multisample strategy with iodixanol. The GFR using the equation with iodixanol was in agreement with that from the multisample method with iodixanol.

    4. Developmental toxicity and endocrine disruption of naphthenic acids on the early life stage of zebrafish (Danio rerio)

      Jie Wang, Xiaofeng Cao, Yi Huang and Xiaoyan Tang

      Article first published online: 21 MAY 2015 | DOI: 10.1002/jat.3166

      Naphthenic acids (NAs) have been considered as the primary toxic components of oil sands process-affected water (OSPW). The developmental toxicity and endocrine disruption on the early life stage of zebrafish were investigated using oil sands NAs (OS-NAs) and commercial NAs (C-NAs). Both OS-NAs and C-NAs exposure resulted in a variety of developmental lesions in the fish larvae. Significant up-regulated gene expressions of CYP19b, ERα and VTG were observed in both OS-NAs and C-NAs groups, which indicated the deleteriously estrogenic potential of NAs.

    5. Directional and color preference in adult zebrafish: Implications in behavioral and learning assays in neurotoxicology studies

      Zachary A. Bault, Samuel M. Peterson and Jennifer L. Freeman

      Article first published online: 20 MAY 2015 | DOI: 10.1002/jat.3169

      While a number of zebrafish neurobehavioral assays are recently reported in the literature, many are still being refined. The initial purpose of this study was to apply a published T-maze assay for adult zebrafish that measures how quickly an organism can discriminate between different color stimuli after receiving reinforcement to measure learning in a study investigating the later life impacts of a developmental lead exposure. The original results were inconclusive as a directional and color preference was observed.

    6. You have free access to this content
      Effect-directed identification of endocrine disruptors in plastic baby teethers

      Elisabeth Berger, Theodoros Potouridis, Astrid Haeger, Wilhelm Püttmann and Martin Wagner

      Article first published online: 18 MAY 2015 | DOI: 10.1002/jat.3159

      We combined bioassays and chemical analysis to identify endocrine disrupting chemicals in plastic teethers for babies. One of the tested samples contained methyl-, ethyl- and propylparaben, another leached unidentified antiandrogens. This demonstrates that plastic teethers can be a source of infant exposure to endocrine disrupting chemicals.

    7. You have full text access to this OnlineOpen article
      Acute and subchronic toxicity of 20  kHz and 60  kHz magnetic fields in rats

      Izumi Nishimura, Atsushi Oshima, Kazumoto Shibuya, Takashi Mitani and Tadashi Negishi

      Article first published online: 17 MAY 2015 | DOI: 10.1002/jat.3161

      Despite increasing use of intermediate frequency (IF) magnetic fields (MFs) in occupational and domestic settings, scientific evidence is insufficient for IF MF health risk assessments. Rats were exposed to 20 kHz or 60 kHz sinusoidal MFs for 22 h day−1 for 14 days (acute) or 13 weeks (subchronic). MF-exposed rats did not exhibit significant and reproducible changes in body and organ weights, hematology, clinical chemistry and histopathology. Our results indicate that IF MF exposure does not carry a significant health risk to mammals.

    8. Silver nanoparticles affect the neural development of zebrafish embryos

      Qi Xin, Jeanette M. Rotchell, Jinping Cheng, Jun Yi and Qiang Zhang

      Article first published online: 15 MAY 2015 | DOI: 10.1002/jat.3164

      Silver nanoparticles (AgNPs) have been widely used in commercial products. This study aims to understand the impact of AgNPs on the early developmental stages in zebrafish (Danio rerio) embryos. Embryos were exposed to two sizes of AgNPs at three dose levels, as well to free Ag+ ions, for a range of 4–96 h post-fertilization (hpf)

    9. Toxicological effects of pet food ingredients on canine bone marrow-derived mesenchymal stem cells and enterocyte-like cells

      M. T. Ortega, B. Jeffery, J. E. Riviere and N. A. Monteiro-Riviere

      Article first published online: 14 MAY 2015 | DOI: 10.1002/jat.3158

      Short abstract

      Food ingredients clove leave oil, eugenol, guanosine monophosphate (GMP), GMP + inosine monophosphate, sorbose, ginger root extract, cinnamon bark oil, cinnamaldehyde, thyme oil, thymol, lemongrass oil and citric acid showed differential toxicity in canine bone marrow-derived mesenchymal stem cells, which differentiated into enterocyte-like cells in vitro. The most toxic ingredients were thymol, eugenol, cinnamon bark oil, cinnamaldehyde, clove leave oil and lemongrass oil (0.002–0.54 mg ml–1). GMP, GMP + inosine monophosphate and sorbose were the least toxic ingredients (56.8–116.7 mg ml–1).

    10. Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity

      Guy Healing, Tabassum Sulemann, Peter Cotton, Jayne Harris, Adam Hargreaves, Rowena Finney, Sarah Kirk, Carolin Schramm, Clare Garner, Perrine Pivette and Lisa Burdett

      Article first published online: 10 MAY 2015 | DOI: 10.1002/jat.3155

    11. Maternal exposure to hexachlorophene targets intermediate-stage progenitor cells in the hippocampal neurogenesis involving myelin vacuolation of cholinergic and glutamatergic inputs in mice

      Mizuho Kato, Hajime Abe, Megu Itahashi, Yoh Kikuchihara, Masayuki Kimura, Sayaka Mizukami, Toshinori Yoshida and Makoto Shibutani

      Article first published online: 5 MAY 2015 | DOI: 10.1002/jat.3162

      This study investigated the effect of maternal hexachlorophene exposure on hippocampal neurogenesis in mouse offspring. Pregnant mice were supplemented with hexachlorophene in diet during gestation and lactation. Offspring displayed reversible decrease of type 2 intermediate-stage progenitor cells in the subgranular zone. Myelin vacuolation might be responsible for changes in neurogenesis possibly by reducing nerve conduction velocity of cholinergic inputs from the septal–hippocampal pathway to granule cell lineages and/or GABAergic interneurons, and of glutamatergic inputs to granule cell lineages.

    12. mRNAs and miRNAs in whole blood associated with lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma after multi-walled carbon nanotube inhalation exposure in mice

      Brandi N. Snyder-Talkington, Chunlin Dong, Linda M. Sargent, Dale W. Porter, Lauren M. Staska, Ann F. Hubbs, Rebecca Raese, Walter McKinney, Bean T. Chen, Lori Battelli, David T. Lowry, Steven H. Reynolds, Vincent Castranova, Yong Qian and Nancy L. Guo

      Article first published online: 29 APR 2015 | DOI: 10.1002/jat.3157

      This study determined global mRNA and miRNA profiles in whole blood from mice exposed by inhalation to MWCNT that correlated with the presence of lung hyperplasia, fibrosis, and bronchiolo-alveolar adenoma and adenocarcinoma. At 17 months post-exposure, whole blood was collected and analyzed using microarray analysis for global mRNA and miRNA expression. The changes in miRNA and mRNA expression, and their respective regulatory networks, identified in this study may potentially serve as blood biomarkers for MWCNT-induced lung pathological changes.

    13. In vitro neurotoxicity evaluation of piperazine designer drugs in differentiated human neuroblastoma SH-SY5Y cells

      M. D. Arbo, R. Silva, D. J. Barbosa, D. Dias da Silva, S. P. Silva, J. P. Teixeira, M. L. Bastos and H. Carmo

      Article first published online: 20 APR 2015 | DOI: 10.1002/jat.3153

      Piperazine designer drugs act as substrates at dopaminergic and serotonergic receptors and/or transporters in the brain. This work aimed to investigate the cytotoxicity of N-benzylpiperazine, 1-(3-trifluoromethylphenyl)piperazine, 1-(4-methoxyphenyl)piperazine and 1-(3,4-methylenedioxybenzyl)piperazine in the differentiated human neuroblastoma SH-SY5Y cell line. Complete cytotoxicity curves were obtained after 24 h incubations with each drug. A significant decrease in intracellular total glutathione content was noted for the drugs. All drugs caused an increase of intracellular free Ca2+ levels, accompanied by mitochondrial hyperpolarization.

    14. Preclinical safety evaluation of low molecular weight heparin–deoxycholate conjugates as an oral anticoagulant

      Ji-young Kim, Ok-Cheol Jeon, Hyun Tae Moon, Seung Rim Hwang and Youngro Byun

      Article first published online: 20 APR 2015 | DOI: 10.1002/jat.3146

      The preclinical safety of an oral anticoagulant (OH09208) was assessed by a comprehensive evaluating program in compliance with standard guidelines. As a result, OH09208 demonstrated acceptable values in single dose acute toxicity studies in rats, repeat dose toxicity studies in rats and dogs, systemic anaphylaxis test, both in vitro and in vivo mutagenicity and genotoxicity studies, and safety pharmacology studies. Overall, there were no unexpected toxicities found in this study that might have precluded the safe administration of OH09208 to humans.

    15. Establishment of a mouse model for amiodarone-induced liver injury and analyses of its hepatotoxic mechanism

      Shohei Takai, Shingo Oda, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima and Tsuyoshi Yokoi

      Article first published online: 20 APR 2015 | DOI: 10.1002/jat.3141

      In this study, an in vivo mouse model of amiodarone-induced liver injury was developed with co-administration of dexamethasone and possible mechanisms were investigated. It was suggested that amiodarone and/or desethylamiodarone contribute to the pathogenesis of amiodarone-induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study provides a new perspective on drug-induced liver injury and is useful for achieving an in vivo hepatotoxicity assay in nonclinical drug development.

    16. Bisphenol A inhibits duodenal movement ex vivo of rat through nitric oxide-mediated soluble guanylyl cyclase and α-adrenergic signaling pathways

      Kaushik Sarkar, Panchali Tarafder and Goutam Paul

      Article first published online: 16 APR 2015 | DOI: 10.1002/jat.3154

      We report here the effect of bisphenol A (BPA) on the duodenal movement of the rat. We found significant depression of duodenal movement by BPA. Furthermore, we observed significant counteractions of BPA-induced inhibition by N-ω-nitro- L-arginine methyl ester (nitric oxide [NO] synthase inhibitor), methylene blue (soluble guanylyl cyclase blocker) and phentolamine (α-adrenergic receptor blocker). The results indicate that NO and norepinephrine secreting intrinsic neurons might be involved in BPA-induced changes. We may conclude that BPA inhibits the duodenal movement by promoting NO- and/or norepinephrine-mediated signaling mechanisms in duodenal smooth muscle cells.

    17. Microminipigs as a new experimental animal model for toxicological studies: comparative pharmacokinetics of perfluoroalkyl acids

      Keerthi S. Guruge, Michiko Noguchi, Koji Yoshioka, Eriko Yamazaki, Sachi Taniyasu, Miyako Yoshioka, Noriko Yamanaka, Mitsutaka Ikezawa, Nobuhiko Tanimura, Masumi Sato, Nobuyoshi Yamashita and Hiroaki Kawaguchi

      Article first published online: 15 APR 2015 | DOI: 10.1002/jat.3145

      A single oral dose of a mixture of 10 PFAAs was given to Microminipigs. The blood depuration half-lives of PFAAs ranged from 1.6 to 86.6 days. PFOS and other long-chain carboxyl acids remained in the tissues for a long period. Persistence of PFAAs in edible tissues raises concerns about the safety of swine products. MMPigs can be excellent novel experimental animals for toxicological studies.

    18. Acrylamide induces locomotor defects and degeneration of dopamine neurons in Caenorhabditis elegans

      Jia Li, Dan Li, Yongsheng Yang, Tiantian Xu, Ping Li and Defu He

      Article first published online: 15 APR 2015 | DOI: 10.1002/jat.3144

      In Caenorhabditis elegans, we showed that 48 h exposure to 10-625 mgl−1 acrylamide resulted in significant declines in locomotor behavior and decrease of crawling speeds and body bending angles, which indicated locomotor defects, along with Parkinsonian-like impairment. Acrylamide also affected chemotaxis plasticity and reduced learning ability. Moreover, acrylamide induced down-expression of Pdat-1 and enhanced expression of unc-54, which indicated degeneration of dopaminergic neurons and aggregation of α-synuclein. It suggests that the neurotoxicity of acrylamide is associated with Parkinson's disease.

    19. PM2.5-induced oxidative stress increases adhesion molecules expression in human endothelial cells through the ERK/AKT/NF-κB-dependent pathway

      Wei Rui, Longfei Guan, Fang Zhang, Wei Zhang and Wenjun Ding

      Article first published online: 15 APR 2015 | DOI: 10.1002/jat.3143

      We explored the underlying mechanisms of PM2.5-induced endothelial dysfucntion in EA.hy926 cells. PM2.5 exposure triggered reactive oxygen species (ROS) generation, phosphorylation of Jun N-terminal kinase (JNK), extracellular signal regulatory kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase B (AKT), activation of nuclear factor kappa B (NF-κB), and increase in expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) as well as adhesion of THP-1 cells. However, ERK, AKT and NF-κB inhibitors significantly down-regulated PM2.5-induced ICAM-1 and VCAM-1 expression, but not JNK inhibitor and p38 MAPK inhibitor. The results suggest that PM2.5-induced ROS trigger ICAM-1 and VCAM-1 expressions via activation of ERK/AKT/NF-κB pathway.

    20. Particulate matter phagocytosis induces tissue factor in differentiating macrophages

      M. Milano, P. Dongiovanni, A. Artoni, S. Gatti, L. Rosso, F. Colombo, V. Bollati, M. Maggioni, P. M. Mannucci, P. A. Bertazzi, S. Fargion and L. Valenti

      Article first published online: 8 APR 2015 | DOI: 10.1002/jat.3156

      Here we show that in human differentiating macrophages, particulate matter with diameter < 10 mcM (PM10) exposure induces tissue factor (TF) and a procoagulant phenotype. This process is dependent on phagocytosis and the activation of stress pathways, and is abolished in differentiated anti-inflammatory macrophages. In rats, alveolar exposure to PM10 causes the recruitment of inflammatory cells and results in local induction of TF, increasing circulating TF levels. TF induction by differentiating lung macrophages, activated following phagocytosis, contributes to the increased risk of thromboembolic complications associated with PM10 exposure.

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