Cardiac mitochondrial compromise in 1-yr-old Erythrocebus patas monkeys perinatally-exposed to nucleoside reverse transcriptase inhibitors

Cardiovasc Toxicol. 2005;5(3):333-46. doi: 10.1385/ct:5:3:333.

Abstract

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.

MeSH terms

  • Animals
  • Animals, Newborn
  • Creatine Kinase / blood
  • DNA / biosynthesis
  • DNA / genetics
  • DNA, Mitochondrial / metabolism
  • Echocardiography
  • Electrocardiography
  • Erythrocebus
  • Female
  • Image Processing, Computer-Assisted
  • Lactic Acid / metabolism
  • Leukocyte Count
  • Luminescent Measurements
  • Microscopy, Electron, Transmission
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism*
  • Pregnancy
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Ventricular Function, Left / drug effects
  • Ventricular Function, Left / physiology

Substances

  • DNA, Mitochondrial
  • Reverse Transcriptase Inhibitors
  • Lactic Acid
  • DNA
  • Creatine Kinase