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Antidote property of polyclonal antibody against Digoxin toxicity
Abstracts / Toxicology Letters 172S (2007) S1–S240
S147
I15 The in vitro effect of bis(tri-n)butyltin)oxide (TBTO) on gene expression in mouse thymocytes
expressed upon exposure of primary thymocytes to TBTO.
Sandra Janssen 1 , Ad Peijnenburg 2 , Kirsten Baken 1 , Henk van Loveren 3
doi:10.1016/j.toxlet.2007.05.379
1 Nutrition
and Toxicology Research Institute Maastricht (NUTRIM), Department of Health Risk Analysis and Toxicology (GRAT), Maastricht University, Maastricht, Netherlands; 2 RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen, Netherlands; 3 National Institute of Public Health and the Environment (RIVM), Department of Toxicology, Pathology and Genetics (TOX), Bilthoven, Netherlands The application of genomics-based technology in toxicological research may finally provide better tools for chemical safety testing since a wealth of information can be obtained about the mode of action of toxic compounds. Furthermore, by using this technology signature gene expression profiles may be identified for the classification of compounds. The overall aim of our work is to generate in vitro gene expression fingerprints that are predictive for direct toxicity to the immune system. In the present study the biocide and environmental pollutant bis(tri-n)butyltin)oxide (TBTO) was used as a model immunotoxicant. TBTO is known to cause thymus atrophy in rodents and thereby interferes with T lymphocyte-mediated immune responses. To study the in vitro effect of TBTO on gene expression we exposed primary thymocytes of C57Bl/6 mice for 3, 6 and 11 h to various non-cytotoxic concentrations of this immunotoxicant, i.e. concentrations that resulted in less then 20% decrease in viability. The experiments were performed using Agilent whole mouse genome (44 K) oligonucleotide microarrays. Upon multivariate analysis, data were further studied using gene ontology term enrichment and pathway finding tools. Pathways and processes found to be affected by TBTO include lipid metabolism, apoptosis, cell cycle control, glucocorticoid receptor signaling, and regulation of transcription. The extent to which these processes were affected, was different among the exposure conditions. Stimulation of glucocorticoid receptor signaling appeared to be a relevant mechanism of action, irrespective of the condition used. In short, the results of our study showed that genes involved in a number of physiologically relevant processes were differentially
I16 Antidote property of polyclonal antibody against Digoxin toxicity Soheila Kashanian 1 , Hadi Ravan 1 , Kobra Omidfar 2 1 Razi
University, Kermanshah, Islamic Republic of Iran; 2 Medical Sciences/Tehran University, Tehran, Islamic Republic of Iran The most commonly used digitalis is Digoxin, Which is effective in heart failure and cardiac arrhythmias. High dose of this drug causes toxicity. In this study, we investigated lethal dose of Digoxin on rabbits and protected them against Digoxin toxicity. At first Digoxin conjugated to bovine serum albumin (BSA) as immunogen, then four rabbits immunized against immunogen as follows; an emulsion of 500 mg of the conjugate in 1 ml of normal saline and an equal volume of complete Freund’s adjuvant prepared and injected subcutaneously to rabbits. One month later, booster injections were given intramuscularly using 250 mg of the immunogen in 1 ml normal saline and 1 ml of incomplete Freund’s adjuvant in 3-week intervals. Then 7 days after the third booster, serum collected for Enzyme Linked ImmunoAssay (ELISA) to indicate rabbit immunization. The lethal dose of Digoxin was determined by administering Digoxin solution to immunized and unimmunized (normal) rabbits. Normal rabbits that received 0.5 mg/kg Digoxin died within 1 h, whereas four rabbits immunized with Digoxin-BSA conjugate formed Digoxin-specific antibodies and survived doses of Digoxin varying between 1 and 1.3 mg/kg. This study indicates that rabbits protected by Digoxin polyclonal antibodies as antidote, against toxicity of this drug. doi:10.1016/j.toxlet.2007.05.380 I17 Lung response in TMA-induced respiratory allergy in Brown Norway rats Frieke Kuper, Kitty Verhoekcx, Andre Boorsma, Rob Stierum, Josje Arts TNO Quality of Life, Zeist, Netherlands Chemical respiratory allergens are expected to exert their allergic effects predominantly via impaction in the upper airways, yet asthma is considered a disease of the lower
S147
I15 The in vitro effect of bis(tri-n)butyltin)oxide (TBTO) on gene expression in mouse thymocytes
expressed upon exposure of primary thymocytes to TBTO.
Sandra Janssen 1 , Ad Peijnenburg 2 , Kirsten Baken 1 , Henk van Loveren 3
doi:10.1016/j.toxlet.2007.05.379
1 Nutrition
and Toxicology Research Institute Maastricht (NUTRIM), Department of Health Risk Analysis and Toxicology (GRAT), Maastricht University, Maastricht, Netherlands; 2 RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen, Netherlands; 3 National Institute of Public Health and the Environment (RIVM), Department of Toxicology, Pathology and Genetics (TOX), Bilthoven, Netherlands The application of genomics-based technology in toxicological research may finally provide better tools for chemical safety testing since a wealth of information can be obtained about the mode of action of toxic compounds. Furthermore, by using this technology signature gene expression profiles may be identified for the classification of compounds. The overall aim of our work is to generate in vitro gene expression fingerprints that are predictive for direct toxicity to the immune system. In the present study the biocide and environmental pollutant bis(tri-n)butyltin)oxide (TBTO) was used as a model immunotoxicant. TBTO is known to cause thymus atrophy in rodents and thereby interferes with T lymphocyte-mediated immune responses. To study the in vitro effect of TBTO on gene expression we exposed primary thymocytes of C57Bl/6 mice for 3, 6 and 11 h to various non-cytotoxic concentrations of this immunotoxicant, i.e. concentrations that resulted in less then 20% decrease in viability. The experiments were performed using Agilent whole mouse genome (44 K) oligonucleotide microarrays. Upon multivariate analysis, data were further studied using gene ontology term enrichment and pathway finding tools. Pathways and processes found to be affected by TBTO include lipid metabolism, apoptosis, cell cycle control, glucocorticoid receptor signaling, and regulation of transcription. The extent to which these processes were affected, was different among the exposure conditions. Stimulation of glucocorticoid receptor signaling appeared to be a relevant mechanism of action, irrespective of the condition used. In short, the results of our study showed that genes involved in a number of physiologically relevant processes were differentially
I16 Antidote property of polyclonal antibody against Digoxin toxicity Soheila Kashanian 1 , Hadi Ravan 1 , Kobra Omidfar 2 1 Razi
University, Kermanshah, Islamic Republic of Iran; 2 Medical Sciences/Tehran University, Tehran, Islamic Republic of Iran The most commonly used digitalis is Digoxin, Which is effective in heart failure and cardiac arrhythmias. High dose of this drug causes toxicity. In this study, we investigated lethal dose of Digoxin on rabbits and protected them against Digoxin toxicity. At first Digoxin conjugated to bovine serum albumin (BSA) as immunogen, then four rabbits immunized against immunogen as follows; an emulsion of 500 mg of the conjugate in 1 ml of normal saline and an equal volume of complete Freund’s adjuvant prepared and injected subcutaneously to rabbits. One month later, booster injections were given intramuscularly using 250 mg of the immunogen in 1 ml normal saline and 1 ml of incomplete Freund’s adjuvant in 3-week intervals. Then 7 days after the third booster, serum collected for Enzyme Linked ImmunoAssay (ELISA) to indicate rabbit immunization. The lethal dose of Digoxin was determined by administering Digoxin solution to immunized and unimmunized (normal) rabbits. Normal rabbits that received 0.5 mg/kg Digoxin died within 1 h, whereas four rabbits immunized with Digoxin-BSA conjugate formed Digoxin-specific antibodies and survived doses of Digoxin varying between 1 and 1.3 mg/kg. This study indicates that rabbits protected by Digoxin polyclonal antibodies as antidote, against toxicity of this drug. doi:10.1016/j.toxlet.2007.05.380 I17 Lung response in TMA-induced respiratory allergy in Brown Norway rats Frieke Kuper, Kitty Verhoekcx, Andre Boorsma, Rob Stierum, Josje Arts TNO Quality of Life, Zeist, Netherlands Chemical respiratory allergens are expected to exert their allergic effects predominantly via impaction in the upper airways, yet asthma is considered a disease of the lower