ToxSci Advance Access originally published online on June 1, 2007
Toxicological Sciences 2007 99(1):203-213; doi:10.1093/toxsci/kfm143
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Erythrocebus patas Monkey Offspring Exposed Perinatally to NRTIs Sustain Skeletal Muscle Mitochondrial Compromise at Birth and at 1 Year of Age
* Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, Maryland 20892-4255
Bioqual Incorporated, 2501 Research Boulevard, Rockville, Maryland 20850
Laboratory of Cell and Molecular Structure, National Cancer Institute, Frederick Cancer Research and Development Center, SAIC, Frederick, Maryland 21702
1 To whom correspondence should be addressed. Fax: (301) 402-8230. E-mail: divir{at}exchange.nih.gov.
Received April 5, 2007; accepted May 24, 2007
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Abstract |
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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 
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.
Key Words: zidovudine; lamivudine; stavudine; didanosine; electron microscopy; mitochondrial DNA quantity; oxidative phosphorylation.
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