Journal of Applied Toxicology

Cover image for Vol. 36 Issue 1

January 2016

Volume 36, Issue 1

Pages 1–174

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. Review articles
    4. Research articles
    1. Issue Information - TOC (pages 1–4)

      Article first published online: 27 NOV 2015 | DOI: 10.1002/jat.3235

  2. Review articles

    1. Top of page
    2. Issue Information
    3. Review articles
    4. Research articles
    1. Recent knowledge: Concepts of dermal absorption in relation to skin decontamination (pages 5–9)

      Christina Phuong and Howard I. Maibach

      Article first published online: 11 SEP 2015 | DOI: 10.1002/jat.3222

      Understanding mechanisms of skin decontamination is critical to protecting humans from percutaneous absorption of toxicants through stratum corneum. Here, highly varied literature is placed in a biological and clinical perspective regarding decontamination, focusing on dermal absorption. Stratum corneum structural heterogeneity results in unique substance partitioning characteristics. As such, attempts to model this behavior in alternative in vitro membranes prove difficult. Further, common decontamination methods are undergoing risk assessment. These recent findings update available knowledge regarding skin decontamination and its challenges.

  3. Research articles

    1. Top of page
    2. Issue Information
    3. Review articles
    4. Research articles
    1. Meloxicam inhibits fipronil-induced apoptosis via modulation of the oxidative stress and inflammatory response in SH-SY5Y cells (pages 10–23)

      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. Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism (pages 24–34)

      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. Establishment of a mouse model for amiodarone-induced liver injury and analyses of its hepatotoxic mechanism (pages 35–47)

      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.

    4. PM2.5-induced oxidative stress increases adhesion molecules expression in human endothelial cells through the ERK/AKT/NF-κB-dependent pathway (pages 48–59)

      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.

    5. Acrylamide induces locomotor defects and degeneration of dopamine neurons in Caenorhabditis elegans (pages 60–67)

      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.

    6. Microminipigs as a new experimental animal model for toxicological studies: comparative pharmacokinetics of perfluoroalkyl acids (pages 68–75)

      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.

    7. Preclinical safety evaluation of low molecular weight heparin–deoxycholate conjugates as an oral anticoagulant (pages 76–93)

      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.

    8. RNA sequencing provides insights into the toxicogenomic response of ZF4 cells to methyl methanesulfonate (pages 94–104)

      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.

    9. Augmenting effects of gestational arsenite exposure of C3H mice on the hepatic tumors of the F2 male offspring via the F1 male offspring (pages 105–112)

      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.

    10. Impaired aquaporins expression in the gastrointestinal tract of rat after mercury exposure (pages 113–120)

      Cinzia Bottino, Marta Vázquez, Vicenta Devesa and Umberto Laforenza

      Article first published online: 8 APR 2015 | DOI: 10.1002/jat.3151

      This study aims to evaluate the effects of mercury species exposure on aquaporin (AQP) expression in the gastrointestinal tract of rats treated during 4 days. Both HgCl2 and CH3HgCl reduced AQP expression in stomach, jejunum and colon. In particular, AQP3 and AQP4 are downregulated in stomach and AQP3 and AQP7 in jejunum and colon. This effect on AQP expression could be one of the causes of the gastrointestinal symptoms observed after mercury exposure (diarrhea, luminal water accumulation, fluid loss).

    11. In vitro neurotoxicity evaluation of piperazine designer drugs in differentiated human neuroblastoma SH-SY5Y cells (pages 121–130)

      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.

    12. Bisphenol A inhibits duodenal movement ex vivo of rat through nitric oxide-mediated soluble guanylyl cyclase and α-adrenergic signaling pathways (pages 131–139)

      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.

    13. Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ß-cyclodextrin causes renal toxicity (pages 140–150)

      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

      For pre-clinical testing, drugs are formulated in vehicles that achieve the best possible exposure. Availability of safety data on vehicles is often limited. Nineteen potentially useful vehicles, for which little safety data have been published, were tested in the rat (28 days). 30% (w/v) hydroxypropyl-ß-cyclodextrin was found unsuitable owing to effects on liver enzymes, urinary volume and the kidneys. Use of 20% (v/v) oleic acid (increased salivation) and 40% (v/v) tetraethylene glycol (changes in urinary parameters) should be carefully considered.

    14. Particulate matter phagocytosis induces tissue factor in differentiating macrophages (pages 151–160)

      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.

    15. 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 (pages 161–174)

      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.