title: Progressive mitochondrial compromise in brains and livers of primates exposed in utero to nucleoside reverse transcriptase inhibitors (NRTIs).
abstract: 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.
authors: 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.
authors: Rao L
authors: RL
authors: Divi
authors: Tracey L
authors: TL
authors: Einem
authors: Sarah L Leonard
authors: SL
authors: Fletcher
authors: Marie E
authors: ME
authors: Shockley
authors: Maryanne M
authors: MM
authors: Kuo
authors: Marisa C
authors: MC
authors: St Claire
authors: Anthony
authors: A
authors: Cook
authors: Kunio
authors: K
authors: Nagashima
authors: Steven W
authors: SW
authors: Harbaugh
authors: Jeffrey W
authors: JW
authors: Harbaugh
authors: Miriam C
authors: MC
authors: Poirier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004272:DNA, Mitochondrial / Q000032:analysis / Q000378:metabolism; D016049:Didanosine / Q000633:toxicity; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004901:Erythrocebus patas; D005260:Female; D019259:Lamivudine / Q000633:toxicity; D018811:Maternal Exposure; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D018119:Stavudine / Q000633:toxicity; D015215:Zidovudine / Q000633:toxicity
chemical_list: D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D018119:Stavudine; D016049:Didanosine