Mitochondrial Toxicity in FetalErythrocebus patasMonkeys Exposed Transplacentally to Zidovudine Plus Lamivudine
- 1 January 2004
- journal article
- research article
- Published by Mary Ann Liebert Inc in AIDS Research and Human Retroviruses
- Vol. 20 (1), 91-100
- https://doi.org/10.1089/088922204322749530
Abstract
This study was designed to investigate fetal mitochondrial toxicity in Erythrocebus patas monkeys exposed in utero to zidovudine (AZT) and lamivudine (3TC), and taken at term. Pregnant patas monkeys were given a daily dose of 40 mg AZT (86% of the human daily dose, based on body weight), for the last 10 weeks (50%) of gestation, and a daily dose of 24 mg 3TC (84% of the human daily dose, based on body weight) for the last 4 weeks of gestation. At term, AZT was found to be incorporated into fetal mitochondrial DNA from skeletal muscle, liver, kidney, and placenta. By transmission electron microscopy (EM) drug-exposed fetal cardiac and skeletal muscle cells showed mitochondrial membrane compromise, mitochondrial proliferation, and damaged sarcomeres, while mitochondria in brain cerebrum and cerebellum were morphologically normal. Substantial depletion of oxidative phosphorylation (OXPHOS) Complex I specific activities was observed in heart (87% reduction in mean, p = 0.02) and skeletal muscle (98% reduction in mean, p = 0.002) from drug-exposed fetuses, compared to unexposed fetuses. In addition Complex IV activity was highly depleted (85% reduction in mean, p = 0.004) in skeletal muscle from the drug-exposed fetuses (p = 0.004). Brain cerebrum and cerebellum showed no statistically significant OXPHOS changes with drug exposure. Mitochondrial DNA quantity was substantially depleted (>50%) in heart, skeletal muscle, cerebellum, and cerebrum from drugexposed fetuses compared to unexposed controls. Overall, the data indicate that significant mitochondrial damage was observed at birth in monkey fetuses exposed in utero to AZT plus 3TC in a human-equivalent dosing protocol.Keywords
This publication has 41 references indexed in Scilit:
- Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS DrugsJournal of Biological Chemistry, 2001
- Genotoxic and Functional Consequences of Transplacental Zidovudine Exposure in Fetal Monkey Brain MitochondriaJAIDS Journal of Acquired Immune Deficiency Syndromes, 2000
- Fetal Mitochondrial Heart and Skeletal Muscle Damage in Erythrocebus patas Monkeys Exposed in Utero to 3'-Azido-3'-DeoxythymidineAIDS Research and Human Retroviruses, 2000
- Human immunodeficiency virus type-1: mother-to-child transmission: Joint Report of AIDS/Infectious Diseases PMP and Mother and Child PMPActa Paediatrica, 2000
- The maternal-fetal transfer of lamivudine in the ex vivo human placentaAmerican Journal of Obstetrics and Gynecology, 1997
- Interaction between lamivudine (3TC) and other nucleoside analogues for intracellular phosphorylationAIDS, 1996
- Persistence, gestation stage-dependent formation and interrelationship of benzo[a]pyrene-induced DNA adducts in mothers, placentae and fetuses of Erythrocebus patas monkeysCarcinogenesis: Integrative Cancer Research, 1993
- Concurrent zidovudine-induced myopathy and hepatoxicity in patients treated for human immunodeficiency virus (HIV) infectionPathology, 1992
- Mitochondrial Myopathy Caused by Long-Term Zidovudine TherapyNew England Journal of Medicine, 1990
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976