Journal of Applied Toxicology

Cover image for Vol. 37 Issue 4

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

Editor-in-Chief: Philip W. Harvey

Impact Factor: 2.722

ISI Journal Citation Reports © Ranking: 2015: 33/90 (Toxicology)

Online ISSN: 1099-1263


  1. 1 - 44
  1. Research articles

    1. Development of haemostatic decontaminants for treatment of wounds contaminated with chemical warfare agents. 3: Evaluation of in vitro topical decontamination efficacy using damaged skin

      Helen L. Lydon, Charlotte A. Hall, Christopher H. Dalton, J. Kevin Chipman, John S. Graham and Robert P. Chilcott

      Version of Record online: 20 FEB 2017 | DOI: 10.1002/jat.3446

      This in vitro study assessed three candidate haemostatic products for effectiveness in the decontamination of superficially damaged porcine skin exposed to the radiolabelled CW agents, soman (GD), VX and sulphur mustard (HD). Controlled physical damage (removal of the upper 100 μm skin layer) resulted in significant enhancement of the dermal absorption of all three CW agents. Of the haemostatic products assessed, WoundStat™ was consistently the most effective, being equivalent in performance to a standard military decontaminant (fuller's earth).

    2. Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor

      Zemin Wang, Xilin Li, Qiangen Wu, James C. Lamb IV and James E. Klaunig

      Version of Record online: 20 FEB 2017 | DOI: 10.1002/jat.3445

      The organochlorine pesticide toxaphene has been shown to induce mouse liver tumors following chronic exposure. Experimental evidence supports a nongenotoxic mode of action through nuclear receptor activation, possibly through CAR/PXR. The current study using CAR and/or PXR knock out mice was performed with and without toxaphene treatment. Removal of CAR resulted in an elimination of the key events associated with toxaphene induced mouse liver tumors and therefore demonstrated conclusively that the toxaphene induced mouse liver tumors was mediated by activation of the CAR receptor.

    3. Automated image analysis of intra-tumoral and peripheral endocrine organ vascular bed regression using ‘Fibrelength’ as a novel structural biomarker

      Adam Hargreaves, Alison Bigley, Shirley Price, Jane Kendrew and Simon T. Barry

      Version of Record online: 10 FEB 2017 | DOI: 10.1002/jat.3438

      The study of vascular modulation has received a great deal of attention in recent years. Here we present the generation of a novel structural biomarker, which can be incorporated into a number of contemporary image analysis platforms and used to compare tumour versus systemic host tissue vascularity. By contrasting the measurements obtained, the preclinical efficacy of vascular modulating chemotherapies can be evaluated in light of concomitant systemic vascular toxicity.

    4. Threshold limit values of the cadmium concentration in rice in the development of itai-itai disease using benchmark dose analysis

      Kazuhiro Nogawa, Masaru Sakurai, Masao Ishizaki, Teruhiko Kido, Hideaki Nakagawa and Yasushi Suwazono

      Version of Record online: 10 FEB 2017 | DOI: 10.1002/jat.3444

      The aim of this study was to estimate the lower limit of the benchmark dose (BMDL) as the threshold limit level of the Cd concentration in rice for itai-itai disease and/or suspected disease based upon a logistic regression model. The estimated BMDLs of the Cd concentration in rice for itai-itai disease and/or suspected disease were 0.62–0.76 and 0.27–0.56 mg kg−1 in men and women, respectively. This result provides important information about the worldwide standard for the Cd concentration in rice.

    5. Effects of neonatal 17α-ethinyloestradiol exposure on female-paced mating behaviour in the rat

      Chiaki Komine, Shingo Nakajima, Yasuhiko Kondo, Yasuyuki Horii, Midori Yoshida and Maiko Kawaguchi

      Version of Record online: 8 FEB 2017 | DOI: 10.1002/jat.3449

      Perinatal exposure to xeno-oestrogens can disrupt female sexual development, leading to changes in reproductive behaviour in adulthood, but the effects remain to be fully determined. We examined the effects of a single perinatal exposure to low (0.02 mg kg−1) and high (2.0 mg kg−1) doses of 17α-ethinyloestradiol (EE) on female rats in a paced mating test. The high EE dose, but not the low dose, disrupted females' sexual behaviours in adulthood. Such exposure could pose a risk to reproductive health.

    6. Role of connexin 43 in cadmium-induced proliferation of human prostate epithelial cells

      Qingping Liu, Xiaoli Ji, Zehe Ge, Haipeng Diao, Xiuli Chang, Lihua Wang and Qing Wu

      Version of Record online: 8 FEB 2017 | DOI: 10.1002/jat.3441

      The roles of the protein connexin 43 (Cx43) in the effects of Cd on the prostate have not been reported previously. In this study, the human prostate epithelial cell line RWPE-1 was exposed to Cd. A low dose of Cd stimulated cell proliferation, along with a lower degree of gap junction intercellular communication and an elevated level of Cx43. Knockdown of Cx43 blocked Cd-induced proliferation. Thus, Cx43 might be a target for prostatic abnormality associated with Cd exposure.

    7. Pancreatic impairment and Igf2 hypermethylation induced by developmental exposure to bisphenol A can be counteracted by maternal folate supplementation

      Zhenxing Mao, Wei Xia, Wenqian Huo, Tongzhang Zheng, Bryan A. Bassig, Huailong Chang, Tian Chen, Feie Li, Yunxin Pan, Yang Peng, Yuanyuan Li and Shunqing Xu

      Version of Record online: 6 FEB 2017 | DOI: 10.1002/jat.3430

      Perinatal BPA exposure can induced epigenetic modification in offspring islet. Maternal folate supplementation can ameliorate perinatal BPA-induced glucose intolerance and β-cell dysfunction in the offspring. Perinatal BPA exposure induced DNA hypermethylation of Igf2 in offspring islets which can be counteracted by maternal folate supplementation. The changes of epigenetics in islet may contribute to the protection.

    8. Carboxylated nanodiamonds can be used as negative reference in in vitro nanogenotoxicity studies

      H. Moche, V. Paget, D. Chevalier, E. Lorge, N. Claude, H. A. Girard, J. C. Arnault, S. Chevillard and F. Nesslany

      Version of Record online: 6 FEB 2017 | DOI: 10.1002/jat.3443

      In the present work, we investigated the genotoxicity of 20, 50 and 100 nm high-pressure high-temperature nanodiamonds. We performed in vitro micronucleus assays and in vitro comet assays (standard and hOGG1-modified) in two human cell lines, the bronchial epithelial 16HBE14o– cells and the colon carcinoma T84 cells. Our results did not show any genotoxic activity, whatever the test, the cell line or the size of nanodiamonds.

    9. Horseradish extract promotes urinary bladder carcinogenesis when administered to F344 rats in drinking water

      Young-Man Cho, Mai Hasumura, Toshio Imai, Shigeaki Takami, Akiyoshi Nishikawa and Kumiko Ogawa

      Version of Record online: 6 FEB 2017 | DOI: 10.1002/jat.3434

      To evaluate the potential hazards of horseradish extract (HRE), a food additive, a 104-week chronic study, a 2-week analysis of cell proliferation in the urinary bladder and a medium-term promotion bioassay of HRE were conducted with administration at concentrations of up to 0.04% HRE in the drinking water to male F344 rats. Although clear tumor induction was not observed, administration of HRE increased cell proliferation in the urothelium and exerted obvious promoting effects on rat urinary bladder carcinogenesis.

  2. Review articles

    1. Preclinical safety assessments of nano-sized constructs on cardiovascular system toxicity: A case for telemetry

      Hoay Yan Cheah, Lik Voon Kiew, Hong Boon Lee, Nina Japundžić-Žigon, Marίa J. Vicent, See Ziau Hoe and Lip Yong Chung

      Version of Record online: 6 FEB 2017 | DOI: 10.1002/jat.3437

      While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, toxicity of NSCs to the cardiovascular system and relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to cardiovascular system toxicity.

  3. Research articles

    1. Arachidonic acid-containing phosphatidylcholine characterized by consolidated plasma and liver lipidomics as an early onset marker for tamoxifen-induced hepatic phospholipidosis

      Kosuke Saito, Keisuke Goda, Akio Kobayashi, Naohito Yamada, Kyoko Maekawa, Yoshiro Saito and Shoichiro Sugai

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3442

      The present study demonstrated the tamoxifen-induced alteration of the plasma and liver lipid profiles in Sprague–Dawley rats. At a stage of hepatic phospholipidosis (PLD) caused by tamoxifen, arachidonic acid (AA)-containing phosphatidylcholines (PCs) were commonly reduced in both plasma and liver and the reduction was linearly associated. We also demonstrated the reduction of AA-containing PCs in the pre-PLD stage. Moreover, free AA levels were decreased by tamoxifen treatment. Our study demonstrated that AA-containing PCs might be potential biomarkers for tamoxifen-induced PLD.

    2. Evaluation of divided attention psychophysical task performance and effects on pupil sizes following smoked, vaporized and oral cannabis administration

      Matthew N. Newmeyer, Madeleine J. Swortwood, Megan E. Taylor, Osama A. Abulseoud, Thomas H. Woodward and Marilyn A. Huestis

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3440

      Frequent and occasional cannabis smokers' performance on the modified Romberg balance, one leg stand (OLS), and walk and turn (WAT) tasks, and pupil size effects were evaluated following smoked, vaporized and oral cannabis. Few significant effects following inhaled doses compared to placebo were observed. Occasional smokers' odds of exhibiting ≥2 clues on the OLS or WAT following oral dosing were 6.4 (95% CI 2.3–18.4) times higher than after placebo. Occasional smokers' impairment was related to blood Δ9-tetrahydrocannabinol and 11-hydroxy-Δ9-tetrahydrocannabinol concentrations.

    3. Megakaryocyte expansion and macrophage infiltration in bone marrow of rats subchronically treated with MNX, N-nitroso environmental degradation product of munitions compound RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine)

      Sindhura Ramasahayam, Sridhar Jaligama, Sahar M. Atwa, Joshua T. Salley, Marissa Thongdy, Benny L. Blaylock and Sharon A. Meyer

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3439

      Results presented here extend previous observations of hematotoxicity upon acute exposure to hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine. These data demonstrate that daily treatment with ¼ LD50 MNX for 6 weeks continues to target bone marrow hematopoiesis. However, subchronic exposure to MNX differs from acute in that megakaryocyte, rather than erythroid and myeloid, lineage is affected.

    4. Glaucarubulone glucoside from Castela macrophylla suppresses MCF-7 breast cancer cell growth and attenuates benzo[a]pyrene-mediated CYP1A gene induction

      Simone A. M. Badal, Malyn M. Asuncion Valenzuela, Dain Zylstra, George Huang, Pallavi Vendantam, Sheena Francis, Ashley Quitugua, Louisa H. Amis, Willie Davis, Tzuen-Rong J. Tzeng, Helen Jacobs, David J. Gangemi, Greg Raner, Leah Rowland, Jonathan Wooten, Petreena Campbell, Eileen Brantley and Rupika Delgoda

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3436

      Glaucarubulone glucoside (Gg), isolated from the plant Castela macrophylla, reduced the viability of MCF-7 breast adenocarcinoma cells (IC50 121 nm) to a greater extent than tamoxifen (IC50 >10 μm) and 4-hydroxytamoxifen (IC50 2.6 μm) and did not impact non-tumorigenic MCF-10A cells. Gg induced apoptosis in MCF-7 cells and downregulated the expression of antioxidant genes. Gg non-competitively inhibited the activities of CYP1A enzymes and attenuated the ability of benzo[a]pyrene to induce CYP1A gene expression.

    5. Prediction of drug-induced liver injury using keratinocytes

      Rika Hirashima, Tomoo Itoh, Robert H. Tukey and Ryoichi Fujiwara

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3435

      Drug-induced liver injury (DILI) is often accompanied by skin reactions. However, it is still unknown whether DILI-associated genes are involved in drug-induced skin toxicity. In the present study, most of the tested hepatotoxic drugs induced DILI-associated genes in keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased interleukin-1β basal expression. These suggest that DILI-associated genes are involved in drug-induced skin toxicity, too. We might be able to identify individuals at higher risk of developing DILI less invasively by examining gene expression patterns in keratinocytes.

  4. Hypothesis review

    1. Current and prospective sights in mechanism of deoxynivalenol-induced emesis for future scientific study and clinical treatment

      Liangkai Chen, Zhao Peng, Andreas K. Nüssler, Liegang Liu and Wei Yang

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3433

      The previously representative studies in DON-induced emesis model. Some studies with different animal models (pigs and minks) suggested that DON could change expressions of 5-HT, PYY, NPY2 and NUCB2/nesfatin-1 in plasma and different areas of brain. The Ca2+ homeostasis and MAPK pathway also could be potential directions in future DON studies.

  5. Research articles

    1. Oxidative stress-mediated developmental toxicity induced by isoniazide in zebrafish embryos and larvae

      Yu Zou, Yun Zhang, Liwen Han, Qiuxia He, Hairong Hou, Jian Han, Ximin Wang, Chengyun Li, Juan Cen and Kechun Liu

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3432

      • Isoniazide (INH) caused a dose- and time-dependent increase in developmental toxicity of zebrafish embryos and larvae.
      • INH reduced the locomotor capacity of the zebrafish larvae.
      • Oxidative stress played an important role in the developmental toxicity induced by INH in zebrafish larvae.
    2. Lethal and sublethal effects of aniline and chlorinated anilines on zebrafish embryos and larvae

      Yoshifumi Horie, Takahiro Yamagishi, Masaaki Koshio, Taisen Iguchi and Norihisa Tatarazako

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3431

      The purpose of this study was to investigate lethal and sublethal effects of chemicals using OECD test 212 with zebrafish, and to examine the correlation of several sublethal effects between embryo and larval stages. Our results show that chlorinated anilines induce not only lethal effects but also a variety of sublethal effects. Moreover, a detailed estimate of these effects requires study during both embryonic and larval stages. OECD test 212 may therefore prove useful as a method for screening chemicals for lethal and sublethal effects.

    3. You have full text access to this OnlineOpen article
      Comparison of protocols measuring diffusion and partition coefficients in the stratum corneum

      H. Rothe, C. Obringer, J. Manwaring, C. Avci, W. Wargniez, J. Eilstein, N. Hewitt, R. Cubberley, H. Duplan, D. Lange, C. Jacques-Jamin, M. Klaric, A. Schepky and S. Grégoire

      Version of Record online: 31 JAN 2017 | DOI: 10.1002/jat.3427

      We compared protocols measuring diffusion and partition coefficients of caffeine, resorcinol and 7-ethoxycoumarin in the stratum corneum: Protocol 1: SC concentration-depth profile using tape-stripping; Protocol 2A: incubation of isolated SC with chemical and Protocol 2B: diffusion through isolated SC mounted on a Franz cell, with non-linear regression fitted data. The different methods produced comparable results and demonstrated that waste pig skin might be a good surrogate for human skin for the three chemicals tested.

    4. The dental resin monomers HEMA and TEGDMA have inhibitory effects on osteoclast differentiation with low cytotoxicity

      Hiroyuki Inamitsu, Kuniaki Okamoto, Eiko Sakai, Kazuhisa Nishishita, Hiroshi Murata and Takayuki Tsukuba

      Version of Record online: 26 JAN 2017 | DOI: 10.1002/jat.3429

      The dental resin monomers 2-hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) influence various biological functions and the viability of cells in the oral environment. However, the effects of these monomers on osteoclasts remain unknown. Here we demonstrated that HEMA and TEGDMA inhibit osteoclast differentiation from bone marrow-derived macrophages or murine monocytic cell line RAW-D in vitro. Although HEMA and TEGDMA had different inhibitory effects on signaling pathways of the osteoclast differentiation, they had little cytotoxic effects on osteoclasts.

    5. Prediction of skin sensitization potency using machine learning approaches

      Qingda Zang, Michael Paris, David M. Lehmann, Shannon Bell, Nicole Kleinstreuer, David Allen, Joanna Matheson, Abigail Jacobs, Warren Casey and Judy Strickland

      Version of Record online: 10 JAN 2017 | DOI: 10.1002/jat.3424

      Replacing animal testing for regulatory classification of skin sensitizers is a high priority for US federal agencies. We developed machine learning approaches combining data from three non-animal methods with physicochemical property data to predict three categories of skin sensitization. The top model surpassed the accuracy of a standard animal test for skin sensitization, suggesting that computational models using data from non-animal methods can provide valuable information to assess skin sensitization potency.

      Supporting Information.

  6. Review articles

    1. Current sights for mechanisms of deoxynivalenol-induced hepatotoxicity and prospective views for future scientific research: A mini review

      Zhao Peng, Liangkai Chen, Andreas K. Nüssler, Liegang Liu and Wei Yang

      Version of Record online: 20 DEC 2016 | DOI: 10.1002/jat.3428

      In this table, we have shown that DON induced liver damage with positive and negative results in different animal models and cell lines. This mycotoxin can evokes obvious pathological changes in tissue by altering repssions of relative enzymes or oxidative stress. Otherwise, DON can induces expressions of apoptotic proteins thereby producing hepatic fibrosis and other kinds of liver damage.

  7. Research articles

    1. Glucose-rich diet aggravates monocrotophos-induced dopaminergic neuronal dysfunction in Caenorhabditis elegans

      Chinnu Salim and P. S. Rajini

      Version of Record online: 20 DEC 2016 | DOI: 10.1002/jat.3426

      Learning and memory were affected by MCP and glucose while basal slowing response of cat-2 worms exposed to MCP and glucose were less affected than N2 of the same treatment. MCP-treated worms showed lesser repulsion to nonanone compared to control worms MCP+ glucose worms showed a greater reduction in repulsion to nonanone. MCP+ glucose worms exhibited a marked reduction in dopamine content BZ555 worms showed a significant degeneration of dopaminergic neurons when exposed to glucose and MCP.

    2. Genotoxic risk of ethyl-paraben could be related to telomere shortening

      F. Finot, A. Kaddour, L. Morat, I. Mouche, N. Zaguia, C. Cuceu, D. Souverville, S. Négrault, O. Cariou, A. Essahli, N. Prigent, J. Saul, F. Paillard, L. Heidingsfelder, P. Lafouge, M. Al Jawhari, W. M. Hempel, M. El May, B. Colicchio, A. Dieterlen, E. Jeandidier, L. Sabatier, J. Clements and R. M'Kacher

      Version of Record online: 20 DEC 2016 | DOI: 10.1002/jat.3425

      The impact of parabens in human breast tissue remains unclear. We demonstrated a genotoxic effect of ethyl-paraben with and without metabolic activation (S9) and a correlation between telomere dysfunction and increased genotoxic response after ethyl-paraben treatment in studies following OECD guidelines. These data demonstrate genotoxicity and a higher MN frequency of cells with telomere shortening in the presence of ethyl-paraben and could advance our knowledge on the role of paraben in breast cancer cells characterized by drastic telomere shortening.

    3. In vitro detection of diesel exhaust particles induced human lung carcinoma epithelial cells damage and the effect of resveratrol

      Qifei Li, Mingjie Tang and Anhong Zhou

      Version of Record online: 9 DEC 2016 | DOI: 10.1002/jat.3423

      A combination of two non-invasive techniques (Atomic force microscopy, AFM, and Raman micro-spectroscopy, RM) and other biological instrument tools (flow cytometry and multiplex ELISA) were applied to evaluate the biophysical, biochemical alterations and cytokine, membrane potential and cell cycle of cells with or without resveratrol (RES) pretreatment to different times of diesel exhausted particles (DEPs) exposure to better understand the mechanisms of DEP-induced cell damages and the study of the roles of RES in DEP damaged lung cancer cells.

    4. You have full text access to this OnlineOpen article
      Responses of A549 human lung epithelial cells to cristobalite and α-quartz exposures assessed by toxicoproteomics and gene expression analysis

      Ngoc Q. Vuong, Patrick Goegan, Francesco De Rose, Dalibor Breznan, Errol M. Thomson, Julie S. O'Brien, Subramanian Karthikeyan, Andrew Williams, Renaud Vincent and Premkumari Kumarathasan

      Version of Record online: 5 DEC 2016 | DOI: 10.1002/jat.3420

      In this study, we used cytotoxicity assays, proteomic and gene expression analyses to examine the difference in response of A549 cells to two silica particles that differ in physical properties, namely cristobalite (CR) and α-quartz (Min-U-Sil 5, MI). Cytotoxicity assays such as lactate dehydrogenase release, 5-bromo-2'-deoxyuridine incorporation and cellular ATP showed that both silica particles could cause cell death, decreased cell proliferation and metabolism in the A549 human lung epithelial cells. While cytotoxicity assays revealed little difference between CR and MI exposures, proteomic and gene expression analyses unveiled both similar and unique molecular changes in A549 cells.

    5. Relationship between increasing concentrations of two carcinogens and statistical image descriptors of foci morphology in the cell transformation assay

      Giulia Callegaro, Raffaella Corvi, Susan Salovaara, Chiara Urani and Federico M. Stefanini

      Version of Record online: 5 DEC 2016 | DOI: 10.1002/jat.3419

      Cell transformation assays have long been proposed for the identification of chemical carcinogenicity potential. The endpoint of cell transformation assays is the induction of foci of transformed cells, characterized by specific morphological features, after treatment with a suspected carcinogen. In this study, foci morphology is shown to be statistically related to the concentration of two known carcinogens, benzo[a]pyrene and NiCl2, as captured by selected statistical image descriptors. Statistical descriptors may represent new quantitative parameters for the assessment of cell transformation.

    6. Activation of interleukin-6 and -8 expressions by methylmercury in human U937 macrophages involves RelA and p50

      Megumi Yamamoto, Noureen Khan, Muflihatul Muniroh, Eriko Motomura, Rie Yanagisawa, Takami Matsuyama and Christoph F. A. Vogel

      Version of Record online: 5 DEC 2016 | DOI: 10.1002/jat.3411

      IL-6 and IL-8 mRNA expression was maximally induced by 10 μM methylmercury (MeHg) in U937 macrophages at 6 h and declined after 24 h of exposure. Involvement of RelA and p50 in MeHg-induced IL-6 and IL-8 activation was shown by siRNA knock down experiments. Exposure to 4 μM MeHg also induced mRNA and protein of IL-8 expression in U-87 MG cells. Five mM N-acetyl- L-cysteine suppressed MeHg-induced activation of IL-6 and IL-8 mRNA expression in U937 macrophages.

    7. Comparative in vitro toxicity assessment of perfluorinated carboxylic acids

      Cecon T. Mahapatra, Nur P. Damayanti, Samuel C. Guffey, Jennifer S. Serafin, Joseph Irudayaraj and Maria S. Sepúlveda

      Version of Record online: 5 DEC 2016 | DOI: 10.1002/jat.3418

      Perfluorooctanoic acid is a toxic and persistent pollutant, but little is known about the toxicity of shorter chain alternatives. We found that the shorter chain alternatives perfluorohexanoic acid and perfluorobutanoic acid caused less gross toxicity to zebrafish liver cells as compared to perfluorooctanoic acid, but all three compounds affected the fluorescence lifetime of free and bound forms of NADH and FAD, indicating a disruption of cell metabolism.

    8. Evidence for direct effects of glyphosate on ovarian function: glyphosate influences steroidogenesis and proliferation of bovine granulosa but not theca cells in vitro

      Maria Chiara Perego, Luis F. Schutz, Francesca Caloni, Cristina Cortinovis, Marco Albonico and Leon J. Spicer

      Version of Record online: 5 DEC 2016 | DOI: 10.1002/jat.3417

      Glyphosate (GLY) is a common herbicide used worldwide but its effect on ovarian function in mammals is unknown. The aim of this study was to determine the potential endocrine disruptor effects of GLY on ovarian function evaluating cell proliferation, steroidogenesis and gene expression using bovine granulosa cells and theca cells as in vitro models. Our results, for the first time, suggest that GLY may affect the reproductive system in cattle via direct action on ovarian function.

    9. Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents

      Normand Podechard, Martine Chevanne, Morgane Fernier, Arnaud Tête, Aurore Collin, Doris Cassio, Olivier Kah, Dominique Lagadic-Gossmann and Odile Sergent

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/jat.3421

      The easy-to-use in vivo model, zebrafish larva, is increasingly used to screen chemical-induced hepatotoxicity. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. Its suitability and sensitivity were demonstrated by the ability to maintain membrane remodeling after 1 week of ethanol exposure, and by alleviating or enhancing ethanol-induced hepatotoxicity after membrane manipulation with membrane stabilizer, lipid raft disrupter or stimulator of lipid raft clustering.

    10. Lack of in vivo mutagenicity of 1,2-dichloropropane and dichloromethane in the livers of gpt delta rats administered singly or in combination

      Tadashi Hirata, Young-Man Cho, Takeshi Toyoda, Jun-ichi Akagi, Isamu Suzuki, Akiyoshi Nishikawa and Kumiko Ogawa

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/jat.3416

      In the present study,we evaluated the in vivo mutagenicity of 1,2-DCP and DCM, alone or combined, in the livers of gpt delta rats. Six-week-old male F344 gpt delta rats were treated with 1,2-DCP, DCM or 1,2-DCP+DCM by oral administration for 4weeks at the dose (200 mg kg−1 body weight 1,2-DCP and 500 mg kg−1 body weight DCM) used in the carcinogenesis study performed by the National Toxicology Program. In vivo mutagenicity was analyzed by gpt mutation/Spi-assays in the livers of rats.

    11. You have full text access to this OnlineOpen article
      Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes

      Susan J. Borghoff, Caroline Ring, Marcy I. Banton and Teresa L. Leavens

      Version of Record online: 24 NOV 2016 | DOI: 10.1002/jat.3412

      Inhalation, but not drinking-water exposure, to a high concentration of ethyl tertiary butyl ether was reported to cause liver tumors in male rats. Using a PBPK model for ethyl tertiary butyl ether and its metabolite tertiary butyl alcohol, under cancer bioassay exposure scenarios, showed a shift from linear to nonlinear kinetics at the exposure concentration associated with liver tumors. This suggests that a liver tumor mode of action that occurs under a high exposure concentration is not relevant for assessing human risk.

    12. Immunotoxic effects of in vitro exposure of dolphin lymphocytes to Louisiana sweet crude oil and Corexit™

      Natasha D. White, Celine Godard-Codding, Sarah J. Webb, Gregory D. Bossart and Patricia A. Fair

      Version of Record online: 20 NOV 2016 | DOI: 10.1002/jat.3414

      The immunotoxicity of Louisiana sweet crude oil and the chemical dispersant Corexit™ was examined using lymphocyte proliferation and natural killer cell assays as measures of impact on the adaptive and innate immune response in bottlenose dolphins, respectively. Bottlenose dolphin peripheral blood leukocytes were exposed to Louisiana sweet crude alone and in combination with Corexit. Results observed in this study indicate that exposure to both oil and dispersants causes functional impairment of cells of both the innate and adaptive immune system of bottlenose dolphins at environmentally relevant concentrations.

    13. Effects of oral exposure to the phthalate substitute acetyl tributyl citrate on female reproduction in mice

      Lindsay M. Rasmussen, Nivedita Sen, Xiaosong Liu and Zelieann R. Craig

      Version of Record online: 20 NOV 2016 | DOI: 10.1002/jat.3413

      Acetyl tributyl citrate (ATBC), is a phthalate substitute used in food, toys, cosmetics and medical plastics. Although safe up to 1000 mg kg−1 day−1, its ability to cause reproductive toxicity in females at levels below 50 mg kg−1 day−1 is currently unknown. The effects of lower ATBC exposures on female reproduction were evaluated using mice. Ovaries from ATBC-treated mice had fewer ovarian follicles in the primordial, primary and secondary stages. These findings suggest that low levels of ATBC may be detrimental to the ovary.

    14. Cytotoxicity, oxidative stress and inflammation induced by ZnO nanoparticles in endothelial cells: interaction with palmitate or lipopolysaccharide

      Yu Gong, Yuejia Ji, Fang Liu, Juan Li and Yi Cao

      Version of Record online: 15 NOV 2016 | DOI: 10.1002/jat.3415

      The interaction of palmitate (PA) or lipopolysaccharide (LPS) on ZnO nanoparticle (NP)-induced toxicity to human umbilical vein endothelial cells (HUVECs) was studied. ZnO NPs induced cytotoxicity and reactive oxygen species (ROS), but not inflammatory cytokines or monocyte adhesion. PA induced cytotoxicity and monocyte adhesion, but not ROS or inflammatory cytokines. LPS induced ROS, inflammatory cytokines and monocyte adhesion. ZnO NPs did not further enhance the toxicity of PA or LPS to HUVECs. We concluded no interaction between ZnO NPs and PA or LPS on toxicity to HUVECs in vitro.

    15. Developmental toxicity of auranofin in zebrafish embryos

      Xiao-Yan Gao, Kang Li, Ling-Ling Jiang, Ming-Fang He, Cun-Hai Pu, Dongzhou Kang and Jingjing Xie

      Version of Record online: 4 NOV 2016 | DOI: 10.1002/jat.3410

      In the present study, we described the developmental toxicity of auranofin. The biochemical levels of oxidative stress enzymes as well as the expressions of a series of genes related to oxidative stress, cardiac, metal stress and pigment formation were detected. Our findings may help gain a better insight into the molecular mechanisms underlying AF-induced development defects.

    16. Antagonistic effect of N-ethylmaleimide on arsenic-mediated oxidative stress-induced poly(ADP-ribosyl)ation and cytotoxicity

      Alexander Sheng-Shin Wang, Yu-Ting Chou and Yeong-Shiau Pu

      Version of Record online: 4 NOV 2016 | DOI: 10.1002/jat.3394

      Until now, the role of arsenic (As2O3) in oxidative stress-mediated PARylation and DNA damage is elusive. We observed that oxidative stress (H2O2)-induced PARylation was suppressed by As2O3 exposure in cancer cells. As2O3 treatment promoted H2O2-induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide can reverse As2O3-mediated effects, thus enhancing PARylation and reducing DNA damage with attenuated cell death in a glutathione-dependent manner. Our findings identify N-ethylmaleimide as a potential antidote against As2O3-mediated DNA damage.

    17. Toxicokinetics and toxicodynamics of chlorpyrifos is altered in embryos of Japanese medaka exposed to oil sands process-affected water: evidence for inhibition of P-glycoprotein

      Hattan A. Alharbi, Jane Alcorn, Ahmed Al-Mousa, John P. Giesy and Steve B. Wiseman

      Version of Record online: 24 OCT 2016 | DOI: 10.1002/jat.3397

      Effects of acidic, basic and neutral fractions of water soluble organic compounds from oil sands process water (OSPW) on the function of P-glycoprotein (P-gp) were investigated using Caco-2 cells and larvae of Japanese medaka. Basic and neutral fractions inhibited P-gp. Acute toxicity, accumulation, bioconcentration, and half-life of chlorpyrifos, a model compound used as a substrate of P-gp, were greater in larvae co-exposed with a mixture basic and neutral compounds. Results support chemosensitization as a potential mechanism of toxicity of OSPW.

    18. Biological factor related to Asian sand dust particles contributes to the exacerbation of asthma

      Akiko Honda, Takahiro Sawahara, Tomohiro Hayashi, Kenshi Tsuji, Wataru Fukushima, Mizuki Oishi, Gaku Kitamura, Hitomi Kudo, Sho Ito, Seiichi Yoshida, Takamichi Ichinose, Kayo Ueda and Hirohisa Takano

      Version of Record online: 7 OCT 2016 | DOI: 10.1002/jat.3395

      Bjerkandera adusta ( and benzo[a]pyrene (BaP) each activated antigen-presenting cells (APCs) in the presence and the absence of heated Asian sand dust particles (H-ASDs). H-ASDs alone slightly activated APCs. The activation induced by was more apparent than that by BaP in the presence and absence of H-ASDs. rather than BaP contributes to the exacerbation of asthma regardless of the presence or absence of sand particles, particularly by activation of the immune system via APCs.

    19. Immunomodulatory effects of metal salts at sub-toxic concentrations

      Carmen Steinborn, Christoph Diegel, Manuel Garcia-Käufer, Carsten Gründemann and Roman Huber

      Version of Record online: 7 OCT 2016 | DOI: 10.1002/jat.3390

      Because different metals are used in complementary medicine for the treatment of diseases related to a dysfunction of the immune system, this study aimed at determining the immunomodulatory potential of Pb(NO3)2, AuCl3, Cu(NO3)2, HgCl2, AgNO3, SnCl2, AsCl3 and SbCl3 and possible toxic side effects of metal preparations. The results show that only copper preparations are promising to have immunomodulatory effects. Comparative analyses with upper limits of metals in the drinking water further showed that toxic side effects of low-concentrated metal preparations are improbable.

    20. Disposition of intravenously or orally administered silver nanoparticles in pregnant rats and the effect on the biochemical profile in urine

      Timothy R. Fennell, Ninell P. Mortensen, Sherry R. Black, Rodney W. Snyder, Keith E. Levine, Eric Poitras, James M. Harrington, Christopher J. Wingard, Nathan A. Holland, Wimal Pathmasiri and Susan C. J. Sumner

      Version of Record online: 3 OCT 2016 | DOI: 10.1002/jat.3387

      Here is presented a comprehensive investigation of the distribution of polyvinylpyrrolidone (PVP)-stabilized AgNP (20 or 110 nm) in pregnant rats after a single injection or oral gavage dose. The biological impacts of AgNP exposure were evaluated by metabolomic analysis, and measurement of biomarkers of cardiovascular injury, oxidative stress and inflammation. The investigation provided a basic understanding of the distribution, internal dose, persistence, metabolomics and elimination of AgNP after exposure in pregnant rats.

    21. Association between perfluorooctanoic acid exposure and degranulation of mast cells in allergic inflammation

      Jun-Kyoung Lee, Soyoung Lee, Moon-Chang Baek, Byung-Heon Lee, Hyun-Shik Lee, Taeg Kyu Kwon, Pil-Hoon Park, Tae-Yong Shin, Dongwoo Khang and Sang-Hyun Kim

      Version of Record online: 29 SEP 2016 | DOI: 10.1002/jat.3389

      In this study, the effect of PFOA on the degranulation of mast cells and mast cell-mediated allergic inflammation in the presence of FcεRI cross-linking was evaluated. In immunoglobulin (Ig) E-stimulated mast cells, PFOA increased the release of histamine and β-hexosaminidase by the up-regulation of intracellular calcium levels. PFOA enhanced gene expression of several pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 by the activationof nuclear factor (NF)-κB in IgE-stimulated mast cells.

    22. Toxicological role of an acyl glucuronide metabolite in diclofenac-induced acute liver injury in mice

      Shingo Oda, Yuji Shirai, Sho Akai, Akira Nakajima, Koichi Tsuneyama and Tsuyoshi Yokoi

      Version of Record online: 27 SEP 2016 | DOI: 10.1002/jat.3388

      The acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs are suggested to be implicated in toxicity, including hepatotoxicity. However, whether AG formation is related to toxicity in vivo remains unknown. We found that pretreatment of mice with the UDP-glucuronosyltransferase inhibitor (−)-borneol alleviated diclofenac (DIC)-induced acute liver injury by suppressing neutrophil infiltration into the liver. Thus, DIC-AG is partly involved in the pathogenesis of DIC-induced acute liver injury in mice by activating innate immunity.


  1. 1 - 44