Journal of Applied Toxicology

Cover image for Vol. 35 Issue 7

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

Editor-in-Chief: Philip W. Harvey

Impact Factor: 3.174

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

Online ISSN: 1099-1263

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  1. 1 - 74
  1. Research Articles

    1. Toxicogenomic responses of human liver HepG2 cells to silver nanoparticles

      Saura C. Sahu, Jiwen Zheng, Jeffrey J. Yourick, Robert L. Sprando and Xiugong Gao

      Article first published online: 26 MAY 2015 | DOI: 10.1002/jat.3170

      This study evaluated global gene expression profiles of human liver HepG2 cells exposed to silver nanoparticles (AgNPs). Exposure to 2.5 µg ml–1 20 nm AgNPs resulted in 811 altered genes after 4 h. Function and pathway analysis of the altered genes suggest that AgNP exposure may lead to increased oxidative stress and DNA damage in the cell and potentially result in genotoxicity and carcinogenicity.

    2. Short-term, low-dose cadmium exposure induces hyperpermeability in human renal glomerular endothelial cells

      Liqun Li, Fengyun Dong, Dongmei Xu, Linna Du, Suhua Yan, Hesheng Hu, Corrinne G. Lobe, Fan Yi, Carolyn M. Kapron and Ju Liu

      Article first published online: 25 MAY 2015 | DOI: 10.1002/jat.3168

      Cadmium enters the human body and circulates for a short period in the bloodstream. In this study, we found that short-term, low-dose cadmium exposure increases permeability without cytotoxic effects in human renal glomerular endothelial cells. The hyperpermeability might be caused by membrane dissociation of vascular endothelial cadherin and is partially mediated by p38 mitogen-activated protein kinase pathway.

    3. 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.

    4. 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.

    5. 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.

    6. 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.

    7. 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.

    8. 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.

    9. 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.

    10. 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)

    11. You have full text access to this OnlineOpen article
      Intracellular calcium levels as screening tool for nanoparticle toxicity

      Claudia Meindl, Tatjana Kueznik, Martina Bösch, Eva Roblegg and Eleonore Fröhlich

      Article first published online: 14 MAY 2015 | DOI: 10.1002/jat.3160

      Nano-sized materials may cause cytotoxicity. Negatively charged, neutral and positively charged polystyrene particles of different sizes and silica nanoparticles were used to study the role of size and surface properties on viability, membrane disruption, apoptosis, lysosome function, intracellular [Ca2+] levels and generation of oxidative stress. Small polystyrene particles and silica particles caused membrane damage and apoptosis with no preference of the surface charge. Increases in intracellular [Ca2+] levels could be used as a screening tool for cytotoxicity.

    12. 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).

    13. 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

    14. 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.

  2. Hypothesis Reviews

    1. You have full text access to this OnlineOpen article
      Adverse Outcome Pathways can drive non-animal approaches for safety assessment

      Natalie Burden, Fiona Sewell, Melvin E. Andersen, Alan Boobis, J. Kevin Chipman, Mark T. D. Cronin, Thomas H. Hutchinson, Ian Kimber and Maurice Whelan

      Article first published online: 5 MAY 2015 | DOI: 10.1002/jat.3165

      This article explores how the development and application of Adverse Outcome Pathways (AOPs) could benefit the science and practice of chemical safety assessment, with a particular focus on how their use in practice could reduce reliance on traditional animal toxicity tests. This includes discussion of the key areas where current and future initiatives should be focused to enable the translation of AOPs into routine chemical safety assessment, and lasting 3Rs benefits.

  3. Research Articles

    1. 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.

    2. 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.

    3. In vitro study of biocompatibility of a graphene composite with gold nanoparticles and hydroxyapatite on human osteoblasts

      Liana Crisan, Bogdan Crisan, Olga Soritau, Mihaela Baciut, Alexandru Radu Biris, Grigore Baciut and Ondine Lucaciu

      Article first published online: 20 APR 2015 | DOI: 10.1002/jat.3152

      The purpose of this study was to evaluate the biocompatibility of composites consisting of different proportions of graphene in combination with gold (Au) nanoparticles and nanostructured hydroxyapatite (HA) on osteoblasts. The cytocompatibility study was performed using the fluorescein diacetate assay. The most favorable composites for cell adhesion and proliferation were HA, Au/HA and Au/HA composites with 1.6% and 3.15% concentration of graphenes. The presence of graphene in the substrate composition induced an increased level of intracellular osteopontin and cytoskeleton reorganization.

    4. 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.

    5. 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.

    6. 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.

    7. The surfactant dipalmitoylphophatidylcholine modifies acute responses in alveolar carcinoma cells in response to low-dose silver nanoparticle exposure

      A. Murphy, K. Sheehy, A. Casey and G. Chambers

      Article first published online: 16 APR 2015 | DOI: 10.1002/jat.3148

      Inhalation presents as the most common route of silver nanoparticle (AgNP) exposure. As such, its interaction with pulmonary surfactant may influence the biological response induced. Toxicological testing was performed on the A549 cell line and it demonstrated toxicity induced by AgNP exposure. Significant changes in acute responses including reactive oxygen species generation and inflammatory marker release was noted. It is postulated that the presence of dipalmitoylphosphatidylcholine interacts with AgNP producing a more reactive particle resulting in modification of acute responses at low dose exposures

    8. 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.

    9. 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.

    10. 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.

    11. Aluminium oxide nanoparticles induced morphological changes, cytotoxicity and oxidative stress in Chinook salmon (CHSE-214) cells

      Koigoora Srikanth, Amit Mahajan, Eduarda Pereira, Armando Costa Duarte and Janapala Venkateswara Rao

      Article first published online: 15 APR 2015 | DOI: 10.1002/jat.3142

      Chinook salmon (CHSE-214) cells exposed to aluminium oxide nanoparticles (Al2O3 NPs) induced dose dependent cytotoxicity. Morphology of CHSE-214 cells exposed to Al2O3 NPs were altered at 6, 12 and 24 h of exposure time. Reduction of SOD, CAT and GSH activity followed by an increase in GST and LPO was evident in CHSE-214 cells exposed to Al2O3 NPs. Thus our current work may serve as a base line study for future evaluation of toxicity studies using CHSE-214 cells.

    12. 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.

    13. Impaired aquaporins expression in the gastrointestinal tract of rat after mercury exposure

      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).

    14. Co-treatment with the non-steroidal anti-androgen drug, flutamide and the natural estrogen, 17β-estradiol does not lead to additive reproductive impairment in juvenile Murray rainbowfish (Melanotaenia fluviatilis)

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

      Article first published online: 8 APR 2015 | DOI: 10.1002/jat.3135

      The aim of this study was to investigate if the anti-androgen, flutamide, and the estrogen, 17β-estradiol work together to feminize juvenile Murray rainbowfish (Melanotaenia fluviatilis). Fish (60 days post-hatch) were exposed to 25 ng/L 17β-estradiol (E2), 25 µg/L flutamide (Flu low), 250 µg/L flutamide (Flu high), E2+Flu low and E2+Flu high. After 35 days of exposure, concentrations of sex steroid hormones, 17β-estradiol and 11-keto testosterone (11-KT), were determined in the head; and vitellogenin (VTG) concentration was measured in the tail.

    15. Titanium dioxide nanoparticles increase plasma glucose via reactive oxygen species-induced insulin resistance in mice

      Hailong Hu, Qian Guo, Changlin Wang, Xiao Ma, Hongjuan He, Yuri Oh, Yujie Feng, Qiong Wu and Ning Gu

      Article first published online: 31 MAR 2015 | DOI: 10.1002/jat.3150

      We explored endocrine effects of oral administration to mice of anatase titanium dioxide (TiO2) nanoparticles. Titanium levels increased in the liver, spleen, small intestine, kidney, and pancreas. ROS levels increased in serum and liver. Biochemical analyses showed plasma glucose significantly increased while there was no difference in insulin secretion. The pathway was TiO2 nanoparticle-increase ROS activated the inflammatory response and phosphokinase, and thus induced phosphorylation of JNK1 and p38 MAPK, resulting in insulin resistance and increasing plasma glucose in mice.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      Yoshio Nakagawa, Akiko Inomata, Akio Ogata and Dai Nakae

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      Mylène Ratelle, Jonathan Coté and Michèle Bouchard

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  4. Review Articles

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

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

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

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

  5. Research Articles

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      Natalie Mesens, Alexander D. Crawford, Aswin Menke, Pham Duc Hung, Freddy Van Goethem, Rik Nuyts, Erik Hansen, Andre Wolterbeek, Jacky Van Gompel, Peter De Witte and Camila V. Esguerra

      Article first published online: 6 FEB 2015 | DOI: 10.1002/jat.3091

      We evaluated lfabp10a as an endpoint for assessing the hepatotoxic effects in zebrafish larvae, and expression analysis was found to be a valid marker, as statistical significant abnormal lfabp10 expression levels correlated with hepatocellular histopathological changes. To assess the applicability for assessing human relevant DILI, 14 drugs were tested that have been marketed for human use, classified according to their mechanism of toxicity. The zebrafish larva showed promising predictivity and was capable of distinguishing between hepatotoxic and non-hepatotoxic chemical analogues.

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

      Marilia Martins Cavariani, Luiz Ricardo de Almeida Kiguti, Josiane de Lima Rosa, Gabriel Adan de Araújo Leite, Patrícia Villela e Silva, André Sampaio Pupo and Wilma De Grava Kempinas

      Article first published online: 2 FEB 2015 | DOI: 10.1002/jat.3089

      Bupropion is used as smoking cessation and antidepressant drug. We evaluated the effects of bupropion on reproductive aspects of male rats and on the epididymal duct in vitro contractility. Bupropion 15 mg/kg increased the epididymal duct contractility; at 30 mg/kg bupropion impaired sperm quality increasing the incidence of non-progressive sperm. Although male sexual behavior and fertility were not modified at both doses, these results suggest the importance of studies evaluating the effects of bupropion on the human male sperm quality.

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

      Hongwei Guo, Hui Yang, Huanhuan Chen, Wen Li, Jinmei Tang, Pei Cheng, Yuchun Xie, Yun Liu, Guoxian Ding, Dai Cui, Xuqin Zheng and Yu Duan

      Article first published online: 2 FEB 2015 | DOI: 10.1002/jat.3032

      Related protein and gene expression levels were observed in a low dose of 2,3′,4,4′,5-pentachlorobiphenyl (PCB118)-exposed human thyroid epithelial cells. We concluded that a low dose of PCB118 could activate the PI3k/Akt pathway, increase the phosphorylation level of FoxO3a protein, and decrease the protein and gene expression level of sodium/iodide symporter (NIS). Our results suggest that PCB118 may induce thyrocyte dysfunction through the Akt/FoxO3a/NIS signalling pathway.

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

      Anna Sieroslawska, Anna Rymuszka and Łukasz Adaszek

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

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

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

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

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

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

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

      Chao Fang, Bo Ning, Ahmed Bilal Waqar, Manabu Niimi, Shen Li, Kaneo Satoh, Masashi Shiomi, Ting Ye, Sijun Dong and Jianglin Fan

      Article first published online: 23 JAN 2015 | DOI: 10.1002/jat.3103

      Watanabe heritable hyperlipidemic (WHHL-MI) rabbits were used to investigate the detrimental effects of bisphenol A (BPA), which has much more common features with humans than mouse and rat especially in the metabolism and cardiovascular system. BPA exposure resulted in insulin resistance, prominent adipose accumulation, hepatic steatosis and myocardial injury. Moreover, BPA exposure also accelerated the development of atherosclerosis in the aortic arch. BPA may exert its toxic effects through eliciting endoplasmic reticulum (ER) stress and an inflammatory reaction.

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

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

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

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

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

      Masaya Uchida, Hiroshi Ishibashi, Ryoko Yamamoto, Akiko Koyanagi, Teruhiko Kusano, Nobuaki Tominaga, Yasuhiro Ishibashi and Koji Arizono

      Article first published online: 22 JAN 2015 | DOI: 10.1002/jat.3098

      Although several previous studies have demonstrated the presence of equine estrogens in the aquatic environment, limited data are currently available on the endocrine-disrupting potentials in fish and the risks they pose to aquatic organisms. To investigate the interactions of major equine estrogens equilin (Eq) and equilenin (Eqn), as well as their metabolites 17α-dihydroequilin, 17β-dihydroequilin, 17α-dihydroequilenin and 17β-dihydroequilenin, with the estrogen receptor α (ERα) of medaka (Oryzias latipes), a three-dimensional model of the ligand-binding domain (LBD) of ERα was built in silico, and docking simulations were performed.

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

      Ayako Inokuchi, Ryoko Yamamoto, Fumiyo Morita, Shota Takumi, Hiromi Matsusaki, Hiroshi Ishibashi, Nobuaki Tominaga and Koji Arizono

      Article first published online: 21 JAN 2015 | DOI: 10.1002/jat.3058

      This study was conducted to clarify the biological effects of lithium compounds on Caenorhabditis elegans. Our findings suggest that LiCl and Li2CO3 potentially affect the biological and physiological function in C. elegans associated with alteration of the gene expression such as cytochrome P450, ABC transporter, glutathione S-transferase, and lipid metabolism genes. The results also provide experimental support for the utility of toxicogenomics by integrating gene expression profiling into a toxicological study of an environmentally important organism such as C. elegans.

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

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

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

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

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

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

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

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

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

      Liang Zheng, Jianlan Yu, Huahong Shi, Liang Xia, Qi Xin, Qiang Zhang, Heng Zhao, Ji Luo, Wenhai Jin, Daoji Li and Junliang Zhou

      Article first published online: 11 JAN 2015 | DOI: 10.1002/jat.3099

      Retinoid X receptor (RXR) antagonists, including some environmental endocrine disruptors, have a teratogenic effect on vertebrate embryos. To investigate the toxicological mechanism on the protein expression level, a quantitative proteomic study was conducted to analyze the proteome alterations of zebrafish (Danio rerio) embryos exposed to gradient concentrations of a representative RXR antagonist UVI3003. Using isobaric Tags for Relative and Absolute Quantitation (iTRAQ) labeling coupled nano high-performance liquid chromatography-tandem mass spectrometry (nano HPLC-MS/MS), in total 6592 proteins were identified, among which 195 proteins were found to be differentially expressed by more than a two-fold change in exposed groups compared with the control.

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

      Barbara Wiśniowska, Aleksander Mendyk, Jakub Szlęk, Michał Kołaczkowski and Sebastian Polak

      Article first published online: 5 JAN 2015 | DOI: 10.1002/jat.3095

      The changing cardiac safety testing paradigm suggests a shift towards in silico models of cellular electrophysiology and assessment of concomitant block of multiple ion channels. In this study a set of four enhanced 2D-QSAR models, predicting ion currents (IKr, IKs, Ina and ICaL) changes were developed. The models combine in vitro study parameters and physico-chemical descriptors. Proposed models provide information which can guide decisions regarding the risk, and thus avoidance of exclusion of potentially safe and effective drugs.

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

      María T. L. Pino and Sandra V. Verstraeten

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      Shyretha Brown and Margaret Whalen

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

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

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