Journal of Applied Toxicology

Cover image for Vol. 37 Issue 12

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. Effects of exposure to six chemical ultraviolet filters commonly used in personal care products on motility of MCF-7 and MDA-MB-231 human breast cancer cells in vitro

      Maha Alamer and Philippa D. Darbre

      Version of Record online: 9 OCT 2017 | DOI: 10.1002/jat.3525

      Benzophenone (BP)-1, BP-2, BP-3, octylmethoxycinnamate, 4-methylbenzilidenecamphor and homosalate are widely used to absorb ultraviolet light in a range of personal care products and have been measured in human milk. The results reported here demonstrate the ability of all these compounds to increase the migration of human breast cancer cells, characteristics that are essential for metastasis.

    2. A genomic characterization of the influence of silver nanoparticles on bone differentiation in MC3T3-E1 cells

      Tao Qing, Meena Mahmood, Yuanting Zheng, Alexandru S. Biris, Leming Shi and Daniel A. Casciano

      Version of Record online: 4 OCT 2017 | DOI: 10.1002/jat.3528

      MC3T3–E1 cells express an increase in bone mineralization when cultured in osteogenic 1 and 2 media. When exposed to silver nanoparticles, genes associated with bone differentiation are induced when assessed by RNA-seq technology. In addition, genes of metabolism and toxicity pathways were significantly regulated as well.

    3. Diethylstilbestrol impaired oogenesis of yellow catfish juveniles through disrupting hypothalamic–pituitary–gonadal axis and germ cell development

      Yaqin Wang, Yingwen Li, Qiliang Chen and Zhihao Liu

      Version of Record online: 28 SEP 2017 | DOI: 10.1002/jat.3529

      In this study, female juveniles of yellow catfish (Pelteobagrus fulvidraco) were exposed to diethylstilbestrol for 28 days. After exposure, reduced ovary weight and gonadosomatic index, impaired oogenesis, decreased plasma estrogen level, as well as altered mRNA levels of genes involved in the hypothalamic–pituitary–gonadal axis, germ cell proliferation, meiotic regulation and apoptosis were observed.

    4. Aberrant expression of miR-451a contributes to 1,2-dichloroethane-induced hepatic glycerol gluconeogenesis disorder by inhibiting glycerol kinase expression in NIH Swiss mice

      Ni Zeng, Hongmei Jiang, Qiming Fan, Ting Wang, Weifeng Rong, Guoliang Li, Ruobi Li, Dandan Xu, Tao Guo, Fei Wang, Lihai Zeng, Manqi Huang, Jiewei Zheng, Fengrong Lu, Wen Chen, Qiansheng Hu, Zhenlie Huang and Qing Wang

      Version of Record online: 28 SEP 2017 | DOI: 10.1002/jat.3526

      To explore whether aberrant miRNA expression is involved in liver abnormalities mediated by 1,2-DCE exposure, we examined alterations in miRNA expression patterns in the livers of NIH Swiss mice after dynamic inhalation exposure to 350 or 700 mg m−3 1,2-DCE for 28 days. Using a microarray chip, we discovered that only mmu-miR-451a was significantly upregulated in the liver tissue of mice exposed to 700 mg m−3 1,2-DCE; this finding was validated by quantitative real-time polymerase chain reaction. In vitro study revealed that it was metabolite 2-chloroacetic acid, not 1,2-DCE that resulted in the upregulation of mmu-miR-451a in the mouse AML12 cell line. Furthermore, our data showed that the upregulation of mmu-miR-451a induced by 2-chloroacetic acid could suppress the expression of glycerol kinase and lead to the inhibition of glycerol gluconeogenesis in mouse liver tissue and AML12 cells.

    5. A practical approach to assess inhalation toxicity of metal oxide nanoparticles in vitro

      Anita C. A. Dankers, C. Frieke Kuper, Anja J. Boumeester, Babs O. Fabriek, Ingeborg M. Kooter, Mariska Gröllers-Mulderij, Peter Tromp, Inge Nelissen, Esther K. Zondervan-Van Den Beuken and Rob J. Vandebriel

      Version of Record online: 28 SEP 2017 | DOI: 10.1002/jat.3518

      The proinflammatory potential of metal oxide NPs CeO2, Mn2O3, CuO, ZnO, Co3O4 and WO3 was studied in human primary 3D airway epithelium and dendritic cells (DC) models. WO3 and ZnO were highly soluble, with and without respiratory mucus. Only CuO increased interleukin-6 and -8, and monocyte chemoattractant protein 1. Only Mn2O3 upregulated DC maturation markers. Addition of medium from Mn2O3-exposed 3D epithelium to Mn2O3-exposed DCs further increased DC maturation in one of five DC donors, at dosages representing up to 27 hours of human airway exposure.

    6. Preventive effects of fructose and N-acetyl-L-cysteine against cytotoxicity induced by the psychoactive compounds N-methyl-5-(2-aminopropyl)benzofuran and 3,4-methylenedioxy-N-methamphetamine in isolated rat hepatocytes

      Yoshio Nakagawa, Toshinari Suzuki and Akiko Inomata

      Version of Record online: 26 SEP 2017 | DOI: 10.1002/jat.3523

      Psychoactive compounds, N-methyl-5-(2-aminopropyl)benzofuran (5-MAPB) and 3,4-methylenedioxy-N-methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N-acetyl-l-cysteine (NAC) on 5-MAPB- and MDMA-induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration-dependent (0–4 mm) and time-dependent (0–3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH.

    7. Allopurinol suppresses expression of the regulatory T-cell migration factors TARC/CCL17 and MDC/CCL22 in HaCaT keratinocytes via restriction of nuclear factor-κB activation

      Makoto Osabe, Toshiyuki Tajika and Masahiro Tohkin

      Version of Record online: 26 SEP 2017 | DOI: 10.1002/jat.3522

      Regulatory T cells (Tregs) in the skin might be involved in the onset of severe cutaneous adverse drug reactions (SCARs). Allopurinol, a drug known to cause SCARs, was found to inhibit HaCaT cell expression of TARC/CCL17 and MDC/CCL22, factors affecting Treg migration, and suppress Treg migration itself. These results suggest that the sparse distribution of Tregs in the skin following allopurinol treatment may induce SCARs.

    8. Potential hazards of fenvalerate in massive pollution influence the apoptosis sensitivity

      Zheng-Guo Cui, Yu-Jie Jin, Lu Sun, Shahbaz Ahmad Zakki, Meng-Ling Li, Qian-Wen Feng, Takashi Kondo, Ryohei Ogawa and Hidekuni Inadera

      Version of Record online: 26 SEP 2017 | DOI: 10.1002/jat.3517

      Fenvalerate (Fen), a synthetic pyrethroid insecticide, is widely used in agricultural, domestic and veterinary applications. Fen induces abnormal cell proliferation and apoptosis, which are linked to its hazardous effects. However, this view is controversial and the underlying molecular mechanisms remain elusive. In the present study, the effects of Fen on cadmium (Cd)-induced apoptosis and the associated molecular mechanisms were investigated in human myeloid leukemia U937 cells. U937 cells were treated with 50 μm cadmium chloride (CdCl2) with or without Fen pretreatment at 1–50 μm.

    9. Cytoprotective effects of xanthohumol against methylglyoxal-induced cytotoxicity in MC3T3-E1 osteoblastic cells

      Kwang Sik Suh, Suk Chon and Eun Mi Choi

      Version of Record online: 20 SEP 2017 | DOI: 10.1002/jat.3521

      Methylglyoxal (MG) has been suggested to be a major source of intracellular reactive carbonyl compounds, and has been implicated in increasing the levels of advanced glycation end products in age-related diseases. Xanthohumol is a prenylated flavonoid found in hops (Humulus lupulus) and beer. In the present study, we investigated the effects of xanthohumol on MG-induced cytotoxicity in osteoblastic MC3T3-E1 cells. Xanthohumol attenuated MG-induced cytotoxicity, as evidenced by improved cell viability, and prevented MG-induced MG-protein adducts, inflammatory cytokines, reactive oxygen species and mitochondrial superoxide production.


    1. Dermatotoxicology of sulfur mustard: Historical perspectives from World War I

      Austin Jiang and Howard Maibach

      Version of Record online: 19 SEP 2017 | DOI: 10.1002/jat.3524

      Sulfur mustard has been used as a chemical warfare agent for the past century. After its introduction by the Germans in World War I, investigators quickly began studying its impact on the human body. This review focuses on two groups in particular who conducted experiments from 1917 to 1918. These researchers anticipated multiple dermatologic phenomena including regional variation of percutaneous penetration, effect of vehicle on penetration and immunologic contact urticaria, setting the groundwork for current dermatotoxicology.


    1. Long-term exposure to bisphenol S damages the visual system and reduces the tracking capability of male zebrafish (Danio rerio)

      Wenmin Liu, Xiaona Zhang, Penghao Wei, Hua Tian, Wei Wang and Shaoguo Ru

      Version of Record online: 11 SEP 2017 | DOI: 10.1002/jat.3519

      This study aimed to examine the effect of bisphenol S (BPS) on the visual system in male zebrafish. Zebrafish embryos were exposed to BPS at concentrations of 1, 10, 100 and 1000 μg l−1 until 120 days post-fertilization in a semi-static system. Results showed that long-term BPS exposure damaged the retinal structure, decreased their tracking capability and stimulated the transcription of opsin genes in the eyes, suggesting a severe deficiency in the visual system in male zebrafish.

    2. Effect of cadmium on kitl pre-mRNA alternative splicing in murine ovarian granulosa cells and its associated regulation by miRNAs

      Wenxiang Wang, Jie Chen, Lingfeng Luo, Yuchen Li, Jin Liu and Wenchang Zhang

      Version of Record online: 11 SEP 2017 | DOI: 10.1002/jat.3516

      Cadmium exposure affects alternative splicing of the kitl pre-mRNA in murine ovarian granulosa cells. The miRNA expression profile of murine ovarian granulosa cells after Cd exposure showed characteristic changes, and the expression of 29 miRNAs involved in alternative splicing of the kitl pre-mRNA was changed. Mmu-miR-34b-5p and mmu-miR-107-3p may be involved in alternative splicing of the kitl pre-mRNA in murine ovarian granulosa cells.

    3. Relationship between peroxisome proliferator-activated receptor alpha activity and cellular concentration of 14 perfluoroalkyl substances in HepG2 cells

      Anna Kjerstine Rosenmai, Lutz Ahrens, Théo le Godec, Johan Lundqvist and Agneta Oskarsson

      Version of Record online: 31 AUG 2017 | DOI: 10.1002/jat.3515

      The relationship between peroxisome proliferator-activated receptor alpha (PPARα) activity and cellular concentrations of perfluoroalkyl substances was investigated in HepG2 cells. PPARα activity was determined in transiently transfected cells by reporter gene assay and cellular concentrations by high-performance liquid chromatography-tandem mass spectrometry The cellular concentrations and PPARα activity of perfluoroalkyl substances was dependent on perfluorocarbon chain -length and functional group, and positive relationships between PPARα activity and cellular concentrations were established for all compounds, except perfluorooctane sulfonate and perfluorooctane sulfonamide


    1. Chronic arsenic intoxication diagnostic score (CAsIDS)

      Sergio Ulhoa Dani and Gerhard Franz Walter

      Version of Record online: 31 AUG 2017 | DOI: 10.1002/jat.3512

      Based on a review of the literature as well as our own clinical experience, we propose a chronic arsenic intoxication diagnostic score (CAsIDS). A distinctive feature of CAsIDS is the use of bone arsenic load as an essential criterion for the individual risk assessment of chronic arsenic intoxication, combined with a systemic clinical assessment. We present clinical examples where CAsIDS is applied for the diagnosis of CAsI, review the main topics of the toxicity of arsenic in different cell and organ systems and discuss the therapy and prevention of disease caused or aggravated by chronic arsenic intoxication.


    1. Butyltin compounds alter secretion of interleukin 6 from human immune cells

      Shyretha Brown, Wendy Wilburn, Tyesha Martin and Margaret Whalen

      Version of Record online: 24 AUG 2017 | DOI: 10.1002/jat.3514

      Butyltins (BTs) altered interleukin (IL)-6 secretions from increasingly complex preparations of human immune cells. Significant decreases of IL-6 secretion were seen at the highest concentration of tributyltin (200 nm) and dibutyltin (5–2.5 μm) while the lower concentrations of dibutyltin (0.05 and 0.1 μm) caused elevation of IL-6 secretion. The data indicate that BT-induced alterations of IL-6 secretion from immune cells may be a significant consequence of BT exposures that may potentially affect immune competence.

    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.


    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%).

    2. 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.

  7. 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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