Journal of Applied Toxicology

Cover image for Vol. 33 Issue 7

July 2013

Volume 33, Issue 7

Pages 527–699

  1. Review Article

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communication
    1. The effect of zinc and the role of p53 in copper-induced cellular stress responses (pages 527–536)

      Alessia Formigari, Elisa Gregianin and Paola Irato

      Version of Record online: 11 FEB 2013 | DOI: 10.1002/jat.2854

      Metals can cause an increase in reactive oxygen species (ROS) accumulation resulting in programmed cell death. The exact role that zinc (Zn) plays in the regulation of apoptosis remains ambiguous. Intracellular free Zn modulates p53 activity and stability, excess Zn alters p53 protein structure and down-regulates binding to DNA. Copper (Cu) accumulation causes apoptosis that is mediated by DNA damage and subsequent p53 activation. This review discusses a central role of Zn and of p53 in cellular stress responses induced by redox active biometal Cu.

  2. Research Articles

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communication
    1. Aneugenic potential of the anticancer drugs melphalan and chlorambucil. The involvement of apoptosis and chromosome segregation regulating proteins (pages 537–545)

      Maria Efthimiou, Georgia Stephanou, Nikos A. Demopoulos and Sotiris S. Nikolaropoulos

      Version of Record online: 25 OCT 2011 | DOI: 10.1002/jat.1743

      It is known that melphalan and chlorambucil exert aneugenic potential mediated through centrosome amplification. To further investigate their aneugenicity we: a) studied whether apoptosis is a mechanism for the elimination of damaged cells generated and b) investigated if chromosome segregation regulating proteins are involved in the modulation of their aneugenicity. We found that: a) apoptosis is not the mechanism of choice for selectively eliminating cells with supernumerary centrosomes and b) the proteins aurora-A, aurora-B and survivin are involved in the modulation of melphalan and chlorambucil aneugenicity.

    2. Proteomic characterization of the late and persistent effects of cadmium at low doses on the rat liver (pages 546–557)

      Bo Wang, Shi Wang, Chen Shao, Guangyi Wang, Yang Li and Lu Cai

      Version of Record online: 11 NOV 2011 | DOI: 10.1002/jat.1757

      Hepatic effects of low-dose cadmium were examined in male Wistar rats given i.p. injection of Cd at 20 nmol kg−1 body weight every other day for 4 weeks. At weeks 20, 44 and 52 after Cd treatment, the livers from Cd-treated and control rats were sampled. Mild histopathological changes, persistent oxidative damage and cell proliferation remained at weeks 44–52. These persistent changes may be associated with the persistent down-regulation of cellular antioxidant systems.

    3. Inter-relationships between different classes of chemical allergens (pages 558–565)

      R. J. Dearman, D. A. Basketter and I Kimber

      Version of Record online: 23 JAN 2012 | DOI: 10.1002/jat.1758

      Sensitisation of the respiratory tract by chemicals associated with occupational asthma is an important occupational health problem. Here the relationships between skin sensitising chemicals and those that preferentially or exclusively cause respiratory sensitisation is explored. It is demonstrated that chemical respiratory allergens test positive in standard methods for the identification of skin sensitising chemicals, and that this might provide important component of the hazard identification process for these chemicals.

    4. iTRAQ: a method to elucidate cellular responses to mycotoxin zearalenone (pages 566–575)

      Amel Chatti Gazzah, Luc Camoin, Salwa Abid, Hassen Bacha and Moncef Ladjimi

      Version of Record online: 25 JUN 2012 | DOI: 10.1002/jat.1766

      The mycotoxin Zearalenone (ZEN) has been associated with a variety of adverse health effects. In order to better understood the mechanism of ZEN toxicity, a proteomic approach, based on the isotope approach iTRAQ, was applied to characterize cellular responses of HepG2 cells to ZEN exposure. This study identified about 982 proteins among which identification and quantification by MALDI-TOF (MS). IPA software was then used to determine the biological functions and canonical pathways associated with the ZEN-responsive proteins.

    5. Toxic effects of cypermethrin on the male reproductive system: with emphasis on the androgen receptor (pages 576–585)

      Jin-xia Hu, Yan-fang Li, Jing Li, Chen Pan, Zhen He, Hong-yan Dong and Li-chun Xu

      Version of Record online: 6 DEC 2011 | DOI: 10.1002/jat.1769

      The adult male rats were treated with different doses of cypermethrin by gavage for consecutive 15 days. The weights of prostates and daily sperm production decreased. Seminiferous tubule changes included atrophy and distortion, reduction and deformation of spermatogonia and spermatocyte. Ultrastructural changes included disrupted cellular junctions, abnormal nucleus, necrosis of spermatogonia, spermatocytes and Sertoli cells. AR expression and serum testosterone reduced. Cypermethrin may impair the seminiferous tubules and spermatogenesis, which can be attributed to the reduced AR expression.

    6. Enantioselective effect of bifenthrin on antioxidant enzyme gene expression and stress protein response in PC12 cells (pages 586–592)

      Xianting Lu

      Version of Record online: 21 JUN 2012 | DOI: 10.1002/jat.1774

      The enantioselective effect of bifenthrin on antioxidant enzyme gene expression and stress protein response in PC12 cells were investigated. The results showed that exposure to 1S-cis-BF resulted in increased transcription of HSP90, HSP70, HSP60, Cu-Zn-SOD, Mn-SOD, CAT and GST, while exposure to 1R-cis-BF and rac-cis-BF exhibited these effects to lesser degrees. Induction of antioxidant enzyme gene expression produced by 1S-cis-BF might occur through activation of p38 MAPK and ERK, while increase of stress protein response might occur through p38 MAPK.

    7. Two-year drinking water carcinogenicity study of methyl tertiary-butyl ether (MTBE) in Wistar rats (pages 593–606)

      Darol Dodd, Gabrielle Willson, Horace Parkinson and Edilberto Bermudez

      Version of Record online: 7 DEC 2011 | DOI: 10.1002/jat.1776

      Exposure of Wistar rats to MTBE in the drinking water for two years resulted in minimal exposure-related effects, including increased kidney weights. Chronic progressive nephropathy was evident in male and female rats and was exacerbated by exposure to MTBE. Brain astrocytomas were present but were not statistically significantly different from concurrent controls and fell within historical control ranges. Furthermore, the brain has not been identified as a target organ in previous chronic studies with MTBE or related compounds.

    8. Toxicokinetic modeling of folpet fungicide and its ring-biomarkers of exposure in humans (pages 607–617)

      Roberto Heredia-Ortiz, Aurélie Berthet and Michèle Bouchard

      Version of Record online: 19 DEC 2011 | DOI: 10.1002/jat.1782

      A human in vivo toxicokinetic model was built to allow a better understanding of the toxicokinetics of folpet fungicide and its key biomarkers of exposure, and to simulate the transformation of folpet into phthalimide and other ring-metabolites: phthalamic and phthalic acids. The model closely reproduced the time courses of phthalimide in blood and urine as well as total ring-metabolites in urine of five volunteers administered orally 1 mg kg−1 and dermally 10 mg kg−1 of folpet.

    9. Effects of Jatropha oil on rats following 28-day oral treatment (pages 618–625)

      Raymond Poon, Victor E. Valli, W. M. Nimal Ratnayake, Marc Rigden and Guillaume Pelletier

      Version of Record online: 22 DEC 2011 | DOI: 10.1002/jat.1785

      Jatropha oil is an emerging feedstock for the production of biodiesels. The increasing use of this non-edible, toxic oil will result in higher potential for accidental exposures. A repeated dose 28-day oral toxicity study was conducted to provide data for risk assessment. It is concluded that Jatropha oil produces adverse effects on female rats starting at 50 mg/kg/day with decreased white blood cell and lymphocyte counts and at 500 mg/kg/day in both genders in term of depressed growth rates.

    10. Protective effects of emodin against cisplatin-induced oxidative stress in cultured human kidney (HEK 293) cells (pages 626–630)

      Mostafa I. Waly, Badreldin H. Ali, Intisar Al-Lawati and Abderrahim Nemmar

      Version of Record online: 23 JAN 2012 | DOI: 10.1002/jat.1788

      Cisplatin inhibited antioxidant enzymes (GST, GPx, GR, SOD and CAT) to a level that is significantly lower than the control group. Meanwhile treatment of cells with cisplatin in the presence of emodin significantly ameliorated the inhibited antioxidant enzymes. Controls contained all the reaction reagents except emodin or cisplatin.

    11. Lead inhibits paraoxonase 2 but not paraoxonase 1 activity in human hepatoma HepG2 cells (pages 631–637)

      Wanida Sukketsiri, Sureerut Porntadavity, Laddawal Phivthong-ngam and Somsong Lawanprasert

      Version of Record online: 23 JAN 2012 | DOI: 10.1002/jat.1789

      Lead-induced liver damage and malfunction are partly due to a disturbance of the cellular antioxidant balance. Paraoxonase 1 (PON1) and PON2 are highly expressed in the liver and have been proposed as antioxidative enzymes. The effects of lead on PON1 and PON2 activities were investigated in human hepatoma HepG2 cells. Lead reduced PON2, but not PON1, activity and that this reduction was reversed by calcium. Lead-induced oxidative stress and decreased PON2 activity lead to the upregulation of PON2 transcript.

    12. Analysis of ethyl glucuronide in hair samples by liquid chromatography-electrospray ionization–tandem mass spectrometry (LC-ESI-MS/MS) (pages 638–643)

      Pamela Cabarcos, Huda M. Hassan, María Jesús Tabernero and Karen S. Scott

      Version of Record online: 10 JAN 2012 | DOI: 10.1002/jat.1791

      Many different biomarkers can be used to evaluate ethanol intake. Ethyl glucuronide (EtG) is a minor metabolite of ethanol. Its investigation is of interest in both clinical and forensic contexts because of the wide window of detection. The analysis was performed by LC-ESI-MS/MS and SPE was used as a pretreatment. The method has been developed and fully validated according to the guidelines of forensic toxicology for the analysis of EtG in hair.

    13. Mass spectrometric detection of CYP450 adducts following oxidative desulfuration of methyl parathion (pages 644–651)

      Patrick B. Kyle, Stanley V. Smith, Rodney C. Baker and Robert E. Kramer

      Version of Record online: 23 JAN 2012 | DOI: 10.1002/jat.1792

      Cytochrome P450-mediated desulfuration of organophosphorus compounds results in mechanism-based enzyme inhibition. Data suggest that reactive sulfur is released and binds to the apoprotein, although the identities of neither the adduct(s) nor the affected amino acid(s) have been clearly determined. In this work, 96 amu adducts to two cysteines of rat CYP3A1 were determined after incubation with methyl parathion. These adducts correspond to the mass of three sulfur atoms, as well as combinations of sulfur and oxygen.

    14. Cadmium exposure increases susceptibility to testicular autoimmunity in mice (pages 652–660)

      Yuki Ogawa, Masahiro Itoh, Shuichi Hirai, Shigeru Suna, Munekazu Naito, Ning Qu, Hayato Terayama, Ayumi Ikeda, Hidenobu Miyaso, Yoshiharu Matsuno, Masatoshi Komiyama and Chisato Mori

      Version of Record online: 23 JAN 2012 | DOI: 10.1002/jat.2713

      We investigated the morphological and functional changes of testes in mice treated with a low dose of cadmium chloride (3mg CdCl2/kg body weight) and also examined its toxicity as to susceptibility to EAO testicular autoimmunity. The results showed that exposure to 3 mg CdCl2/kg body weight did not affect the spermatogenic state. However, the blood-testis barrier BTB at the tubuli recti and the rete testis, but not the seminiferous tubules, was slightly weakened, and intra-testicular mRNA expression of interleukin (IL)-6, tumor necrosis factor-α and IL-1β was significantly increased by the CdCl2 treatment. Furthermore, immunization with testicular antigens after the CdCl2 exposure significantly augmented the EAO severity. Therefore, exposure to a low dose of CdCl2 induces no significant disturbance of spermatogenesis, however, it does the CdCl2 treatment change the immunological microcircumstances in the testis, resulting in increased susceptibility to testicular autoimmunity.

    15. Apoptosis of rat ovarian granulosa cells by 2,5-hexanedione in vitro and its relevant gene expression (pages 661–669)

      Wenchang Zhang, Lei Huang, Cancan Kong, Jin Liu, Lingfeng Luo and Huiling Huang

      Version of Record online: 15 FEB 2012 | DOI: 10.1002/jat.2714

      Although n-hexane is toxic to the ovary, the related mechanism remains unknown. Apoptosis of rat ovarian granulosa cells is thought to be one of the important reasons for ovarian toxicity. Rat ovarian granulosa cells were exposed in vitro to different concentrations of 2,5-hexanedione (HD, a major metabolite of n-hexane; 0, 20, 40 and 60 mmol l−1) to observe the apoptosis, and its relevant gene expression was investigated. It was found by MTT assay that different exposure doses and different exposure time could inhibit the viability of ovarian granulosa cells.

    16. Toxicity assessment and vitellogenin expression in zebrafish (Danio rerio) embryos and larvae acutely exposed to bisphenol A, endosulfan, heptachlor, methoxychlor and tetrabromobisphenol A (pages 670–678)

      Wing Shan Chow, Winson Ka-Lun Chan and King Ming Chan

      Version of Record online: 21 FEB 2012 | DOI: 10.1002/jat.2723

      In the present study, zebrafish embryos and larvae were used to investigate the sublethal and lethal effects of three different organochlorine pesticides, namely methoxychlor, endosulfan and heptachlor, as well as the flame retardant tetrabromobisphenol A, and its precursor compound bisphenol A. The use of vtg1 mRNA induction in zebrafish embryos and larvae was found to be a sensitive biomarker of exposure to these organic compounds, and was helpful in elucidating their adverse effects and setting water quality guidelines.

    17. Cadmium inhibits the ovary δ-aminolevulinate dehydratase activity in vitro and ex vivo: protective role of seleno-furanoside (pages 679–684)

      Laura Musacchio Vargas, Melina Bucco Soares, Aryele Pinto Izaguirry, Diogo Seibert Lüdtke, Hugo C. Braga, Lucielli Savegnago, Suzi Wollenhaupt, Daniela dos Santos Brum, Fábio Gallas Leivas and Francielli Weber Santos

      Version of Record online: 4 JUL 2012 | DOI: 10.1002/jat.2783

      The cadmium (Cd) effect on ovary δ-aminolevulinate dehydratase (δ-ALA-D) activity was investigated in vitro and ex vivo. Cadmium inhibited cow ovary δ-ALA-D activity and seleno-furanoside did not reverse the Cd toxicity in vitro. Acute Cd exposure caused a significant inhibition on ovary δ-ALA-D activity in mice and seleno-furanoside was able in restoring enzyme activity. Ovarian δ-ALA-D activity is inhibited by Cd both in vitro and ex vivo and the seleno-furanoside therapy was effective after Cd acute exposure in mice.

    18. Uranium dynamics and developmental sensitivity in rat kidney (pages 685–694)

      Shino Homma-Takeda, Toshiaki Kokubo, Yasuko Terada, Kyoko Suzuki, Shunji Ueno, Tatsuo Hayao, Tatsuya Inoue, Keisuke Kitahara, Benjamin J. Blyth, Mayumi Nishimura and Yoshiya Shimada

      Version of Record online: 26 APR 2013 | DOI: 10.1002/jat.2870

      To investigate renal sensitivity to uranium exposure during development, we examined uranium distribution and uranium-induced apoptosis in the kidneys of neonate (7-day-old), prepubertal (25-day-old), and adult (70-day-old) male Wistar rats. Our findings suggest that age-at-exposure and exposure level are important parameters for uranium toxicity; uranium tends to persist in developing kidneys after low-level exposures, although renal toxicity is more pronounced in adults.

  3. Short Communication

    1. Top of page
    2. Review Article
    3. Research Articles
    4. Short Communication
    1. Cytotoxicity on human cells of Cry1Ab and Cry1Ac Bt insecticidal toxins alone or with a glyphosate-based herbicide (pages 695–699)

      R. Mesnage, E. Clair, S. Gress, C. Then, A. Székács and G.-E. Séralini

      Version of Record online: 15 FEB 2012 | DOI: 10.1002/jat.2712

      The study of combined effects of pesticides represents a challenge for toxicology. In the case of the new growing generation of genetically modified (GM) plants with stacked traits, glyphosate-based herbicides (like Roundup) residues are present in the Roundup-tolerant edible plants (especially corns) and mixed with modified Bt insecticidal toxins that are produced by the GM plants themselves. The potential side effects of these combined pesticides on human cells are investigated in this work.