Cardiac mitochondrial compromise in 1-yr-old Erythrocebus patas monkeys perinatally-exposed to nucleoside reverse transcriptase inhibitors.
Hearts from 1-yr-old Erythrocebus patas monkeys were examined after in utero and 6-wk-postbirth exposure to antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs). Protocols were modeled on those given to human immunodeficiency virus (HIV)-1-infected pregnant women. NRTIs were administered daily to the dams for the last 20% or 50% of gestation, and to the infants for 6 wk after birth. Exposures included: no drug (n = 4); Zidovudine, 3'-azido-3'-deoxythymidine (AZT; n = 4); AZT/Lamivudine, (-)-beta-L-2', 3'-Dideoxy-3'-thiacytidine (Epivir, 3TC) (n = 4); AZT/Didanosine (Videx, ddI) (n = 4); and Stavudine (Zerit, d4T)/3TC (n = 4). Echocardiograms and clinical chemistry showed no drug-related changes, but the d4T/3TC-exposed fetuses at 6 and 12 mo had increased white cell counts (p < 0.05). At 1 yr of age, oxidative phosphorylation (OXPHOS) enzyme activities were similar in heart mitochondria from all groups. Mitochondrial pathology, that included clones of damaged mitochondria (p < 0.05), was found in hearts of all 1-yr drug-exposed infants. Levels of mtDNA were elevated (p < 0.05) in hearts of all NRTI-exposed monkeys in the following order: control < d4T/3TC < AZT < AZT/3TC < AZT/ddI. The clinical status of NRTI-exposed infants, as evidenced by behavior, clinical chemistry, OXPHOS activity and echocardiogram, was normal. However, extensive mitochondrial damage with clusters of similar-appearing damaged heart mitochondria observed by electron microscopy, and an increase in mtDNA quantity, that persisted at 1 yr of age, suggest the potential for cardiotoxicity later in life.
Divi
Rao L
RL
Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD 20892-4255, USA.
Leonard
Sarah L
SL
Kuo
Maryanne M
MM
Walker
Brettania L
BL
Orozco
Christine C
CC
St Claire
Marisa C
MC
Nagashima
Kunio
K
Harbaugh
Steven W
SW
Harbaugh
Jeffrey W
JW
Thamire
Chandrasekhar
C
Sable
Craig A
CA
Poirier
Miriam C
MC
D000818:Animals; D000831:Animals, Newborn; D003402:Creatine Kinase / Q000097:blood; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004272:DNA, Mitochondrial / Q000378:metabolism; D004452:Echocardiography; D004562:Electrocardiography; D016669:Erythrocebus; D005260:Female; D007091:Image Processing, Computer-Assisted; D019344:Lactic Acid / Q000378:metabolism; D007958:Leukocyte Count; D008163:Luminescent Measurements; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D019344:Lactic Acid; D004247:DNA; D003402:Creatine Kinase