| Evaluation of Macaca mulatta as a model for genotoxicity studies. | |
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MedLine Citation:
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PMID: 19073277 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have investigated the use of peripheral blood from the nonhuman primate (NHP) rhesus monkey (Macaca mulatta) as a model system for mutation detection. The rhesus monkey is metabolically closer to humans than most common laboratory animals, and therefore may be a relevant model for hazard identification and human risk assessment. To validate the model, conditions were determined for in vitro selection and expansion of 6-thioguanine-resistant (6-TGr) HPRT mutant and proaerolysin-resistant (ProAERr) PIG-A mutant lymphocytes from peripheral blood obtained by routine venipuncture. Also, flow cytometric methods were developed for the rapid detection of PIG-A mutant erythrocytes. The flow cytometric analysis of PIG-A mutant erythrocytes was based on enumerating cells deficient in surface markers attached to the cellular membrane via glycosylphosphatidyl inositol (GPI) anchors. Mutant cells were enumerated over an extended period of time in peripheral blood of male monkeys receiving daily doses of the electrolyte replenisher Prangtrade mark (a common carrier for oral delivery of drugs in NHPs), and in the blood of one male monkey treated with a single i.p. dose of 50mg/kg of N-ethyl-N-nitrosourea at approximately 2 years of age and another similar injection at approximately 3.5 years of age. The spontaneous PIG-A and HPRT T-cell mutant frequency (MF) was low in animals receiving Prang (0-8x10(-6)), and treatment with ENU resulted in a clearly detectable increase in the frequency of ProAERr and 6-TGr lymphocytes (up to approximately 28x10(-6) and approximately 30x10(-6), respectively). Also, the ENU-treated animal had higher frequency of GPI-deficient erythrocytes (46.5x10(-6) in the treated animal vs. 7.8+/-4.2x10(-6) in control animals). Our results indicate that the rhesus monkey can be a valuable model for the identification of agents that may impact upon human health as mutagens and that the PIG-A gene can be a useful target for detection of mutation in both white and red blood cells. |
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Authors:
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Vasily N Dobrovolsky; Joseph G Shaddock; Roberta A Mittelstaedt; Mugimane G Manjanatha; Daishiro Miura; Makoto Uchikawa; Donald R Mattison; Suzanne M Morris |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-11-27 |
Journal Detail:
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Title: Mutation research Volume: 673 ISSN: 0027-5107 ISO Abbreviation: Mutat. Res. Publication Date: 2009 Feb |
Date Detail:
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Created Date: 2009-02-02 Completed Date: 2009-03-31 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0400763 Medline TA: Mutat Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 21-8 Citation Subset: IM |
Affiliation:
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US FDA, National Center for Toxicological Research, Division of Genetic and Reproductive Toxicology, 3900 NCTR Rd., HFT-120, Jefferson, AR 72079, USA. vasily.dobrovolsky@fda.hhs.gov |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bacterial Toxins / pharmacology Cells, Cultured Erythrocytes / drug effects, metabolism Flow Cytometry Hypoxanthine Phosphoribosyltransferase / genetics Lymphocytes / drug effects, metabolism Macaca mulatta* Male Membrane Proteins / genetics Models, Biological Mutagens / pharmacology Mutation / drug effects, genetics Pore Forming Cytotoxic Proteins / pharmacology Thioguanine / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Bacterial Toxins; 0/Membrane Proteins; 0/Mutagens; 0/Pore Forming Cytotoxic Proteins; 0/phosphatidylinositol glycan-class A protein; 0/proaerolysin; 154-42-7/Thioguanine; EC 2.4.2.8/Hypoxanthine Phosphoribosyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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