Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.
Genotoxic and functional consequences of transplacental zidovudine exposure in fetal monkey brain mitochondria.
J Acquir Immune Defic Syndr. 2000 Jun 1;24(2):100-5. Unique Identifier : AIDSLINE MED/20388727 Ewings EL; Gerschenson M; St Claire MC; Nagashima K; Skopets B; Harbaugh SW; Harbaugh JW; Poirier MC; Division of Basic Sciences, National Cancer Institute, National; Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Abstract:
Mitochondrial toxicity was assessed in the brains of developing Erythrocebus patas monkey fetuses exposed in utero to the nucleoside analogue drug zidovudine (3'-azido-3'deoxythymidine or AZT). Pregnant E. patas monkeys were given 0 (n = 5), 10 (n = 3), and 40 (n = 3) mg of AZT/day, equivalent to 21 and 86% of the human daily dose, for the last half (about 10 weeks) of gestation. Mitochondria were isolated from fetal cerebrum and cerebellum at birth and mitochondrial morphology was examined in these tissues by transmission electron microscopy (TEM). Oxidative phosphorylation (OXPHOS) enzyme specific activities were measured spectrophotometrically. Mitochondrial DNA (mtDNA) integrity and quantity were determined by Southern blot and slot blot analysis. In the cerebral mitochondria, reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase (complex I) specific activity decreased by 25% in monkeys treated with 40 mg of AZT/day compared with unexposed monkeys (p > or = .05). At the same AZT dose in the cerebral mitochondria, succinate dehydrogenase (complex II) and cytochrome c reductase (complex IV)-specific activities showed dose-dependent increases (p > or = .05), compared with those in controls. In the cerebellum, no difference was seen in mitochondrial OXPHOS enzyme activities between unexposed and exposed fetuses. Furthermore, TEM demonstrated no difference in mitochondrial morphology in frontal cerebrum or cerebellum from unexposed and exposed fetuses, and all fetuses had similar amounts of mtDNA in both tissues. Cerebral mtDNA degradation was noted in the highest AZT dosage group, whereas mtDNA from cerebellum was uneffected. Thus, in fetal patas monkeys given a human equivalent daily dose of AZT during the last half of pregnancy, mitochondria in the fetal cerebrum appear to sustain moderate damage, while the fetal cerebellum mitochondria were not effected.
Keywords: JOURNAL ARTICLE Animal Animals, Newborn Brain/*DRUG EFFECTS/EMBRYOLOGY/METABOLISM Cerebellum/DRUG EFFECTS/EMBRYOLOGY/METABOLISM DNA, Mitochondrial/DRUG EFFECTS/GENETICS Erythrocebus patas Female Human *Maternal-Fetal Exchange Mitochondria/*DRUG EFFECTS/METABOLISM/ULTRASTRUCTURE Multienzyme Complexes/GENETICS/METABOLISM *Mutagens NADH Dehydrogenase/GENETICS/METABOLISM Oxidative Phosphorylation/DRUG EFFECTS Oxidoreductases/GENETICS/METABOLISM Pregnancy *Prenatal Exposure Delayed Effects Succinate Dehydrogenase/GENETICS/METABOLISM Support, U.S. Gov't, P.H.S. Zidovudine/*TOXICITY 001030
A00A0533
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Important note: Information in this article was accurate in 2000. The state of the art may have changed since the publication date.
