Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity

Environ Mol Mutagen. Apr-May 2007;48(3-4):201-9. doi: 10.1002/em.20201.

Abstract

Effective reduction in maternal-fetal human immunodeficiency virus-1 (HIV-1) transmission has been achieved by administration of nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy, and although most exposed children are clinically normal at birth, mitochondrial dysfunction has been reported. To examine mitochondrial integrity on a molecular level, we evaluated mitochondrial morphology by electron microscopy (EM) and mitochondrial DNA (mtDNA) quantity in umbilical cords and cord blood from NRTI-exposed and unexposed human and monkey newborns. Human subjects included infants born to HIV-1-infected mothers who received Combivir (Zidovudine [AZT] plus Lamivudine [3TC]) (n = 9) or AZT plus Didanosine [ddI] (n = 2) during pregnancy, and infants born to HIV-1-uninfected mothers (n = 7). NRTI-exposed Erythrocebus patas monkey dams (n = 3 per treatment group) were given human-equivalent dosing regimens containing 3TC, AZT/3TC, AZT/ddI, or Stavudine (d4T)/3TC during gestation. Four infants born to unexposed patas dams served as controls. Mitochondria in umbilical cord endothelial cells from NRTI-exposed monkey and human infants showed substantial abnormal pathology by EM, the extent of which was quantified from coded photomicrographs and shown to be different (P < 0.05) from the unexposed monkey and human newborns. Significant (P < 0.05) mtDNA depletion was found in umbilical cords from both human and monkey NRTI-exposed infants and in human, but not in monkey, cord blood leukocytes. For umbilical cords, an increase in mitochondrial morphological damage correlated with reduction in mtDNA quantity in fetal monkeys (r = 0.94). The treatment-induced mitochondrial compromise in infant monkeys ranked as follows: d4T/3TC > AZT/ddI > AZT/3TC > 3TC. The study demonstrates that transplacental NRTI exposures induce similar mitochondrial damage in cord blood and umbilical cords taken from retroviral-uninfected monkey infants and from human infants born to HIV-1-infected women.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / adverse effects*
  • Anti-HIV Agents / toxicity
  • Clinical Trials as Topic
  • DNA, Mitochondrial / analysis
  • Didanosine / adverse effects
  • Disease Models, Animal*
  • Drug Combinations
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Endothelial Cells / ultrastructure
  • Erythrocebus patas
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / prevention & control
  • Humans
  • Infant, Newborn
  • Lamivudine / adverse effects
  • Maternal-Fetal Exchange
  • Mitochondria / drug effects*
  • Mitochondria / pathology
  • Mitochondria / ultrastructure
  • Pregnancy
  • Pregnancy Complications, Infectious / drug therapy
  • Pregnancy Complications, Infectious / prevention & control
  • Retrospective Studies
  • Reverse Transcriptase Inhibitors / administration & dosage
  • Reverse Transcriptase Inhibitors / adverse effects*
  • Reverse Transcriptase Inhibitors / toxicity
  • Umbilical Cord / metabolism
  • Umbilical Cord / ultrastructure
  • Zidovudine / adverse effects

Substances

  • Anti-HIV Agents
  • DNA, Mitochondrial
  • Drug Combinations
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Zidovudine
  • Didanosine