Journal of Applied Toxicology

Cover image for Vol. 34 Issue 2

February 2014

Volume 34, Issue 2

Pages 113–226

  1. Research Articles

    1. Top of page
    2. Research Articles
    3. Short Communication
    1. Environmental epigenetics: from novelty to scientific discipline (pages 113–116)

      Heather H. Burris and Andrea A. Baccarelli

      Version of Record online: 9 JUL 2013 | DOI: 10.1002/jat.2904

      Epigenetic investigation has increased dramatically over the past two decades. Environmental epigenetics remains a small proportion of this growing field, but funding agencies have dedicated increasing proportions of their resources to epigenetic studies. Such investment highlights the hypothesis that epigenetic marks are affected by environmental exposures and the hope that interventions targeted at epigenetic mechanisms may ultimately lead to improved health outcomes. Here we describe our vision for the future of this exciting field.

    2. Fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin transactivates aryl hydrocarbon receptor-responsive element III in the tyrosine hydroxylase immunoreactive neurons of the mouse midbrain (pages 117–126)

      Takashi Tanida, Ken Tasaka, Eiichi Akahoshi, Mitsuko Ishihara-Sugano, Michiko Saito, Shigehisa Kawata, Megumi Danjo, Junko Tokumoto, Youhei Mantani, Daichi Nagahara, Yoshiaki Tabuchi, Toshifumi Yokoyama, Hiroshi Kitagawa, Mitsuhiro Kawata and Nobuhiko Hoshi

      Version of Record online: 8 JAN 2013 | DOI: 10.1002/jat.2839

      Previously, we identified the novel binding motif of aryl hydrocarbon receptor (AhR), “AhR-responsive element III (AHRE-III)” upstream from the tyrosine hydroxylase (TH) gene. We investigated whether or not 2,3,7,8”tetrachlorodibenzo-p-dioxin (TCDD) could regulate AHRE-III transcriptional activitywithin TH-immunoreactive (ir) neurons of midbrain dopaminergic nuclei. Using transgenic mice, it was demonstrated that fetal exposure to TCDD significantly increased TH-ir intensity and the numbers of TH-ir neurons within midbrain at 8 wk. It is suggested that this increase is caused via AhR-AHRE-III-mediated pathway.

    3. Comparing the effects of two neurotoxins in cortical astrocytes obtained from rats of different ages: involvement of oxidative damage (pages 127–138)

      Adriana Alarcón-Aguilar, Viridiana Yazmín González-Puertos, Armando Luna-López, Ambar López-Macay, Julio Morán, Abel Santamaría and Mina Königsberg

      Version of Record online: 21 DEC 2012 | DOI: 10.1002/jat.2841

      Oxidative stress has been recognized as a potential mediator of cell death. Astrocytes play an active role in brain physiology responding to harmful stimuli by activating astrogliosis, which in turn has been associated either with survival or degenerative events. The characterization of the mechanistic actions exerted by different toxins in astrocytes is essential to understand the brain function and pathology. As age plays a critical role in degenerative processes, the aim of this study was to determine whether the administration.

    4. Human cardiotoxic drugs delivered by soaking and microinjection induce cardiovascular toxicity in zebrafish (pages 139–148)

      Jun-Jing Zhu, Yi-Qiao Xu, Jian-Hui He, Hang-Ping Yu, Chang-Jiang Huang, Ji-Min Gao, Qiao-Xiang Dong, Yao-Xian Xuan and Chun-Qi Li

      Version of Record online: 11 JAN 2013 | DOI: 10.1002/jat.2843

      In this study we assessed cardiovascular toxicity of seven known human cardiotoxic drugs (aspirin, clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride) and two non-cardiovascular toxicity drugs (gentamicin sulphate and tetracycline hydrochloride) in zebrafish larvae using six specific phenotypic endpoints: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage and thrombosis. All the tested drugs were delivered into zebrafish by direct soaking and yolk sac microinjection, respectively, and cardiovascular toxicity was quantitatively or qualitatively assessed at 4 and 24 h post drug treatment. The results showed that aspirin accelerated the zebrafish heart rate (tachycardia), whereas clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride induced bradycardia. Quinidine and terfenadine also caused atrioventricular (AV) block. Nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating. All the tested human cardiotoxic drugs also induced pericardial edema and circulatory disturbance in zebrafish. Therewas no sign of cardiovascular toxicity in zebrafish treated with non-cardiotoxic drugs gentamicin sulphate and tetracycline hydrochloride. The overall prediction success rate for cardiotoxic drugs and non-cardiotoxic drugs in zebrafish were 100% (9/9) as compared with human results, suggesting that zebrafish is an excellent animal model for rapid in vivo cardiovascular toxicity screening.

    5. Gas chromatography–mass spectrometry-based profiling of serum fatty acids in acetaminophen-induced liver injured rats (pages 149–157)

      Yin-Hua Xiong, Ying Xu, Li Yang and Zheng-Tao Wang

      Version of Record online: 12 DEC 2012 | DOI: 10.1002/jat.2844

      A simple, accurate and sensitive gas chromatography-mass spectrometry (GC-MS) method has been developed and validated for analyzing the metabolic profile of fatty acids and simultaneous quantification of 18 fatty acids including non-esterified fatty acids (NEFA) and esterified fatty acids (EFA) in acetaminophen (APAP)-induced liver injured and control rats serum.

      Along with the chemometrics analyses of principle component analysis (PCA) and partial least squares- discriminant analysis (PLS-DA), APAP-induced and control rats could be differentiated and NEFAs such as oleic acid (C18:1n9), linoleic acid (C18:2n6), docosahexaenoic acid (C22:6n3) and arachidonic acid (C20:4n6) were identified as the potential biomarkers of APAP-induced hepatic injury.

      The novel combined study of GC-MS analysis and chemometric analysis based on the metabolic profile of fatty acids was a prospective technique for the assessment of chemical-induced hepatotoxicity.

    6. Development of an albuminous reactive oxygen species assay for photosafety evaluation under experimental biomimetic conditions (pages 158–165)

      Satomi Onoue, Masashi Kato and Shizuo Yamada

      Version of Record online: 28 JAN 2013 | DOI: 10.1002/jat.2846

      A new reactive oxygen species (ROS) assay using serum albumin (aROS assay) was developed for photosafety assessment in biomimetic solution, and validation study demonstrated the high robustness of the aROS assay and improved applicability to poorly soluble chemicals. Assessments on 31 test samples were also indicative of good predictive capacity of the aROS assay. The aROS assay may allow photosafety assessment of new drug entities with a wide range of applicability partly under experimental biomimetic conditions.

    7. Enantiomer-specific profenofos-induced cytotoxicity and DNA damage mediated by oxidative stress in rat adrenal pheochromocytoma (PC12) cells (pages 166–175)

      Xianting Lu and Cheng Yu

      Version of Record online: 13 MAR 2013 | DOI: 10.1002/jat.2847

      This study investigated the role of oxidative stress in enantiomer-specific, profenofos (PFF)-induced cytotoxicity and genotoxicity in PC12 cells. A concentration- and time-dependent significant reduction of cell viability and induction of DNA damage, reactive oxygen species, malondialdehyde and gene expression was observed in (−)PFF, while (+)PFF and rac-PFF exhibited these effects to lesser degrees. Pre-treatment with vitamin E (600 μM) caused a significant attenuation in the toxic effect, further strengthening the involvement of oxidative stress in PFF mediated toxicity.

    8. Metabonomics evaluation of urine from rats administered with phorate under long-term and low-level exposure by ultra-performance liquid chromatography-mass spectrometry (pages 176–183)

      Xiaowei Sun, Wei Xu, Yan Zeng, Yurong Hou, Lin Guo, Xiujuan Zhao and Changhao Sun

      Version of Record online: 21 DEC 2012 | DOI: 10.1002/jat.2848

      The purpose of this study was to investigate the toxic effect of long-term and low-level exposure to phorate using a metabonomics approach. Male Wistar rats were given phorate daily in drinking water at low doses of 0.05, 0.15 or 0.45 mg kg–1 body weight (BW) for 24 weeks consecutively. The control group was given an equivalent volume of drinking water. Compared with the control group, 12 metabolites were significantly changed in the phorate-treated groups. Diethylthiophosphate (DETP) was considered as a biomarker of exposure to phorate. Phorate can cause disturbances in the energy-related metabolism, and other tissues and cell damages.

    9. Early detection of renal injury using urinary vanin-1 in rats with experimental colitis (pages 184–190)

      Keiko Hosohata, Hitoshi Ando and Akio Fujimura

      Version of Record online: 11 JAN 2013 | DOI: 10.1002/jat.2849

      Renal complications are often detected in patients with inflammatory bowel disease (IBD). Because renal conventional markers are not sensitive and/or specific, a new renal biomarker is needed. We have recently identified urinary vanin-1 as an early biomarker for the detection of nephrotoxicant-induced renal injury. In this study, we compared the usefulness of urinary vanin-1 with other newly developed biomarkers for the detection of renal complications in rats with experimental colitis.

    10. Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death (pages 191–204)

      Yoo Seob Shin, Suk Jin Song, SungUn Kang, Hye Sook Hwang, Young-Sik Jung and Chul-Ho Kim

      Version of Record online: 8 JAN 2013 | DOI: 10.1002/jat.2852

      We evaluated the effectiveness of a novel synthetic compound, 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR-22335) as an otoprotective agent against cisplatin. The effect of KR-22335 was tested in HEI-OC1 cells and in a zebrafish model. KR-22335 inhibited cisplatin-induced apoptosis, mitochondrial injury, and activation of JNK, p-38, caspase-3 and PARP in HEI-OC1 cells. KR-22335 prevented cisplatin-induced destruction of zebrafish neuromasts. The results of this study suggest that KR-22335 may prevent ototoxicity caused by cisplatin through the inhibition of mitochondrial dysfunction and suppression of ROS generation.

    11. Acute enhancement of non-rapid eye movement sleep in rats after drinking water contaminated with cadmium chloride (pages 205–213)

      Katsuya Unno, Kurumi Yamoto, Kouhei Takeuchi, Aya Kataoka, Tomoya Ozaki, Takatoshi Mochizuki, Kazuki Honda, Nobuhiko Miura and Masayuki Ikeda

      Version of Record online: 24 JAN 2013 | DOI: 10.1002/jat.2853

      Drinking water contaminated with 100 ppm CdCl2 promoted non-rapid-eye-movement (REM) sleep and reduced locomotor activities during the active phase of rats. The duration of CdCl2 exposure required to modify these behaviors (28 h) was far shorter than that to produce apparent hepatic/renal damage by cadmium ingestion. Because CdCl2 administration increased the cerebral concentration of oxidized glutathione, we suggest cadmium-induced sleep as a response for oxidative stress clearance. We propose that facilitated non-REM sleep could be a behavioral marker for CdCl2 poisoning.

    12. Set-up of an infrared fast behavioral assay using zebrafish (Danio rerio) larvae, and its application in compound biotoxicity screening (pages 214–219)

      Darío Bichara, Nora B. Calcaterra, Silvia Arranz, Pablo Armas and Sergio H. Simonetta

      Version of Record online: 11 FEB 2013 | DOI: 10.1002/jat.2856

    13. Induction and transfer of resistance to poisoning by Amorimia (Mascagnia) septentrionalis in goats (pages 220–223)

      Amélia L. L. Duarte, Rosane M. T. Medeiros, Fabrício K. L. Carvalho, Stephen T. Lee, Daniel Cook, James A. Pfister, Valéria M. M. Costa and Franklin Riet-Correa

      Version of Record online: 12 FEB 2013 | DOI: 10.1002/jat.2860

      Amorimiaseptentrionalis contains sodium monofluoroactetate and can cause acute heart failure in ruminants when ingested in toxic doses. In this study we demonstrate that resistance to poisoning by A. septentrionalis can be improved in goats by the repeated administration of non-toxic doses of A. septentrionalis. We also show that increased resistance to poisoning by A. septentrionalis can also be achieved by the transfaunation of ruminal content from goats previously conditioned to beresistant to naïve goats.

  2. Short Communication

    1. Top of page
    2. Research Articles
    3. Short Communication
    1. In vitro exposure to cigarette smoke induces oxidative stress in follicular cells of F1 hybrid mice (pages 224–226)

      Shabana Siddique, Jean C. Sadeu, Warren G. Foster, Yong-lai Feng and Jiping Zhu

      Version of Record online: 30 MAY 2013 | DOI: 10.1002/jat.2884

      Influence of cigarette smoke condensate (CSC) and benzo(a)pyrene (B(a)P) on the levels of two oxidative stress biomarkers (8-isoprostane and 8-hydroxy-2-deoxy Guanosine)in spent media of follicle cellswas assessed. CSC and B(a)P treatment induced a significant, dose-dependent increase in the concentrations of these two markers, indicating that CSC and B(a)P exposure can induce oxidative stress in ovarian follicles.