Fetal patas monkeys sustain mitochondrial toxicity as a result of in utero zidovudine exposure.
Mitochondrial toxicity was examined in near-term fetuses of pregnant Erythrocebus patas monkeys given human equivalent doses of 3'-azido-3'deoxythymidine (AZT) during the second half of gestation. Pregnant monkeys were dosed daily with 10 or 40 mg AZT, equivalent to about 21% and 86% of the daily AZT dose (500 mg) given to HIV-1-positive pregnant women to prevent maternal-fetal virus transmission. The fetal tissues examined include heart and skeletal muscle, which have high energy requirements, and placenta, which is less dependent on mitochondrial integrity. Slot blot quantitation of mitochondrial DNA (mtDNA) levels showed dose-dependent depletion in heart, skeletal muscle, and placenta from AZT-exposed fetuses compared to unexposed controls. Furthermore, mtDNA degradation, observed by Southern blot analysis, appeared more extensive in AZT-exposed tissues compared to unexposed controls. Mitochondrial functional integrity, as determined by oxidative phosphorylation (OXPHOS) enzyme assays, was also examined in heart, skeletal muscle, and placenta. All three tissues showed strong dose-related decreases in Complex I. In placenta, dose-related increases for Complexes II and IV and a decrease for Complex III were observed. Dose-related increases for Complexes II and IV observed in heart and skeletal muscle have been reported. The increase in Complex IV (cytochrome c oxidase) activity in heart and skeletal muscle tissue from patas fetuses exposed to 40 mg AZT/day has been confirmed here by histochemical staining. Overall, data demonstrate that mitochondrial toxicity, evidenced by depletion in mtDNA and OXPHOS enzyme abnormalities, is manifested similarly in heart, skeletal muscle, and placenta of AZT-exposed monkey fetuses. It is therefore possible that the placenta, which is a readily accessible tissue, might be an indicator of potential mitochondrial toxicity in human pregnancies involving nucleoside analog drug exposure.
Gerschenson
M
M
Division of Basic Sciences, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892-4255, USA.
Poirier
M C
MC
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D004901:Erythrocebus patas; D005260:Female; D006321:Heart / Q000196:embryology; D006801:Humans; D008297:Male; D008431:Maternal-Fetal Exchange; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000196:embryology; D010920:Placenta / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015215:Zidovudine; D003576:Electron Transport Complex IV