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ToxSci Advance Access published online on June 1, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm143
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Erythrocebus patas Monkey Offspring Exposed Perinatally to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Sustain Skeletal Muscle Mitochondrial Compromise at Birth and at 1 Year of Age

Rao L. Divi*, Sarah L. Leonard*, Brettania L. Walker*, Maryanne M. Kuo*, Marie E. Shockley*, Marisa C. St. Claire{dagger}, Kunio Nagashima{ddagger}, Steven W. Harbaugh{dagger}, Jeffrey W. Harbaugh{dagger} and Miriam C. Poirier*

* Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD 20892-4255 {dagger} Bioqual Incorporated, 2501 Research Boulevard, Rockville, MD, 20850 {ddagger} Laboratory of Cell and Molecular Structure, National Cancer Institute, Frederick Cancer Research and Development Center, SAIC, Frederick, MD, 21702

Correspondence to: Rao L. Divi, National Cancer Institute, NIH, Bldg.37 Rm. 4032, 37 Convent Drive, MSC-4255, Bethesda, MD, 20892-4255, Phone: 301-435-7844, FAX: 301-402-8230, EMAIL: divir{at}exchange.nih.gov

Received April 5, 2007; revision received May 23, 2007; accepted May 24, 2007


  Abstract

Antiretroviral NRTIs, given to HIV-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 NRTIs 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/group) and 1 year (n=4/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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