Erythrocebus patas monkey offspring exposed perinatally to NRTIs sustain skeletal muscle mitochondrial compromise at birth and at 1 year of age
| Autor: | Kunio Nagashima, Marisa St. Claire, Steven W. Harbaugh, Jeffrey W. Harbaugh, Brettania L. Walker, Miriam C. Poirier, Marie E. Shockley, Sarah L. Leonard, Maryanne M. Kuo, Rao L. Divi |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Offspring
Anti-HIV Agents Physiology Gestational Age Toxicology DNA Mitochondrial Erythrocebus patas Zidovudine Microscopy Electron Transmission immune system diseases Multienzyme Complexes Pregnancy medicine Animals Muscle Skeletal Didanosine Creatine Kinase biology Histocytochemistry Stavudine virus diseases Lamivudine biochemical phenomena metabolism and nutrition medicine.disease Mitochondria Muscle Animals Newborn Maternal Exposure Immunology biology.protein Gestation Reverse Transcriptase Inhibitors Creatine kinase Drug Therapy Combination Female medicine.drug |
| Zdroj: | Toxicological sciences : an official journal of the Society of Toxicology. 99(1) |
| ISSN: | 1096-6080 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|