Document Detail

Progressive mitochondrial compromise in brains and livers of primates exposed in utero to nucleoside reverse transcriptase inhibitors (NRTIs).
MedLine Citation:
PMID:  20702595     Owner:  NLM     Status:  MEDLINE    
Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these human exposures, we examined mitochondrial integrity at birth and 1 year in brain cortex and liver from offspring of retroviral-free Erythrocebus patas dams-administered human-equivalent NRTI doses for the last half (10 weeks) of gestation. Additional infants, followed for 1 year, were given the same drugs as their mothers for the first 6 weeks of life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. In brain and liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, and IV) showed minimal differences between unexposed and NRTI-exposed offspring at both times. Brain and liver mitochondria from most NRTI-exposed patas, both at birth and 1 year of age, contained significant (p < 0.05) morphological damage observed by electron microscopy (EM), based on scoring of coded photomicrographs. Brain and liver mitochondrial DNA (mtDNA) levels in NRTI-exposed patas were depleted significantly in the 3TC and d4T/3TC groups at birth and were depleted significantly (p < 0.05) at 1 year in all NRTI-exposed groups. In 1-year-old infants exposed in utero to NRTIs, mtDNA depletion was 28.8-51.8% in brain and 37.4-56.5% in liver. These investigations suggest that some NRTI-exposed human infants may sustain similar mitochondrial compromise in brain and liver and should be followed long term for cognitive integrity and liver function.
Rao L Divi; Tracey L Einem; Sarah L Leonard Fletcher; Marie E Shockley; Maryanne M Kuo; Marisa C St Claire; Anthony Cook; 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., Extramural; Research Support, N.I.H., Intramural     Date:  2010-08-11
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  118     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-15     Completed Date:  2011-01-25     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  191-201     Citation Subset:  IM    
Carcinogen-DNA Interactions Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
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MeSH Terms
Animals, Newborn
Cerebral Cortex / drug effects*,  metabolism,  ultrastructure
DNA, Mitochondrial / analysis,  metabolism
Didanosine / toxicity
Disease Models, Animal
Drug Therapy, Combination
Erythrocebus patas*
Lamivudine / toxicity
Maternal Exposure
Mitochondria, Liver / drug effects*,  metabolism,  ultrastructure
Oxidative Phosphorylation / drug effects
Reverse Transcriptase Inhibitors / toxicity*
Stavudine / toxicity
Zidovudine / toxicity
Reg. No./Substance:
0/DNA, Mitochondrial; 0/Reverse Transcriptase Inhibitors; 134678-17-4/Lamivudine; 30516-87-1/Zidovudine; 3056-17-5/Stavudine; 69655-05-6/Didanosine

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