Fetal Mitochondrial Heart and Skeletal Muscle Damage in Erythrocebus patas Monkeys Exposed in Utero to 3'-Azido-3'-Deoxythymidine

Abstract

3'-azido-3'-deoxythymidine (AZT) is given to pregnant women positive for the human immunodeficiency virus type 1 (HIV-1) to reduce maternal-fetal viral transmission. To explore fetal mitochondrial consequences of this exposure, pregnant Erythrocebus patas monkeys were given daily doses of 1.5 mg (21% of the human daily dose) and 6.0 mg (86% of the human daily dose) of AZT/kg body weight (bw), for the second half of gestation. At term, electron microscopy of fetal cardiac and skeletal muscle showed abnormal and disrupted sarcomeres with myofibrillar loss. Some abnormally shaped mitochondria with disrupted cristae were observed in skeletal muscle myocytes. Oxidative phosphorylation (OXPHOS) enzyme assays showed dose-dependent alterations. At the human-equivalent dose of AZT (6 mg of AZT/kg bw), there was an approximately 85% decrease in the specific activity of NADH dehydrogenase (complex I) and three- to sixfold increases in specific activities of succinate dehydrogenase (complex II) and cytochrome-c oxidase (complex IV). Furthermore, a dose-dependent depletion of mitochondrial DNA levels was observed in both tissues. The data demonstrate that transplacental AZT exposure causes cardiac and skeletal muscle mitochondrial myopathy in the patas monkey fetus.

In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration

“…It is important to design experiments with larger sample size to interpret the results more accurately. Compared with skeletal muscle, kidney, and liver, the cardiac muscle has the highest cytochrome b/actin ratio, which is consistent with literatures [17,19] . Mitochondrial dysfunction has been most clearly associated with AZT [17] in both humans [29] and in primates [17] , which is consistent with our results in this study.…”

“…These specimens were used for extracting mitochondria and determining the activities of respiratory chain complexes and the mitochondrial DNA (mtDNA) contents. Also, some tissues were fixed in 3% glutaraldehyde and were used for the observation of mitochondrial morphology and structure under electron microscope [17,19,20] . Observation of the ultramicro-structure of mitochondria with transmission electron microscope (TEM): Fresh tissues (including liver, kidney, skeletal muscle, and cardiac muscle) were cut into 1 mm cubes, which were fixed in 3% glutaraldehyde for 2 h, and then fixed in 1% osmium tetroxide, stepwise dehydrated in graded acetone, and infiltrated, embedded, and polymerized in EPON 812.…”

“…Determination of the activities of respiratory chain complexes I-IV: We used animal tissue mitochondria isolation 1668 www.nature.com/aps Zeng W et al Acta Pharmacologica Sinica npg kit to isolate mitochondria, and used mitochondrial respiratory chain complex determination kit to evaluate the enzyme activities of complexes I (NADH-CoQ reductase), II (sccinateCoQ reductase), III (CoQ-cytochrome C reductase), and IV (cytochrome C oxidase) [17,19] . Also, we used animal mitochondrial protein content determination kit to determine the mitochondrial protein content in animal tissues.…”

“…A study of maternal-fetal exposure to AZT in patas monkeys also showed evidence for mitochondrial dysfunction including respiratory-chain defects and mtDNA reduction [17] . Metacavir is a noval deoxyguanosine analog with a molecular formula of C 11 H 15 N 5 O 3 [18] .…”

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

“…Contrasting evidence in other reports suggests that AZT CM in pediatric patients may be more prevalent than previously reported (Domanski et al, 1995). In vivo data from Erythrocebus patas treated with AZT in utero suggest some evidence of a mitochondrial toxicity of AZT to heart and skeletal muscle that resembles those features described in experimental systems with rodents (Gerschenson et al, 2000).…”