Effects of BDE-99 exposure in liver antioxidant status

Effects of BDE-99 exposure in liver antioxidant status

S120 Abstracts / Toxicology Letters 189S (2009) S57–S273 62 control subjects (19–63 years of age, median 37). The concentrations of MDA were measure...

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S120

Abstracts / Toxicology Letters 189S (2009) S57–S273

62 control subjects (19–63 years of age, median 37). The concentrations of MDA were measured using method of Drury et al. (1997) by HPLC with UV detector. Concentration of MDA in plasma samples of Pb-workers (3.054 ± 0.237 mmol/L; mean ± SEM) was significantly higher than in plasma samples of controls (1.895 ± 0.133 mmol/L, P < 0.05) indicating that the increased lipid peroxidation in Pbworkers occurs before the clinical symptoms of toxicity. Since there are a number of studies on the higher rate of severe neurological diseases that are supposed to be caused by increased lipid peroxidation, Pb-workers should be thoroughly followed.

B15 Renal effects of BDE-99 exposure and its relation to oxidative stress

Reference

Polybrominated diphenyl ethers (PBDEs) are used as flame retardant additives in a variety of consumer products. Brominated diphenyl ether congener BDE-99 is ubiquitous in the environment and is regarded as one of the most persistent congeners present in wildlife and humans. However, little is known about their potential toxicological properties. In this study, we investigated the effects in renal function. We hypothesized an oxidative stress-like mechanism inductor of renal toxicity. Adult male rats (10/group) received BDE-99 by gavage at single dose of 0, 0.6 or 1.2 mg/kg/body weight. Forty-five days after the exposure kidneys were removed and processed to examine the following oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione transferase (GST), superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). Histological examination of kidneys showed phagolysosomes and dropsical degeneration in rats exposed to 1.2 mg BDE-99/kg. CAT activity was significantly decreased while GSSG/GSH ratio was significantly increased by BDE-99 exposure at the highest dose. Urine biochemical analysis showed a significative increase of total protein content at the highest dose. Lactate dehydrogenase (LDH), N-acetyl-b-D-glucosaminidase (NAG) and gamma-GT activities were significantly decreased by BDE exposure. This results suggest that BDE-99 exposure causes renal impairment and that oxidative damage can be a mechanism for nephrotoxicity.

Drury, J.A., Nycyk, J.A., Cooke RWI, 1997. Clin Chim Acta 263, 177. Esterbauer, H., 1996. Path Biol 44, 25.

doi:10.1016/j.toxlet.2009.06.414

B14 Effects of oral N-acetyl cysteine on plasma oxidative stress biomarkers in end-stage renal disease patients Fatemeh Babaei 1,∗ , Majid Shohrati 2 , Behzad Einollahi 3 , Mahvash Jafari 4 1

Payamenoor University, Basic Science, Tehran, Islamic Republic of Iran, 2 Baqiyatallah Hospital, Chemical Injury, Tehran, Islamic Republic of Iran, 3 Baqiyatallah Hospital, Nephrology, Tehran, Islamic Republic of Iran, 4 Baqiyatallah Hospital, Basic Science, Biochemistry, Tehran, Islamic Republic of Iran Objective: Reactive oxygen species (ROS) play an important role in the pathophysiological processes of wide variety of renal diseases. There are good evidences indicating that during hemodialysis (HD), the interaction of blood with artificial membranes leads to production of ROS in these patients, so use of antioxidants such as N-acetyl cysteine (NAC) might have positive effects to scavenge ROS in these patients. Methods: In this double blind randomized clinical trial, which is approved by the ethical committee of Baqiyatallah Medical Science University, 100 patients with history of ESRD were selected, and randomly divided into 2 groups for 2 doses of oral N-acetyl cysteine and placebo (600 and 1200 mg/day), half of each group receive drug and the other receive placebo, for 45 days. Biochemistry values of plasma glutathione (GSH), malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD) activity were measured before and after using drug or placebo. The results were analyzed by SPSS software. Results: In both NAC groups, GSH significantly increased in comparison to placebo groups (P < 0.05). MDA levels were reduced in both drug groups compared to the placebo groups (P < 0.05). CAT activity was decreased but this reduction was significant in group 600 mg/day when compared to placebo group (P < 0.05). It was also observed a slight but not significant decrease in the activity of SOD after using NAC. Conclusion: Our results demonstrated that administration of NAC significantly attenuated the effect of ROS, and have beneficial effect on renal function and antioxidant systems in ESRD patients. doi:10.1016/j.toxlet.2009.06.415

Virginia Alonso 1,∗ , Victoria Linares 1 , Montserrat Bellés 1 , Maria Luisa Albina 1 , Joan Sirvent 2 , José Luis Domingo 1 , Domèmec Sánchez 1 1 School of Medicine, Laboratory of Toxicology and Environmental Health, Reus, Spain, 2 School of Medicine, Pathology Unit, Reus, Spain

doi:10.1016/j.toxlet.2009.06.416

B16 Effects of BDE-99 exposure in liver antioxidant status Victoria Linares ∗ , Virginia Alonso ∗ , Montserrat Bellés, Maria Luisa Albina, Joan Sirvent, José Luís Domingo, Domènec Sánchez School of Medicine, Laboratory of Toxicology and Environmental Health, Reus, Spain Polybrominated diphenyl ethers (PBDEs) are used as flame retardant additives. They are ubiquitous in the environment and bioaccumulate in humans and wildlife. However, little is known about their potential toxic effects in liver. In this study, we investigated the modifications in endogenous antioxidant capacity and oxidative damage in liver tissue by the exposure to one of the most persistent PBDE congeners, the 2,2 ,4,4 ,5-pentabromodiphenyl ether (BDE-99). Adult male rats (10/group) received BDE-99 by gavage at single dose of 0, 0.6 or 1.2 mg/kg/body weight. Forty-five days after the exposure, liver was removed and processed to examine the following stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and thiobarbituric acid reactive substances (TBARS). Liver endogenous antioxidant capacity was affected. BDE-

Abstracts / Toxicology Letters 189S (2009) S57–S273

99 exposure significantly increased SOD activity, GSSG levels, and GSSG/GSH ratio at both doses; while GSH levels were decreased. Moreover, CAT activity only was reduced at the higher dose. Blood biochemical analysis showed a significant increase of GPT activity at dose of 1.2 mg BDE-99/kg. In conclusion, oxidative damage could be a mechanism for BDE-99 toxicity in liver tissue.

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B18 Acute toxicity of diepoxybutane to human mononuclear lymphocytes Filipa Ponte 1,∗ , Félix Carvalho 1 , Beatriz Porto 2 1

Faculty of Pharmacy, University of Porto, Toxicology, Porto, Portugal, Institute of Biomedical Sciences Abel Salazar, University of Porto, Laboratory of Cytogenetics, Porto, Portugal 2

doi:10.1016/j.toxlet.2009.06.417

B17 Oxidative stress-induced cytotoxicity is mediated by beta arrestins Xiaokun Zeng 1,∗ , Rui-Ping Xiao 2 Medstar Research Institute, Baltimore, United States, 2 National Institute on Aging, LCS, Baltimore, United States

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Background and questions: Beta-arrestin1 and beta-arrestin2 are coexisted in most type of cells. Increasing evidence has placed betaarrestins in the center of signaling pathways that regulate vital cellular processes such as cell survival. Here, we determine whether beta-arrestin1 and beta-arrestin2 are differentially involved in the regulation of cell viability under basal and oxidative stress conditions. Method and results: Cardiomyocytes and fibroblasts isolated from beta-arrestin1 or beta-arrestin2 deficient mice or wild type counterparts were subjected to hydrogen peroxide (H2 O2 ) insult. We found that in cells lacking beta-arrestin2, beta-arrestin1 alone protected cells against oxidative stress (H2 O2 )-induced cytotoxicity assayed by cell viability. Inhibition of either ERK1/2 or Src with PD98059 or PP2, respectively, fully abolished beta-arrestin1 mediated cell protection, suggesting beta-arrestin1 mediated cell protection is ERK1/2- and Src-dependent. Moreover, beta-arrestin2 ablation led to a profound increase in beta-arrestin1-Ser412 phosphorylation which was associated with increased beta-arrestin1 protective effect. Adenoviral gene transfer of beta-arrestin2 fully prevented the increase in beta-arrestin1 phosphorylation and its protective effect, revealing a novel negative regulation of betaarrestin1 phosphorylation and its cell protective function by beta-arrestin2. Conclusions: We demonstrate, for the first time, that betaarrestin1 plays a key role in protecting cells against oxidative stress-induced cytotoxicity, whereas beta-arrestin2 is a powerful negative regulator of beta-arrestin1 phosphorylation and biological function. Because oxidative stress is the most common mechanism of pharmaceutical drug-induced cytotoxicity and cardiotoxicity, as manifested by cardiomyocyte apoptosis or necrosis, heart failure and even severe morbidity, our findings bear important clinical implications in understanding and preventing drug-related adverse effects. doi:10.1016/j.toxlet.2009.06.418

The hypersensitivity of lymphocytes to the clastogenic (chromosome breaking) effect of DNA cross-linking agents, in particular to diepoxybutane (DEB), provides a unique marker for the diagnosis of Fanconi anaemia (FA). However, little is known about the susceptibility of these cells to the toxic effects mediated by DEB. It is our goal to evaluate the direct and indirect toxicity of DEB in mononuclear leucocytes through formation of reactive intermediates and activation of cellular signalling pathways. Blood samples were collected from normal subjects recruited among male students and blood donors, aged 20–40 years, with the informed consent obtained from all the participants. From each individual, 10 ml of heparinized blood was collected by venipuncture and then lymphocytes were isolated using a histopaque-1077 procedure. In a first phase of the study, the toxic effects of DEB were evaluated in cellular suspensions of lymphocytes for 5 h, by determining cellular viability, levels of GSH and levels of intracellular ATP. In a second phase, these parameters were measured using the same cellular suspension model pre-treated with cyclohexamide (CHX), an inhibitor of protein synthesis, and N-acetyl-cysteine (NAC), an antioxidant agent known to be donor of SH groups. Our results showed that DEB induce a strong ATP and GSH depletion, followed by cell death and that CHX does not protect lymphocytes from DEB toxicity, though NAC shows a potent protective effect. These results suggest that the acute mechanism of DEB toxicity induces cellular damage at the mitochondrial level and involves oxidative stress. doi:10.1016/j.toxlet.2009.06.419

B19 Lysine acetylsalicylate elicits full survival of Wistar rats exposed to a lethal dose of paraquat Ricardo Dinis-Oliveira 1,2,3 , Helena Pontes 1 , Fernando Remião 1 , Maria de Lourdes Bastos 1 , José Alberto Duarte 4 , Félix Carvalho 1,∗ 1

Faculty of Pharmacy, University of Porto, Toxicology, Porto, Portugal, Faculty of Medicine, University of Porto, Institute of Legal Medicine, Porto, Portugal, 3 Center of Research in Health Technologies (CITS)-IPSN-CESPU, Clinical Analysis and Public Health, Vila Nova de Famalicão, Portugal, 4 Faculty of Sport, University of Porto, CIAFEL, Porto, Portugal 2

Sodium salicylate (NaSAL) has been shown to have a multifactorial protection mechanism against paraquat (PQ)-induced toxicity, due to its ability to modulate inflammatory signalling systems, to prevent oxidative stress and to its capacity to chelate PQ. Considering that currently there is no pharmaceutical formulation available for parenteral administration of NaSAL, the aim of the present study was to evaluate the antidotal feasibility of a salicylate prodrug, lysine acetylsalicylate (LAS), accessible for parenteral administrations. PQ was administered to Wistar rats by gavage (125 mg/kg of PQ ion) and the treatment was performed intraperitoneally with