Journal of Applied Toxicology

Cover image for Vol. 37 Issue 10

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

Editor-in-Chief: Philip W. Harvey

Impact Factor: 3.159

ISI Journal Citation Reports © Ranking: 2016: 26/92 (Toxicology)

Online ISSN: 1099-1263


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    1. NOX4- and Nrf2-mediated oxidative stress induced by silver nanoparticles in vascular endothelial cells

      Xia Sun, Yi Yang, Junpeng Shi, Chengcheng Wang, Zhenfeng Yu and Hongwu Zhang

      Version of Record online: 16 AUG 2017 | DOI: 10.1002/jat.3511

      Silver nanoparticles (AgNPs) induced excess reactive oxygen species production that affected the signaling pathways by a mechanism that depended on activation of nicotinamide adenine dinucleotide phosphate oxidase activity through upregulation of NOX4 protein expression. Moreover, AgNPs could disrupt the nuclear factor erythroid 2-related factor 2-mediated antioxidant response, which is considered another important element for oxidative stress caused by AgNPs in human umbilical vein endothelial cells. The redox imbalance between NOX4 and nuclear factor erythroid 2-related factor 2 was an important cause for the reactive oxygen species overproduction that led to cell injury in human umbilical vein endothelial cells.

    2. A novel endpoint for the assessment of chemotherapy-induced peripheral neuropathy in rodents: biomechanical properties of peripheral nerve

      Chang-Ning Liu, Edwin Berryman, David Zakur, Ahmed M. Shoieb, Ingrid D. Pardo, Magalie Boucher, Chris J. Somps, Chedo M. Bagi and Jon C. Cook

      Version of Record online: 16 AUG 2017 | DOI: 10.1002/jat.3513

      Rats and mice administered vincristine were employed as the chemotherapy-induced peripheral neuropathy models. Behavior and ex vivo sural (rats) or sciatic nerve (mice) were assessed. It was found that the load and the load/extension ratio were decreased in the nerves collected from the animals dosed with vincristine. We concluded that mechanical properties of the nerves are a sensitive endpoint for chemotherapy-induced peripheral neuropathy prediction.

    3. You have full text access to this OnlineOpen article
      In vitro genotoxicity of airborne Ni-NP in air–liquid interface

      Siiri Latvala, Daniel Vare, Hanna L. Karlsson and Karine Elihn

      Version of Record online: 16 AUG 2017 | DOI: 10.1002/jat.3510

      The aim of this study was to investigate the genotoxicity of airborne Ni nanoparticles using a recently developed air-liquid interface exposure system that mimics real-life exposure. Cytotoxicity, DNA damage and mutagenicity were in the V79 cell line. Ni nanoparticle exposure of the cells in the air-liquid interface resulted in increased DNA strand breaks and reduced cellular viability at concentrations of 0.15 and 0.32 μg cm −2. These DNA lesions were repaired with BER in an error-free manner without resulting in mutations



    1. Comparison of four different fuller's earth formulations in skin decontamination

      Annick Roul, Cong-Anh-Khanh Le, Marie-Paule Gustin, Emmanuel Clavaud, Bernard Verrier, Fabrice Pirot and Françoise Falson

      Version of Record online: 26 JUL 2017 | DOI: 10.1002/jat.3506

      Industrial accidents, wars and terrorist threats are potential sources of skin contamination by highly toxic chemical warfare agents and manufacturing chemicals. We compare the time-dependent adsorption capacity of four formulations of FE and the decontamination efficiency for the water-soluble molecular tracer, 4-cyanophenol, in vitro and ex vivo using water decontamination as standard. Successful decontamination of fuller's earth suspension, enabling a dramatic reduction of skin contamination after a brief exposure scenario, appears to be rapid, reliable and could be developed for self-decontamination.

  4. Special issue reviews

    1. Introduction to graphene special edition

      Roger Buchanan

      Version of Record online: 25 JUL 2017 | DOI: 10.1002/jat.3501


    1. In vitro evaluation of the internalization and toxicological profile of silica nanoparticles and submicroparticles for the design of dermal drug delivery strategies

      Sara Vicente, Claudia Moia, Huijun Zhu and Xavier Vigé

      Version of Record online: 25 JUL 2017 | DOI: 10.1002/jat.3507

      The toxicological characterization of silica particles (SiPs) in keratinocytes and fibroblasts evidenced a strong cell type dependency in terms of cytotoxicity and internalization. Particle size was only relevant for ultra-small SiPs (20 nm), being the most toxic SiPs. Phagocytosis and caveolae-mediated endocytosis were identified as main entry pathways for keratinocytes and fibroblasts, respectively. These differences determine their different toxic effect in both cell types and enable to define adequate drug delivery strategies.

    2. Targeting nano drug delivery to cancer cells using tunable, multi-layer, silver-decorated gold nanorods

      Zeid A. Nima, Ahmed M. Alwbari, Vijayalakshmi Dantuluri, Rabab N. Hamzah, Natasha Sra, Pooja Motwani, Konstantinos Arnaoutakis, Rebecca A. Levy, Amani F. Bohliqa, Dmitry Nedosekin, Vladimir P. Zharov, Issam Makhoul and Alexandru S. Biris

      Version of Record online: 21 JUL 2017 | DOI: 10.1002/jat.3495

      In this study, tunable, multi-layer, plasmonic, silver-decorated gold nanorods were successfully used to deliver specific, targeted chemotherapy agents to breast cancer (MCF7) and prostate carcinoma (PC3) cell lines. The nanorods were able to induce the death of more than 50% of cancer cells with much smaller dose than the doxorubicin required when drugs were delivered alone. This nanodrug system also has unique spectral signature surface enhanced Raman spectroscopy characteristics, enabling reliable detection and monitoring of the presence of the nanomaterials inside cells.


    1. Combinations of genotoxic tests for the evaluation of group 1 IARC carcinogens

      Jacky Bhagat

      Version of Record online: 11 JUL 2017 | DOI: 10.1002/jat.3496

      Combinations of genotoxic tests provide a better and efficient prediction of human carcinogens. This study summarizes in vivo and in vitro comet assay (CMT) results of group 1 carcinogens selected from the International Agency for Research on Cancer and to discuss the utility of the CMT assay along with other genotoxic assays such as Ames, in vivo micronucleus, and in vivo chromosomal aberration test. In vivo CMT in combination with in vivo chromosomal aberration provided the highest sensitivity (96.7%).


    1. Nuclear magnetic resonance- and mass spectrometry-based metabolomics to study maleic acid toxicity from repeated dose exposure in rats

      Charlene Wu, Chi-Hung Chen, Hsin-Chang Chen, Hao-Jan Liang, Shu-Ting Chen, Wan-Yu Lin, Kuen-Yuh Wu, Su-Yin Chiang and Ching-Yu Lin

      Version of Record online: 10 JUL 2017 | DOI: 10.1002/jat.3500

      We aimed to elucidate possible mechanisms of maleic acid toxicity by (1) determining the changes of metabolic profile, and (2) investigating the occurrence of oxidative stress. In rats that underwent a 28 day toxicity study via oral gavage, statistical significant body and organ weight changes were observed in the treatment groups, urinary concentrations of 8-hydroxy-2′-deoxyguanosine, 8-nitroguanine and 8-iso-prostaglandin F and levels of several endogenous metabolites, with time- and dose-dependent variations. Findings elucidate the possible mechanisms by which nephro- and hepatotoxicity occur.

    2. Assessment of genotoxicity and biodistribution of nano- and micron-sized yttrium oxide in rats after acute oral treatment

      Archana Panyala, Srinivas Chinde, Srinivas Indu Kumari and Paramjit Grover

      Version of Record online: 7 JUL 2017 | DOI: 10.1002/jat.3505

      In vivo oral toxicity of yttrium oxide nanoparticles (NPs) and microparticles was performed in female rats. There was a clear size-, time- and dose-dependent genotoxicity as well as biodistribution. The majority of yttrium from NP- and microparticle-treated rats was excreted via urine and feces respectively, and the toxic effect of Y2O3 particles was probably induced by yttrium ions. Y2O3 NP-induced toxicity could be mediated through the modified antioxidant status of the cells.

    3. Maternal nicotine exposure leads to decreased cardiac protein disulfide isomerase and impaired mitochondrial function in male rat offspring

      Nicole G. Barra, Maria Lisyansky, Taylor A. Vanduzer, Sandeep Raha, Alison C. Holloway and Daniel B. Hardy

      Version of Record online: 6 JUL 2017 | DOI: 10.1002/jat.3503

      Although nicotine replacement therapies are considered safer than smoking, recent rodent studies suggest that perinatal nicotine exposure results in cardiac dysfunction; however, the underlying mechanisms are not completely understood. Our study demonstrates that perinatal nicotine exposed male rats at 3 months have a significant decrease in cardiac protein disulfide isomerase, superoxide dismutase 2, tissue inhibitor of metalloproteinase 4 and mitochondrial complex protein expression. This suggests that nicotine may indirectly disrupt cardiac function by decreasing protein disulfide isomerase expression, leading to oxidative damage and mitochondrial damage.

    4. Untargeted metabolomics of neuronal cell culture: A model system for the toxicity testing of insecticide chemical exposure

      Sarah Hayton, Garth L. Maker, Ian Mullaney and Robert D. Trengove

      Version of Record online: 6 JUL 2017 | DOI: 10.1002/jat.3498

      The use of mammalian cell culture models combined with powerful molecular profiling techniques can uncover unknown biochemical bases of toxicity and provide an alternative to toxicity testing in animals. An untargeted metabolomics approach was used to characterize the metabolome of B50 rat neuronal cells, following exposure to two neurotoxic insecticides, permethrin and malathion. Cells were profiled by gas chromatography–mass spectrometry. A number of key intracellular metabolites were identified and important cellular events including energy metabolism were disrupted by chemical exposure.


    1. Maternal alcohol consumption and altered miRNAs in the developing fetus: Context and future perspectives

      Chanchal Mandal, Debasish Halder, Kyoung Hwa Jung and Young Gyu Chai

      Version of Record online: 5 JUL 2017 | DOI: 10.1002/jat.3504

      Researchers have shown the involvement of epigenetic mechanisms in alcohol-mediated disorders. Non-coding RNAs are one of the major sources of epigenetic modifications, especially microRNAs. The association of microRNAs with alcohol consumption leads to a new focus on finding the molecular mechanisms of alcohol toxicity.


    1. Increased incidence of non-alcoholic fatty liver disease in male rat offspring exposed to fluoxetine during fetal and neonatal life involves the NLRP3 inflammasome and augmented de novo hepatic lipogenesis

      Nicole E. De Long, Daniel B. Hardy, Noelle Ma and Alison C. Holloway

      Version of Record online: 5 JUL 2017 | DOI: 10.1002/jat.3502

      There is limited information available regarding the long-term metabolic consequences of fetal and neonatal exposure to selective serotonin reuptake inhibitors (SSRI) antidepressants. The present study demonstrates that in male SSRI-exposed offspring at 6 months, the increase in the prevalence of fatty liver is associated with upregulation of genes important for de novo lipogenesis and activation of the NLRP3 inflammasome. This suggests that early life exposure to SSRIs may increase the risk of developing chronic liver disease in postnatal life.

  10. Special issue articles

    1. Physicochemical characteristics of pristine and functionalized graphene

      Shawn E. Bourdo, Radwan Al Faouri, Robert Sleezer, Zeid A. Nima, Andersen Lafont, Bijay P. Chhetri, Mourad Benamara, Betty Martin, Gregory J. Salamo and Alexandru S. Biris

      Version of Record online: 5 JUL 2017 | DOI: 10.1002/jat.3493

      Graphene-based nanomaterials have potential uses in a wide variety of applications. These materials have also been shown to be toxic in certain environments based on the physical and chemical properties of the graphene or graphene derivative. To provide a snapshot of the types of graphene used in toxicity projects that are highlighted in this special issue, pristine and functionalized graphene samples have been extensively characterized.


    1. Endocrine disruption: In silico interactions between phthalate plasticizers and corticosteroid binding globulin

      Ishfaq A. Sheikh and Mohd A. Beg

      Version of Record online: 4 JUL 2017 | DOI: 10.1002/jat.3497

      Phthalates as endocrine-disrupting compounds (EDC) have assumed considerable importance as a result of environmental pollution. Corticosteroid-binding globulin (CBG) transports cortisol in the blood circulation and is a potential target for endocrine disruption. An imbalance of cortisol in the body leads to many health problems. Induced fit docking of important phthalate plasticizers revealed similarity in structural binding characteristics of phthalate compounds and native ligand cortisol. These results suggest competitive conflicts in CBG-cortisol binding function and potential disruption of cortisol homeostasis.

    2. Impact of dispersant on early life stages of the water flea Daphnia magna and the eastern oyster Crassostrea virginica

      Maryam Salehi, Rachel Rodriguez, Anne Boettcher, Sean Powers, Nick Geitner, David A. Ladner, Scott Rikard and Andrew J. Whelton

      Version of Record online: 27 JUN 2017 | DOI: 10.1002/jat.3494

      Corexit 9500 was the most applied dispersant in the 2010 oil spill in the Gulf of Mexico. Acute 48-h toxicity testing of Corexit 9500 and HPEI polymers was studied on D. magna and C. virginica. Corexit demonstrated toxicity (EC50 of 0.14 ppm) similar to 10-kDa HPEI (EC50 of 0.16) for D. magna and increased as a function of molecular weight. Corexit was more toxic than 10-kDa HPEI (>30%) to larval oysters. Lower toxicity of HPEI polymers warrants further study.

  12. Special issue articles

    1. T lymphocytes dominate local leukocyte infiltration in response to intradermal injection of functionalized graphene-based nanomaterial

      G. F. Erf, D. M. Falcon, K. S. Sullivan and S. E. Bourdo

      Version of Record online: 16 JUN 2017 | DOI: 10.1002/jat.3492

      Graphene-based nanomaterials have many potential biomedical applications. Information regarding their biological properties and interactions with cells and/or soluble factors within a complex tissue is limited. Using an avian cutaneous test-site, we examined the local cellular/tissue response to intradermal injection of a functionalized graphene (f-GBN) sample over seven days. Local leukocyte infiltration was dominated by T cells and exhibited characteristics of a delayed-type-hypersensitivity response to the non-biodegradable f-GBN. Peripheral-blood leukocyte profiles were not affected by the intradermal administration of f-GBN.

  13. Review articles

    1. Effect of bisphenol A on reproductive processes: A review of in vitro, in vivo and epidemiological studies

      Agnieszka Tomza-Marciniak, Paulina Stępkowska, Jarosław Kuba and Bogumiła Pilarczyk

      Version of Record online: 13 JUN 2017 | DOI: 10.1002/jat.3480

      Review summarizes data on the influence of bisphenol A (BPA) exposure on reproductive health. There is strong proof confirming that BPA is an ovarian, uterine and prostate toxicant at a level below lowest observed adverse effect level (50 mg kg−1 bodyweight [bw]) as well as a level below the proposed safe level (4 μg kg−1 bw). Limited evidence also pertains to the case of the potential of BPA to affect polycystic ovary syndrome occurrence. No unambiguous results were obtained in relation to the evaluation of associations between BPA and implantation failure in women and sexual dysfunction in men.


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