Mitochondrial toxicity in fetal Erythrocebus patas monkeys exposed transplacentally to zidovudine plus lamivudine.
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 drug-exposed 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.
Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, 6701 Rockledge Drive, Bethesda, MD 20892, USA.
Mariana
M
Gerschenson
Vi
V
Nguyen
Ember L
EL
Ewings
Andrea
A
Ceresa
Jaclyn A
JA
Shaw
Marisa C
MC
St  Claire
Kunio
K
Nagashima
Steven W
SW
Harbaugh
Jeffrey W
JW
Harbaugh
Ofelia A
OA
Olivero
Rao L
RL
Divi
Paul S
PS
Albert
Miriam C
MC
Poirier
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D001921:Brain / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects; D004901:Erythrocebus patas; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D019259:Lamivudine / Q000008:administration & dosage / Q000633:toxicity*; D008431:Maternal-Fetal Exchange; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects; D009206:Myocardium; D009928:Organ Specificity; D010920:Placenta / Q000187:drug effects; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000633:toxicity*; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine