Journal of Applied Toxicology

Cover image for Vol. 33 Issue 11

November 2013

Volume 33, Issue 11

Pages 1193–1364

  1. Review Article

    1. Top of page
    2. Review Article
    3. Research Articles
    1. Blood transcriptomics: applications in toxicology (pages 1193–1202)

      Pius Joseph, Christina Umbright and Rajendran Sellamuthu

      Version of Record online: 1 MAR 2013 | DOI: 10.1002/jat.2861

      A vast majority of toxic agents target internal organs for their toxicity. The difficulty in obtaining human internal target organs to determine toxicity is a major obstacle in preventing diseases potentially resulting from exposure to toxic agents. Peripheral blood gene expression profiling has been hypothesized as a practical, highly sensitive and mechanistically relevant surrogate approach to determine target organ toxicity. Recent developments in this emerging toxicology research area, with a special emphasis on hepatotoxicity and pulmonary toxicity, are discussed in this review article.

  2. Research Articles

    1. Top of page
    2. Review Article
    3. Research Articles
    1. Effects of individual and a mixture of pharmaceuticals and personal-care products on cytotoxicity, EROD activity and ROS production in a rainbow trout gonadal cell line (RTG-2) (pages 1203–1212)

      Carlos Fernández, Gregoria Carbonell and Mar Babín

      Version of Record online: 21 JUN 2012 | DOI: 10.1002/jat.2752

      The presence of pharmaceuticals and personal-care products (PPCPs) in aquatic environments is of concern. The aim of the present study was to use the RTG-2 cell line to analyse toxic effects of PPCPs present in wastewater-treatment-plant (WWTPs) effluents and their mixtures. The present study clearly shows that the stress response through which cells mount a homeostatic response to toxicants can be potentially used for an initial, rapid and cost-effective assessment of the complex mixtures of PPCP present in WWTP effluents.

    2. Developmental effects of oral exposure to diethylstilbestrol on mouse placenta (pages 1213–1221)

      Tetsuji Nagao, Nao Kagawa, Yoshiaki Saito and Munekazu Komada

      Version of Record online: 25 JUN 2012 | DOI: 10.1002/jat.2766

      Developmental effects of synthetic estrogen, diethylstilbestrol (DES), on mouse placentas were investigated by oral administration during early to mid-stage of gestation. Dose-dependent embryo mortality was observed. Exposure to DES impaired the development of the labyrinth and induced poor rough-surfaced endoplasmic reticulum in trophoblast giant cells. The results suggest that developmental changes induced by DES may be related to interference with nutrition and oxygen exchange between mother and fetus or a decrease in protein synthesis, resulting in fetal mortality.

    3. Ecotoxicity and screening level ecotoxicological risk assessment of five antimicrobial agents: triclosan, triclocarban, resorcinol, phenoxyethanol and p-thymol (pages 1222–1229)

      Ikumi Tamura, Kei-ichiro Kagota, Yusuke Yasuda, Saori Yoneda, Junpei Morita, Norihide Nakada, Yutaka Kameda, Kumiko Kimura, Norihisa Tatarazako and Hiroshi Yamamoto

      Version of Record online: 13 JUL 2012 | DOI: 10.1002/jat.2771

      Acute and chronic (or sub-chronic) toxicity of five selected antimicrobial agents, triclosan, triclocarban, resorcinol, phenoxyethanol and p-thymol, was investigated using green algae, daphnia and fish. Having compared the predicted no effect concentration (PNEC) determined from the toxicity data with measured environmental concentrations (MEC), a preliminary ecological risk assessment of these antimicrobials was conducted. The MEC/PNEC ratios were >1 for triclosan and triclocarban for some sites but were <0.1 for the other compounds in most cases.

    4. Modulation of aryl hydrocarbon receptor-regulated genes by acute administration of ammonium metavanadate in kidney, lung and heart of C57BL/6 mice (pages 1230–1240)

      Ghada Abdelhamid, Issa E.A. Amara, Anwar Anwar-Mohamed and Ayman O.S. El-Kadi

      Version of Record online: 18 MAY 2012 | DOI: 10.1002/jat.2774

      We previously reported that V5+ was able to decrease the TCDD-mediated induction of Cyp1a1 and Nqo1 gene expression levels in Hepa 1c1c7 and HepG2 cells; however, little is known regarding the in vivo effect. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of co-exposure to V5+ and TCDD on the AhR-regulated genes. Our results demonstrated that V5+ modulates TCDD-induced AhR-regulated genes.

    5. Establishment and intra-/inter-laboratory validation of a standard protocol of reactive oxygen species assay for chemical photosafety evaluation (pages 1241–1250)

      Satomi Onoue, Kazuhiro Hosoi, Shinobu Wakuri, Yumiko Iwase, Toshinobu Yamamoto, Naoko Matsuoka, Kazuichi Nakamura, Tsuguto Toda, Hironori Takagi, Naoto Osaki, Yasuhiro Matsumoto, Satoru Kawakami, Yoshiki Seto, Masashi Kato, Shizuo Yamada, Yasuo Ohno and Hajime Kojima

      Version of Record online: 13 JUN 2012 | DOI: 10.1002/jat.2776

      In three participating laboratories, photochemical reactivities of 42 coded chemicals and two standard controls were assessed by reactive oxygen species (ROS) assay for photosafety evaluation. Outcomes from the validation study were indicative of satisfactory transferability, intra- and inter-laboratory variability, and predictive capacity of the ROS assay. Thus, results from the present validation study provided sufficient support for the ROS assay as an alternative method for photosafety assessment.

    6. Potential metabolomic biomarkers for evaluation of adriamycin efficacy using a urinary 1H-NMR spectroscopy (pages 1251–1259)

      Kyu-Bong Kim, Ji-Young Yang, Seung Jun Kwack, Hyung Sik Kim, Do Hyun Ryu, Yeon-Joo Kim, Jung Yun Bae, Duck Soo Lim, Seul Min Choi, Mi Jung Kwon, Du Yeon Bang, Seong Kwang Lim, Young Woo Kim, Geum-Sook Hwang and Byung-Mu Lee

      Version of Record online: 11 JUL 2012 | DOI: 10.1002/jat.2778

      A metabolomics approach using proton nuclear magnetic resonance (NMR) was applied to investigate metabolic alterations following adriamycin (ADR) treatment for gastric adenocarcinoma. After BALB/c-nu/nu mice were implanted with human gastric adenocarcinoma, ADR (1 or 3 mg kg−1 per day) was intraperitoneally administered for 5 days. Urinary endogenous metabolites related to the TCA cycle might be considered as therapeutic targets to potentiate the efficacy of ADR.

    7. DNA damage kinetics and apoptosis in ivermectin-treated chinese hamster ovary cells (pages 1260–1267)

      Gabriela Molinari, Maciej Kujawski, Anna Scuto, Sonia Soloneski and Marcelo L. Larramendy

      Version of Record online: 7 SEP 2012 | DOI: 10.1002/jat.2782

      Ivermectin (IVM)- and Ivomec® (IVO)-induced DNA damage kinetics was analyzed by SCGE in CHO-K1 treated with 50 µg ml–1 for 80 min. Viability remained unchanged up to 3 h. Afterwards, survival decreased up to 79% at 6 h, remaining unchanged within 12-24 h. An increase of induced damage was observed within 0-3 h whereas a decrease was revealed during the final 18 h. Both compounds induced apoptosis. The decrease in DNA lesions is mostly related to cytotoxicity than repair.

    8. Perfluorooctane sulfonate induces apoptosis in lung cancer A549 cells through reactive oxygen species-mediated mitochondrion-dependent pathway (pages 1268–1276)

      Zhenxing Mao, Wei Xia, Jun Wang, Tian Chen, Qianqian Zeng, Bing Xu, Weiyong Li, Xi Chen and Shunqing Xu

      Version of Record online: 13 SEP 2012 | DOI: 10.1002/jat.2785

      Perfluorooctane sulfonate (PFOS) is a widespread environmental contaminant that is detected in the lung of mammalian. The mechanisms underlying PFOS-induced lung cytotoxicity remain unclear. We treated human lung cancer A549 cells with PFOS and the cellular apoptosis, mitochondrial membrane potential, intracellular ROS were determined. PFOS induced a dose-dependent increase in A549 cells toxicity via apoptosis pathway with obvious oxidative stress. N-acetylcysteine (NAC) as an antioxidant can block PFOS-induced ROS generation, mitochondrial membrane potential loss and cell apoptosis.

    9. Exposure time to caffeine affects heartbeat and cell damage-related gene expression of zebrafish Danio rerio embryos at early developmental stages (pages 1277–1283)

      Tamer Said Abdelkader, Seo-Na Chang, Tae-Hyun Kim, Juha Song, Dong Su Kim and Jae-Hak Park

      Version of Record online: 9 AUG 2012 | DOI: 10.1002/jat.2787

      Caffeine has various biological effects. Effect of (100 μM) caffeine on heartbeat, survival and expression of cell damage-related genes were studied. Hatching decreased significantly in caffeine treatment at 60 and 72 hpf. Heartbeat increased significantly at 72 and 96 hpf. Significant up-regulation was found in all tested genes, Bax/Bcl2 ratio, and significant down-regulation in Bcl2. Caffeine exposure, increase heartbeats, stimulates oxidative stress and may trigger apoptosis via a mitochondrial-dependent pathway. Use of caffeine harm the human fetus by affecting the cell-damage related genes.

    10. Toxicogenomics discrimination of potential hepatocarcinogenicity of non-genotoxic compounds in rat liver (pages 1284–1293)

      Fumihiro Yamada, Kayo Sumida, Takeki Uehara, Yuji Morikawa, Hiroshi Yamada, Tetsuro Urushidani and Yasuo Ohno

      Version of Record online: 13 JUL 2012 | DOI: 10.1002/jat.2790

      Toxicogenomics was applied to develop a good model for the carcinogenicity prediction.

    11. Microcystin-LR induces cytotoxicity and affects carp immune cells by impairment of their phagocytosis and the organization of the cytoskeleton (pages 1294–1302)

      Anna Rymuszka

      Version of Record online: 25 SEP 2012 | DOI: 10.1002/jat.2791

      The present study investigated the in vitro toxic microcystin-LR (MC-LR) effects on immune cells isolated from the blood of carp. Moreover, the effect of the toxin on the phagocytic activity of leukocytes and on actin and tubulin re-organization in phagocytic cells was studied. Incubation of the cells with MC-LR inhibited phagocytosis without affecting apoptosis or glutathione levels. The toxin induced a significant re-organization of the actin cytoskeleton in phagocytes. These results suggest that fish phagocytes and lymphocytes are targets for MC-LR.

    12. Evaluation of the GADD45α-GFP GreenScreen HC assay for rapid and reliable in vitro early genotoxicity screening (pages 1303–1315)

      Anne-Pascale Luzy, Nicolas Orsini, Jean-Michel Linget and Guy Bouvier

      Version of Record online: 13 JUL 2012 | DOI: 10.1002/jat.2793

      Proprietary and reference molecules were used to compare the GADD45α-GFP ‘GreenScreen HC’ assay (GS) with in vitro screening tests. The GS renders the SOS-ChromoTest obsolete, confirms all results of the mini-Ames test and shows concordance of 82% with the micronucleus assay. The GS detected accurately catecholamines, carbendazim, tetracycline antibiotics and carbaryl. The GS produced negative results for metronidazole, dexamethasone, for rosiglitazone and for clindamycin and neomycin. The GS appears reproducible, robust, specific and sensitive test for genotoxicity screening.

    13. Proteomic profiling of halloysite clay nanotube exposure in intestinal cell co-culture (pages 1316–1329)

      Xianyin Lai, Mangilal Agarwal, Yuri M. Lvov, Chetan Pachpande, Kody Varahramyan and Frank A. Witzmann

      Version of Record online: 22 APR 2013 | DOI: 10.1002/jat.2858

      In view of their potential application in oral drug delivery, we investigated the effect of halloysite nanotubes in an in vitro model of the large intestine. Toxicity tests and label-free quantitative mass spectrometric analysis indicate that halloysite exhibits a high degree of biocompatibility characterized by an absence of cytotoxicity, despite elevated proinflammatory cytokine release. Bioinformatic analysis of differentially expressed protein profiles suggest that halloysite stimulates processes related to cell growth and proliferation, subtle responses to cell infection, irritation and injury, enhanced antioxidant capability, and an overall adaptive response to exposure.

    14. Identification of endogenous reference genes for RT-qPCR analysis of plasma microRNAs levels in rats with acetaminophen-induced hepatotoxicity (pages 1330–1336)

      Yan Wang, Naping Tang, Taotao Hui, Shuyan Wang, Xiancheng Zeng, Hua Li and Jing Ma

      Version of Record online: 4 APR 2013 | DOI: 10.1002/jat.2864

      In the present study, we perform the first systematic reference gene screening for normalization of plasma miRNA quantitative real-time PCR (RT-qPCR) data in a rat model of acetaminophen-induced hepatotoxicity. By employing four independent algorithms, we evaluated the expression stability of six candidate reference genes and results show that U6 and 5S, two of the most commonly used housekeeping genes, were not ideal reference genes and miR-103 was verified to be a most stable normalizer for circulating microRNAs analysis in rats with acetaminophen-induced liver injury.

    15. A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation (pages 1337–1352)

      Andreas Natsch, Cindy A. Ryan, Leslie Foertsch, Roger Emter, Joanna Jaworska, Frank Gerberick and Petra Kern

      Version of Record online: 9 APR 2013 | DOI: 10.1002/jat.2868

      Alternative tests for skin sensitization under prevalidation address three endpoints: surface marker expression on dendritic cell lines, peptide reactivity and activation of Nrf2. Here we report a database on 145 chemicals measured in a dendritic cell activation test, the direct peptide reactivity assays and the KeratinoSensTM assay. This comprehensive database may serve to develop a data-driven integrated testing strategy and serve as reference database when benchmarking new molecules with in vitro based read-across.

    16. Bayesian integrated testing strategy to assess skin sensitization potency: from theory to practice (pages 1353–1364)

      Joanna Jaworska, Yuri Dancik, Petra Kern, Frank Gerberick and Andreas Natsch

      Version of Record online: 14 MAY 2013 | DOI: 10.1002/jat.2869

      The current challenge in safety assessments is to find ways to integrate mechanistic insight, in vitro data, in silico and in chemico information to predict in vivo effects. This study follows up on our proof of concept work and presents an updated Integrated Testing Strategy (ITS) to assess skin sensitization potency. The refined ITS predicted correctly 95% and 86% of chemicals in a test set (n = 21) for hazard and local lymph node assay (LLNA) potency classes, respectively. The study includes a detailed validation analysis and illustrations of practical applications.