Molecular biomarkers of oxidative stress associated with bromate carcinogenicity.

2.50
Hdl Handle:
http://hdl.handle.net/10146/56864
Title:
Molecular biomarkers of oxidative stress associated with bromate carcinogenicity.
Authors:
Delker, Don; Hatch, Gary; Allen, James; Crissman, Bobby; George, Michael; Geter, David; Kilburn, Steve; Moore, Tanya; Nelson, Gail; Roop, Barbara; Slade, Ralph; Swank, Adam; Ward, William; DeAngelo, Anthony
Abstract:
Potassium bromate (KBrO3) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water ozonation. Chronic exposures to KBrO3 cause renal cell tumors in rats, hamsters and mice and thyroid and testicular mesothelial tumors in rats. Experimental evidence indicates that bromate mediates toxicological effects via the induction of oxidative stress. To investigate the contribution of oxidative stress in KBrO3-induced cancer, male F344 rats were administered KBrO3 in their drinking water at multiple concentrations for 2-100 weeks. Gene expression analyses were performed on kidney, thyroid and mesothelial cell RNA. Families of mRNA transcripts differentially expressed with respect to bromate treatment included multiple cancer, cell death, ion transport and oxidative stress genes. Multiple glutathione metabolism genes were up-regulated in kidney following carcinogenic (400 mg/L) but not non-carcinogenic (20 mg/L) bromate exposures. 8-Oxodeoxyguanosine glycosylase (Ogg1) mRNA was up-regulated in response to bromate treatment in kidney but not thyroid. A dramatic decrease in global gene expression changes was observed following 1mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 (18O) labeled KBrO3 was administered to male rats by oral gavage and tissues were analyzed for 18O deposition. Tissue enrichment of 18O was observed at 5 and 24 h post-KBr18O3 exposure with the highest enrichment occurring in the liver followed by the kidney, thyroid and testes. The kidney dose response observed was biphasic showing similar statistical increases in 18O deposition between 0.25 and 50 mg/L (equivalent dose) KBr18O3 followed by a much greater increase above 50 mg/L. These results suggest that carcinogenic doses of potassium bromate require attainment of a threshold at which oxidation of tissues occurs and that gene expression profiles may be predictive of these physiological changes in renal homeostasis.
Citation:
Toxicology 2006, 221 (2-3):158-165
Journal:
Toxicology
Issue Date:
17-Apr-2006
URI:
http://hdl.handle.net/10146/56864
DOI:
10.1016/j.tox.2005.12.011
PubMed ID:
16442688
Additional Links:
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCN-4J49VDG-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=0bbaf02c44edc98d5074902731e6c153
Type:
Article
Language:
en
Description:
Biomarkers of exposure & effect:: validationBiomarker: oxidative stress (gene expression)Exposure/effect represented: potassium bromate (KBrO3)/ DNA damageStudy type (in vitro, animals, humans): male F344 ratsMode of exposure (if in vivo) (acute, chronic, root of exposure): drinking waterMethod of analysis: RealTime-PCR, Dose-response: up-regulated genes observed in the high dose group are glutathione S-transferase M1 (Gstm1, J02810), P1 (Gstp1, L29427), glutathione peroxidase 2 (Gpx2, BG664050) and glutamate cysteine ligase (Gclm, BC078867)Expression of 8-oxodeoxyguanosine glycosylase (Ogg1, AF029690)was up-regulated (approximately four-fold) following bromate exposure in kidney but not in rat thyroid. KEYWORDS CLASSIFICATION: Animals;Bromates;chemically induced;Carcinogens;drug effects;dietary modulation of carcinogenesis-related pathways;Dose-Response Relationship,Drug;Epithelium;genetics;Gene Expression;Gene Expression Profiling;Kidney;metabolism;Male;mechanisms of carcinogenesis;Neoplasms;Oligonucleotide Array Sequence Analysis;Oxidative Stress;pathology;Potassium;Rats;Rats,Inbred F344;Research;RNA,Messenger;toxicity;Thyroid Gland;Tumor Markers,Biological.
ISSN:
0300-483X
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
dc.contributor.authorDelker, Don-
dc.contributor.authorHatch, Gary-
dc.contributor.authorAllen, James-
dc.contributor.authorCrissman, Bobby-
dc.contributor.authorGeorge, Michael-
dc.contributor.authorGeter, David-
dc.contributor.authorKilburn, Steve-
dc.contributor.authorMoore, Tanya-
dc.contributor.authorNelson, Gail-
dc.contributor.authorRoop, Barbara-
dc.contributor.authorSlade, Ralph-
dc.contributor.authorSwank, Adam-
dc.contributor.authorWard, William-
dc.contributor.authorDeAngelo, Anthony-
dc.date.accessioned2009-03-23T11:15:34Z-
dc.date.available2009-03-23T11:15:34Z-
dc.date.issued2006-04-17-
dc.identifier.citationToxicology 2006, 221 (2-3):158-165en
dc.identifier.issn0300-483X-
dc.identifier.pmid16442688-
dc.identifier.doi10.1016/j.tox.2005.12.011-
dc.identifier.urihttp://hdl.handle.net/10146/56864-
dc.descriptionBiomarkers of exposure & effect:: validationBiomarker: oxidative stress (gene expression)Exposure/effect represented: potassium bromate (KBrO3)/ DNA damageStudy type (in vitro, animals, humans): male F344 ratsMode of exposure (if in vivo) (acute, chronic, root of exposure): drinking waterMethod of analysis: RealTime-PCR, Dose-response: up-regulated genes observed in the high dose group are glutathione S-transferase M1 (Gstm1, J02810), P1 (Gstp1, L29427), glutathione peroxidase 2 (Gpx2, BG664050) and glutamate cysteine ligase (Gclm, BC078867)Expression of 8-oxodeoxyguanosine glycosylase (Ogg1, AF029690)was up-regulated (approximately four-fold) following bromate exposure in kidney but not in rat thyroid. KEYWORDS CLASSIFICATION: Animals;Bromates;chemically induced;Carcinogens;drug effects;dietary modulation of carcinogenesis-related pathways;Dose-Response Relationship,Drug;Epithelium;genetics;Gene Expression;Gene Expression Profiling;Kidney;metabolism;Male;mechanisms of carcinogenesis;Neoplasms;Oligonucleotide Array Sequence Analysis;Oxidative Stress;pathology;Potassium;Rats;Rats,Inbred F344;Research;RNA,Messenger;toxicity;Thyroid Gland;Tumor Markers,Biological.en
dc.description.abstractPotassium bromate (KBrO3) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water ozonation. Chronic exposures to KBrO3 cause renal cell tumors in rats, hamsters and mice and thyroid and testicular mesothelial tumors in rats. Experimental evidence indicates that bromate mediates toxicological effects via the induction of oxidative stress. To investigate the contribution of oxidative stress in KBrO3-induced cancer, male F344 rats were administered KBrO3 in their drinking water at multiple concentrations for 2-100 weeks. Gene expression analyses were performed on kidney, thyroid and mesothelial cell RNA. Families of mRNA transcripts differentially expressed with respect to bromate treatment included multiple cancer, cell death, ion transport and oxidative stress genes. Multiple glutathione metabolism genes were up-regulated in kidney following carcinogenic (400 mg/L) but not non-carcinogenic (20 mg/L) bromate exposures. 8-Oxodeoxyguanosine glycosylase (Ogg1) mRNA was up-regulated in response to bromate treatment in kidney but not thyroid. A dramatic decrease in global gene expression changes was observed following 1mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 (18O) labeled KBrO3 was administered to male rats by oral gavage and tissues were analyzed for 18O deposition. Tissue enrichment of 18O was observed at 5 and 24 h post-KBr18O3 exposure with the highest enrichment occurring in the liver followed by the kidney, thyroid and testes. The kidney dose response observed was biphasic showing similar statistical increases in 18O deposition between 0.25 and 50 mg/L (equivalent dose) KBr18O3 followed by a much greater increase above 50 mg/L. These results suggest that carcinogenic doses of potassium bromate require attainment of a threshold at which oxidation of tissues occurs and that gene expression profiles may be predictive of these physiological changes in renal homeostasis.en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TCN-4J49VDG-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=0bbaf02c44edc98d5074902731e6c153en
dc.subjectPotassium bromateen
dc.subjectOxidative stressen
dc.subjectGene expressionen
dc.subjectTissue oxidationen
dc.subjectOxygen-18en
dc.subjectGlutathione metabolismen
dc.subjectThresholden
dc.subjectRisk assessmenten
dc.subjectMolecular biomarkersen
dc.subject.meshAnimals-
dc.subject.meshBromates-
dc.subject.meshCarcinogens-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshEpithelium-
dc.subject.meshGene Expression-
dc.subject.meshGene Expression Profiling-
dc.subject.meshKidney-
dc.subject.meshMale-
dc.subject.meshNeoplasms-
dc.subject.meshOligonucleotide Array Sequence Analysis-
dc.subject.meshOxidative Stress-
dc.subject.meshRNA, Messenger-
dc.subject.meshRats-
dc.subject.meshRats, Inbred F344-
dc.subject.meshThyroid Gland-
dc.subject.meshTumor Markers, Biological-
dc.titleMolecular biomarkers of oxidative stress associated with bromate carcinogenicity.en
dc.typeArticleen
dc.identifier.journalToxicologyen

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