Persistence of mitochondrial toxicity in hearts of female B6C3F1 mice exposed in utero to 3'-azido-3'-deoxythymidine.
Cardiac toxicity has been associated with HIV infection and exposure to nucleoside reverse transcriptase inhibitors (NRTIs), but the role of the latter in the development of cardiac disease of HIV-infected patients is uncertain. To investigate the cardiotoxicity of transplacentally administered zidovudine (AZT) or AZT plus lamivudine (3TC) in the absence of HIV infection, we evaluated several biomarkers of cardiac mitochondrial structure and cardiac structure and function in a B6C3F1 mouse model. In utero exposure to AZT-3TC resulted in ultrastructural pathology, loss of mitochondria, and altered echocardiographic measurements in newborn mice. Cardiac pathology and dysfunction persisted into the adult life of female mice exposed in utero to AZT, as evidenced by significant dose-dependent heart enlargement, clusters of atypical mitochondria and myofibril alterations, significantly increased cytochrome c oxidase activity, and significantly higher numbers of mutations in mitochondrial tRNA genes compared with unexposed controls at 18 to 24 mo of age. These data led to the hypothesis that the long-term pathology of peri-natal exposure to these NRTIs is related to persistent mitochondrial DNA mutations in cardiac tissue; that is, the primary damage during drug treatment is mutational (as opposed to affecting polymerase gamma and/or other mitochondrial elements) and leads over time to delayed, progressive cardiotoxicity.
Walker
Dale M
DM
Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA.
Poirier
Miriam C
MC
Campen
Matthew J
MJ
Cook
Dennis L
DL
Divi
Rao L
RL
Nagashima
Kunio
K
Lund
Amie K
AK
Cossey
Patsy Y
PY
Hahn
Fletcher F
FF
Walker
Vernon E
VE
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000196:embryology* / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics; D004347:Drug Interactions; D004562:Electrocardiography; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D010865:Pilot Projects; D011247:Pregnancy; D012737:Sex Factors; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D019259:Lamivudine; D015215:Zidovudine; D003576:Electron Transport Complex IV