Fetal mitochondrial heart and skeletal muscle damage in Erythrocebus patas monkeys exposed in utero to 3'-azido-3'-deoxythymidine.
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.
Gerschenson
M
M
Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA. gerschem@exchange.nih.gov
Erhart
S W
SW
Paik
C Y
CY
St Claire
M C
MC
Nagashima
K
K
Skopets
B
B
Harbaugh
S W
SW
Harbaugh
J W
JW
Quan
W
W
Poirier
M C
MC
D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004901:Erythrocebus patas; D005260:Female; D005318:Fetal Heart / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000139:chemically induced* / Q000196:embryology* / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000196:embryology* / Q000378:metabolism / Q000648:ultrastructure; D009245:NADH Dehydrogenase / Q000378:metabolism; D010085:Oxidative Phosphorylation; D011247:Pregnancy; D012518:Sarcomeres / Q000187:drug effects / Q000648:ultrastructure; D013385:Succinate Dehydrogenase / Q000378:metabolism; D015215:Zidovudine / Q000008:administration & dosage / Q000633:toxicity*
D004272:DNA, Mitochondrial; D015215:Zidovudine; D013385:Succinate Dehydrogenase; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV