Document Detail


Erythrocebus patas monkey offspring exposed perinatally to NRTIs sustain skeletal muscle mitochondrial compromise at birth and at 1 year of age.
MedLine Citation:
PMID:  17545213     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs), given to human immunodeficiency virus-1-infected pregnant women to prevent vertical viral transmission, have caused mitochondrial dysfunction in some human infants. Here, we examined mitochondrial integrity in skeletal muscle from offspring of pregnant retroviral-free Erythrocebus patas dams administered human-equivalent NRTI doses for the last 10 weeks of gestation or for 10 weeks of gestation and 6 weeks after birth. Exposures included no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. Offspring were examined at birth (n=3 per group) and 1 year (n=4 per group, not including 3TC alone). Circulating levels of creatine kinase were elevated at 1 year in the d4T/3TC-exposed group. Measurement of oxidative phosphorylation enzyme activities (complexes I, II, and IV) revealed minimal NRTI-induced changes at birth and at 1 year. Histochemistry for complex IV activity showed abnormal staining with activity depletion at birth and 1 year in groups exposed to AZT alone and to the 2-NRTI combinations. Electron microscopy of skeletal muscle at birth and 1 year of age showed mild to severe mitochondrial damage in all the NRTI-exposed groups, with 3TC inducing mild damage and the 2-NRTI combinations inducing extensive damage. At birth, mitochondrial DNA (mtDNA) was depleted by approximately 50% in groups exposed to AZT alone and the 2-NRTI combinations. At 1 year, the mtDNA levels had increased but remained significantly below normal. Therefore, skeletal muscle mitochondrial compromise occurs at birth and persists at 1 year of age (46 weeks after the last NRTI exposure) in perinatally exposed young monkeys, suggesting that similar events may occur in NRTI-exposed human infants.
Authors:
Rao L Divi; Sarah L Leonard; Brettania L Walker; Maryanne M Kuo; Marie E Shockley; Marisa C St Claire; Kunio Nagashima; Steven W Harbaugh; Jeffrey W Harbaugh; Miriam C Poirier
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2007-06-01
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  99     ISSN:  1096-6080     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-08-13     Completed Date:  2007-10-04     Revised Date:  2010-09-17    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  203-13     Citation Subset:  IM    
Affiliation:
Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892-4255, USA. divir@exchange.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Anti-HIV Agents / toxicity*
Creatine Kinase / metabolism
DNA, Mitochondrial / analysis,  drug effects
Drug Therapy, Combination
Erythrocebus patas
Female
Gestational Age
Histocytochemistry
Maternal Exposure / adverse effects*
Microscopy, Electron, Transmission
Mitochondria, Muscle / drug effects*,  genetics,  ultrastructure
Multienzyme Complexes / metabolism
Muscle, Skeletal / drug effects*,  enzymology,  ultrastructure
Pregnancy
Reverse Transcriptase Inhibitors / toxicity*
Chemical
Reg. No./Substance:
0/Anti-HIV Agents; 0/DNA, Mitochondrial; 0/Multienzyme Complexes; 0/Reverse Transcriptase Inhibitors; EC 2.7.3.2/Creatine Kinase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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