Cardiovascular Toxicology

, Volume 10, Issue 2, pp 87–99

In Utero Exposure of Female CD-1 Mice to AZT and/or 3TC: II. Persistence of Functional Alterations in Cardiac Tissue

Authors

  • Salina M. Torres
    • College of Pharmacy, University of New Mexico
    • Lovelace Respiratory Research Institute
  • Rao L. Divi
    • Center for Cancer Research, National Cancer Institute, NIH
  • Dale M. Walker
    • SKS Consulting Services
  • Consuelo L. McCash
    • Lovelace Respiratory Research Institute
  • Meghan M. Carter
    • Lovelace Respiratory Research Institute
  • Matthew J. Campen
    • Lovelace Respiratory Research Institute
  • Tracey L. Einem
    • Center for Cancer Research, National Cancer Institute, NIH
  • Yvonne Chu
    • Center for Cancer Research, National Cancer Institute, NIH
  • Steven K. Seilkop
    • SKS Consulting Services
  • Huining Kang
    • Department of Internal Medicine, Division of Epidemiology and BiostatisticsUniversity of New Mexico
  • Miriam C. Poirier
    • Center for Cancer Research, National Cancer Institute, NIH
    • College of Pharmacy, University of New Mexico
    • Lovelace Respiratory Research Institute
    • BioMosaics, Inc.
    • Department of PathologyUniversity of Vermont
    • Genetic Toxicology LaboratoryUniversity of Vermont
Article

DOI: 10.1007/s12012-010-9065-z

Cite this article as:
Torres, S.M., Divi, R.L., Walker, D.M. et al. Cardiovasc Toxicol (2010) 10: 87. doi:10.1007/s12012-010-9065-z

Abstract

To delineate temporal changes in the integrity and function of mitochondria/cardiomyocytes in hearts from mice exposed in utero to commonly used nucleoside analogs (NRTIs), CD-1 mice were exposed in utero to 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during days 12–18 of gestation and hearts from female mouse offspring were examined at 13 and 26 weeks postpartum. Alterations in cardiac mitochondrial DNA (mtDNA) content, oxidative phosphorylation (OXPHOS) enzyme activities, mtDNA mutations, and echocardiography of NRTI-exposed mice were assessed and compared with findings in vehicle-exposed control mice. A hybrid capture-chemiluminescence assay showed significant twofold increases in mtDNA levels in hearts from AZT- and AZT/3TC-exposed mice at 13 and 26 weeks postpartum, consistent with near doubling in mitochondrial numbers over time compared with vehicle-exposed mice. Echocardiographic measurements at 13 and 26 weeks postpartum indicated progressive thinning of the left ventricular posterior wall in NRTI-exposed mice, relative to controls, with differences becoming statistically significant by 26 weeks. Overall, progressive functional changes occurred in mouse mitochondria and cardiac tissue several months after in utero NRTI exposures; AZT and 3TC acted in concert to cause additive cardiotoxic effects of AZT/3TC compared with either drug alone.

Keywords

AZT3TCCardiotoxicityEchocardiographyMitochondrial DNA contentMitochondrial DNA mutationMitochondrial dysfunctionMitochondrial toxicityOXPHOSTransplacental exposure

Abbreviations

AZT

Zidovudine or 3′-azido-2′,3′-dideoxythymidine

DGGE

Denaturing gradient gel electrophoresis

FS

Fractional shortening

HAART

Highly active antiretroviral therapy

HC-CIA

Hybrid capture-chemiluminescence immunoassay

LVED

Left ventricle in end-diastole

LVES

Left ventricle in end-systole

LVPW

Left ventricular posterior wall

mtDNA

Mitochondrial DNA

NRTIs

Nucleoside reverse transcriptase inhibitors

OXPHOS

Oxidative phosphorylation

3TC

Lamivudine or 2′,3′-dideoxy-3′-thiacytidine

Copyright information

© Springer Science+Business Media, LLC 2010