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
Article

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

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

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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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