Erythrocebus patas monkey offspring exposed perinatally to NRTIs sustain skeletal muscle mitochondrial compromise at birth and at 1 year of age.
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.
Divi
Rao L
RL
Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892-4255, USA. divir@exchange.nih.gov
Leonard
Sarah L
SL
Walker
Brettania L
BL
Kuo
Maryanne M
MM
Shockley
Marie E
ME
St Claire
Marisa C
MC
Nagashima
Kunio
K
Harbaugh
Steven W
SW
Harbaugh
Jeffrey W
JW
Poirier
Miriam C
MC
D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000633:toxicity*; D003402:Creatine Kinase / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis / Q000187:drug effects; D004359:Drug Therapy, Combination; D004901:Erythrocebus patas; D005260:Female; D005865:Gestational Age; D006651:Histocytochemistry; D018811:Maternal Exposure / Q000009:adverse effects*; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D009097:Multienzyme Complexes; D018894:Reverse Transcriptase Inhibitors; D003402:Creatine Kinase