Cardiovascular Toxicology

, Volume 10, Issue 2, pp 87–99 | Cite as

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

  • Salina M. Torres
  • Rao L. Divi
  • Dale M. Walker
  • Consuelo L. McCash
  • Meghan M. Carter
  • Matthew J. Campen
  • Tracey L. Einem
  • Yvonne Chu
  • Steven K. Seilkop
  • Huining Kang
  • Miriam C. Poirier
  • Vernon E. Walker


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.


AZT 3TC Cardiotoxicity Echocardiography Mitochondrial DNA content Mitochondrial DNA mutation Mitochondrial dysfunction Mitochondrial toxicity OXPHOS Transplacental exposure 



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


Denaturing gradient gel electrophoresis


Fractional shortening


Highly active antiretroviral therapy


Hybrid capture-chemiluminescence immunoassay


Left ventricle in end-diastole


Left ventricle in end-systole


Left ventricular posterior wall


Mitochondrial DNA


Nucleoside reverse transcriptase inhibitors


Oxidative phosphorylation


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



We wish to thank Mr. Steve Randock, Ms. Cynthia Herrera, and Ms. Wendy Piper (LRRI) for technical assistance in preparing figures and the manuscript; Dr. Beth Goens (University of New Mexico) for assistance with the echocardiography. This work was supported, in part, by NIH grant R01 HL 72727 to VEW and 1 F31 HL081928 to SMT from the National Heart, Lung, and Blood Institute and in part by the intramural program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.


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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Salina M. Torres
    • 1
    • 2
  • Rao L. Divi
    • 3
  • Dale M. Walker
    • 4
  • Consuelo L. McCash
    • 2
  • Meghan M. Carter
    • 2
  • Matthew J. Campen
    • 2
  • Tracey L. Einem
    • 3
  • Yvonne Chu
    • 3
  • Steven K. Seilkop
    • 4
  • Huining Kang
    • 5
  • Miriam C. Poirier
    • 3
  • Vernon E. Walker
    • 1
    • 2
    • 6
    • 7
    • 8
  1. 1.College of Pharmacy, University of New MexicoAlbuquerqueUSA
  2. 2.Lovelace Respiratory Research InstituteAlbuquerqueUSA
  3. 3.Center for Cancer Research, National Cancer Institute, NIHBethesdaUSA
  4. 4.SKS Consulting ServicesSiler CityUSA
  5. 5.Department of Internal Medicine, Division of Epidemiology and BiostatisticsUniversity of New MexicoAlbuquerqueUSA
  6. 6.BioMosaics, Inc.BurlingtonUSA
  7. 7.Department of PathologyUniversity of VermontBurlingtonUSA
  8. 8.Genetic Toxicology LaboratoryUniversity of VermontBurlingtonUSA

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