Journal of Applied Toxicology

Cover image for Vol. 33 Issue 12

December 2013

Volume 33, Issue 12

Pages 1365–1524

  1. Review Article

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communications
    1. Review: Toxicometabolomics (pages 1365–1383)

      Mounir Bouhifd, Thomas Hartung, Helena T. Hogberg, Andre Kleensang and Liang Zhao

      Version of Record online: 30 MAY 2013 | DOI: 10.1002/jat.2874

      This review summarizes the current state of metabolomics technologies and principles, their uses in toxicology and gives a thorough overview on metabolomics bioinformatics, pathway identification and quality assurance

  2. Research Articles

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communications
    1. Maternal lead exposure during lactation persistently impairs testicular development and steroidogenesis in male offspring (pages 1384–1394)

      Hua Wang, Yan-Li Ji, Qun Wang, Xian-Feng Zhao, Huan Ning, Ping Liu, Cheng Zhang, Tao Yu, Ying Zhang, Xiu-Hong Meng and De-Xiang Xu

      Version of Record online: 13 JUL 2012 | DOI: 10.1002/jat.2795

      Lead (Pb) is a testicular toxicant. In the present study, we investigated the effects of maternal Pb exposure during lactation on testicular development and steroidogenesis in male offspring. Maternal mice were exposed to different concentration of lead acetate (200 or 2000 ppm) through drinking water from postnatal day (PND) 0 to PND21. Results showed that Pb could be transported from dams to pups through milk. Maternal Pb exposure during lactation persistently disrupted testicular development and steroidogenesis in male offspring.

    2. Development of a chronic noncancer oral reference dose and drinking water screening level for sulfolane using benchmark dose modeling (pages 1395–1406)

      Chad M. Thompson, David W. Gaylor, J. Andrew Tachovsky, Camarie Perry, Michael C. Carakostas and Laurie C. Haws

      Version of Record online: 31 AUG 2012 | DOI: 10.1002/jat.2799

      Sulfolane is a widely used industrial solvent that is often used for gas treatment, in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent. The lowest, most conservative, RfD of 0.01 mg kg−1 per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l−1.

    3. Unraveling toxicological mechanisms and predicting toxicity classes with gene dysregulation networks (pages 1407–1415)

      Tessa E. Pronk, Eugene P. van Someren, Rob H. Stierum, Janine Ezendam and Jeroen L.A. Pennings

      Version of Record online: 10 AUG 2012 | DOI: 10.1002/jat.2800

      In this paper we combine network reconstruction with classification of unseen compounds to their appropriate toxicity class. We select gene pairs that are linked by a common expression pattern in one class and differ in this expression pattern in another class. The resulting gene dysregulation network provides novel and well-distinguishing pairs of markers. Moreover, paired expressions by their specific pattern generate new hypotheses on regulatory origin and/or common functionality of genes in the pairs, and how these differ between classes.

    4. Hepatic gene expression analysis of mice exposed to raw water from Meiliang Bay, Lake Taihu, China (pages 1416–1423)

      Bing Wu, Su Liu, Shupei Cheng, Yan Zhang and Xuxiang Zhang

      Version of Record online: 17 AUG 2012 | DOI: 10.1002/jat.2805

      Male mice were exposed to raw water from Meiliang Bay, Lake Taihu, China for 90 days. Hepatic transcriptomic profiles were determined. Compared with control group, raw water altered expression of 170 hepatic genes. Nine biological processes and nine biological pathways were significantly perturbed, mainly linked to the regulation of cell processes, DNA repair, chromatin modification, oxidative reduction and carbohydrate metabolism. This study provided excellent insights into early toxicological effects related to raw Lake Taihu water.

    5. Low dose of carbon monoxide intraperitoneal injection provides potent protection against GalN/LPS-induced acute liver injury in mice (pages 1424–1432)

      Zongmei Wen, Yan Liu, Feng Li and Tao Wen

      Version of Record online: 27 SEP 2012 | DOI: 10.1002/jat.2806

      The protective effects of exogenous CO via intraperitoneal injection were investigated in a murine model of acute liver damage induced by GalN/LPS. It showed that CO remarkably improved the survival rate of mice and led to attenuated hepatocellular damage. CO inhibits hepatic MDA contents and restores SOD and GSH, as well as reducing iNOS/NO production. Additionally, CO substantially inhibits hepatocyte apoptosis and reduces pro-inflammatory cytokines levels. Thus, the protective effects of CO are mainly dependent on its anti-oxidative, anti-inflammatory and anti-apoptotic properties.

    6. Oxidative DNA damage and in vivo mutagenicity caused by reactive oxygen species generated in the livers of p53-proficient or -deficient gpt delta mice treated with non-genotoxic hepatocarcinogens (pages 1433–1441)

      Masako Tasaki, Yuichi Kuroiwa, Tomoki Inoue, Daisuke Hibi, Kohei Matsushita, Yuji Ishii, Soichi Maruyama, Takehiko Nohmi, Akiyoshi Nishikawa and Takashi Umemura

      Version of Record online: 12 SEP 2012 | DOI: 10.1002/jat.2807

      p53-proficient and -deficient gpt delta mice were given pentachlorophenol (PCP), phenobarbital (PhB), or piperonylbutoxide (PBO) for 13 weeks. PCP or PBO significantly increased 8-OHdG levels in liver DNA. PhB or PBO significantly elevated CYP 2B10 mRNA levels while NQO1 levels were significantly increased in PCP- or PBO-treated mice. They failed to increase gpt and red/gam gene mutations in the liver independently of p53. The action of oxidative stress by these chemicals is likely limited to tumor promotion.

    7. Metabolic profiling reveals disorder of carbohydrate metabolism in mouse fibroblast cells induced by titanium dioxide nanoparticles (pages 1442–1450)

      Chengyu Jin, Yumin Liu, Limin Sun, Tianlu Chen, Yinan Zhang, Aihua Zhao, Xiaoyan Wang, Melanie Cristau, Kaisheng Wang and Wei Jia

      Version of Record online: 20 SEP 2012 | DOI: 10.1002/jat.2808

      In this study, the cytotoxicity of TiO2 nanoparticles was investigated by analyzing the changes in metabolite profiles both in mouse fibroblast (L929) cells and their corresponding culture media using gas chromatograph with a time-of-flight mass spectrometry (GC/TOFMS)-based metabolomic strategy. It was found that the major biochemical metabolism (carbohydrate metabolism) was suppressed in TiO2 nanoparticle-treated L929 cells and their corresponding culture media. These results might account for the serious damage to energy metabolism in mitochondria and the increased cellular oxidation stress in TiO2 nanoparticle-induced L929 cells.

    8. Brominated flame retardants stimulate mouse immune cells in vitro (pages 1451–1459)

      Eiko Koike, Rie Yanagisawa, Hidetaka Takigami and Hirohisa Takano

      Version of Record online: 12 SEP 2012 | DOI: 10.1002/jat.2809

      Brominated flame retardants (BFRs) are widely used in consumer products. To evaluate the effects of BFRs on immune responses, we investigated whether BFRs affect phenotypes and the function of splenocytes and bone marrow-derived dendritic cells in vitro. Polybrominated diphenyl ethers, hexabromocyclododecane, and tetrabromobisphenol A were examined. The results demonstrate that some BFRs may stimulate immune cells. BFRs can induce or enhance immune/allergic responses by increasing antigen presentation-related molecule expression and interleukin-4 production.

    9. Quercetin reduces oxidative damage induced by paraquat via modulating expression of antioxidant genes in A549 cells (pages 1460–1467)

      Tamanna Zerin, Yong-Sik Kim, Sae-Yong Hong and Ho-Yeon Song

      Version of Record online: 20 SEP 2012 | DOI: 10.1002/jat.2812

      We examined quercetin-mediated changes in the expression of genes associated with oxidative stress and antioxidant defense in A549 type II-like alveolar epithelial cells exposed to PQ. Quercetin was shown to attenuate PQ-induced oxidative damage in alveolar A549 cells through the activation of the transcription factor Nrf2, induction of its target HO-1 expression and other antioxidant-related genes, which ultimately improves cell viability by reducing cellular ROS and increasing cellular GSH. These combined results indicate that quercetin may be used to mitigate or minimize oxidative stress via reduction of oxygen radicals.

    10. Protective effect of curcumin against formaldehyde-induced genotoxicity in A549 Cell Lines (pages 1468–1473)

      Ben-Yan Zhang, Yu-Qin Shi, Xin Chen, Juan Dai, Zhong-Fa Jiang, Ning Li and Zhi-Bing Zhang

      Version of Record online: 12 OCT 2012 | DOI: 10.1002/jat.2814

      Formaldehyde is ubiquitous in the environment. It is a genotoxic substance. In this study, we investigated the effects of antioxidant on formaldehyde-induced genotoxicity in A549 Cell Lines. Formaldehyde caused induction of DPCs, increased MDA levels, and decreased SOD and GSH-Px activity. Moreover, the activation of NF-κB and AP-1 were induced. Curcumin is an important antioxidant. Pretreatment with curcumin could counteracted above effects. These results suggest that formaldehyde-induced genotoxicity induce through its ROS and lipid peroxidation and cause DPCs effects.

    11. Initial preclinical safety of non-replicating human endogenous retrovirus envelope protein-coated baculovirus vector-based vaccines against human papillomavirus (pages 1474–1483)

      Su-Eun Han, Mi-Gyeong Kim, Soondong Lee, Hee-Jeong Cho, Youngro Byun, Sujeong Kim, Young Bong Kim, Yongseok Choi and Yu-Kyoung Oh

      Version of Record online: 14 SEP 2012 | DOI: 10.1002/jat.2815

      Human endogenous retrovirus (HERV) envelope protein-coated, baculovirus vector-based HPV16L1 (AcHERV-HPV16L1) is a non-replicating DNA vaccine. AcHERV-HPV16L1 DNA vaccine did not cause significant changes in body weight. No hematological changes were observed on day 30 post-treatment. In a repeated-dose toxicity study, a transient decrease in the body weights was recovered by post-treatment day 20. Organ weights had normalized by day 30. A AcHERV-based HPV16L1 DNA vaccine demonstrated preclinical safety criteria in acute and range-finding toxicity studies.

    12. Diethyl phthalate enhances expression of SIRT1 and DNMT3a during apoptosis in PC12 cells (pages 1484–1492)

      Yongkun Sun, Zhikun Guo, Shouhei Iku, Takeshi Saito and Masaaki Kurasaki

      Version of Record online: 11 SEP 2012 | DOI: 10.1002/jat.2816

      We investigate whether diethyl phthalate, one of the potential endocrine disrupters, affect sirtuins (SIRT1 and SIRT2) and methyltranferases (DNMT1 and DNMT3a) on the apoptosis of PC12 cells, because diethyl phthalate was reported previously to enhance apoptosis induced by serum deprivation. We found that DNMT3a was significantly decreased by serum deprivation. However, DNMT3a, DNMT3b and SIRT1were significantly increased under the enhancement of apoptosis induced by serum deprivation. These results suggest that SIRT1, DNMT3a and DNMT3b play multiple and complex roles in different apoptotic stages.

    13. In vivo genotoxicity and cytotoxicity assessment of a novel quinoxalinone with trichomonacide activity (pages 1493–1499)

      Norma Rivera, Marcela Rojas, Armando Zepeda, Filiberto Malagón, Vicente J. Arán, Yovani Marrero-Ponce, Ernesto Rivera and Teresa I. Fortoul

      Version of Record online: 10 OCT 2012 | DOI: 10.1002/jat.2819

      Compound VAM2-6, a 7-nitro-4-(5-piperidinopentyl)quinoxalin-2-one, has been shown previously to exhibit an in vitro trichomonacide efficacy of 100% at a concentration of 100 µg ml–1. The present study was undertaken to evaluate its ability to induce DNA damage in the peripheral blood of mice using the comet and micronucleus assays. Cell viability was assessed by the fluorochrome-mediated viability test. VAM2-6 induced DNA damage in a dose-dependent manner and decreased cell viability 24 h after treatment.

    14. Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells (pages 1500–1505)

      Yu Sun, Shusheng Tang, Xi Jin, Chaoming Zhang, Wenxia Zhao and Xilong Xiao

      Version of Record online: 30 OCT 2012 | DOI: 10.1002/jat.2829

      The aim of this study was to determine the effects of FZD on HepG2 cells by activating and inhibiting p38 MAPK signaling pathway. The cell cycle and proliferation of HepG2 cells treated with FZD were detected by flow cytometry and MTT assay in the presence or absence of p38 MAPK inhibitors (SB203580), respectively. Cyclin D1, cyclin D3, and CDK6 were detected by quantitative real-time PCR and western blot analysis. Our data showed that p38 MAPK became phosphorylated after stimulation with FZD. Activation of p38 MAPK could arise S-phase cell-cycle arrest and suppress cell proliferation. Simultaneously, inhibition of p38 MAPK significantly prevented S-phase cell-cycle arrest, increased the percentage of cell viability, and decreased the expression of cyclin D1, cyclin D3, CDK6. These results demonstrated that FZD arose S-phase cell-cycle arrest via activating p38 MAPK signaling pathway in HepG2 cells. Cyclin D1, cyclin D3, and CDK6 are target genes functioning at the downstream of p38 MAPK in HepG2 cells induced by FZD.

    15. Effects of gold and silver nanoparticles in cultured human osteoarthritic chondrocytes (pages 1506–1513)

      Nicola Antonio Pascarelli, Elena Moretti, Gaia Terzuoli, Antonello Lamboglia, Tommaso Renieri, Antonella Fioravanti and Giulia Collodel

      Version of Record online: 11 SEP 2013 | DOI: 10.1002/jat.2912

      In the present study, we evaluated the effects of the nanoparticles engineered of the gold and silver, of a size frequently used in common industrial products, in cultured human osteoarthritic chondrocytes. We tested different concentrations of nanoparticles up to high concentrations in order to clarify whether these compounds can exert a toxic effect, and in particular to explore their possible ability to penetrate inside the cells and to define their localization.

  3. Short Communications

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communications
    1. Newly developed mouse newborn behavioral testing method for evaluating the risk of neurotoxicity of environmental toxicants (pages 1514–1519)

      Tetsuji Nagao, Nao Kagawa and Munekazu Komada

      Version of Record online: 10 AUG 2012 | DOI: 10.1002/jat.2802

      We developed a rodent newborn behavioral test method for evaluating the risk of neurotoxicity of chemicals, by means of determining the newborn's activity using the tare function of an analytical balance, and confirmed the usefulness of our developed testing method by determining the activity of mouse newborns with microcephaly induced by prenatal exposure to a neurotoxicant, methylnitrosourea.

    2. Combined effects of metal contamination and temperature on the potworm Enchytraeus doerjesi (Oligochaeta) (pages 1520–1524)

      Patricks Voua Otomo, Sophie A. Reinecke and Adriaan J. Reinecke

      Version of Record online: 10 OCT 2012 | DOI: 10.1002/jat.2820

      The separate effects of Cd and Zn were studied on Enchytraeus doerjesi at 15, 20 and 25 °C. Cd LC50/EC50 generally decreased with increasing temperature. Zn LC50/EC50 consistently increased with increasing temperature. This indicates that Cd toxicity to E. doerjesi increases with increasing temperature while Zn toxicity decreases. Increasing temperature may have differential effects on metal toxicity depending on the biological importance of the metal and the endpoints of interest. Further research on more ecologically relevant metal mixtures is needed.