Research Article

Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination†‡

  1. Sherine S.L. Chan1,
  2. Janine H. Santos1,
  3. Joel N. Meyer1,
  4. Bhaskar S. Mandavilli1,
  5. Dennis L. Cook Jr.2,
  6. Consuelo L. McCash2,
  7. Grace E. Kissling3,
  8. Abraham Nyska4,
  9. Julie F. Foley4,
  10. Bennett van Houten1,
  11. William C. Copeland1,
  12. Vernon E. Walker2,
  13. Kristine L. Witt5,
  14. Jack B. Bishop5,*

Article first published online: 4 JAN 2006

DOI: 10.1002/em.20191

Issue

Environmental and Molecular Mutagenesis

Environmental and Molecular Mutagenesis

Volume 48, Issue 3-4, pages 190–200, April - May 2007

Additional Information

How to Cite

Chan, S. S.L., Santos, J. H., Meyer, J. N., Mandavilli, B. S., Cook, D. L., McCash, C. L., Kissling, G. E., Nyska, A., Foley, J. F., van Houten, B., Copeland, W. C., Walker, V. E., Witt, K. L. and Bishop, J. B. (2007), Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Environ. Mol. Mutagen., 48: 190–200. doi: 10.1002/em.20191

Author Information

  1. 1

    Laboratory of Molecular Genetics, National Institute of Environmental HealthSciences, National Institutes of Health, Research Triangle Park, North Carolina

  2. 2

    Lovelace Respiratory Research Institute, Albuquerque, New Mexico

  3. 3

    Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

  4. 4

    Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

  5. 5

    Toxicology Operations Branch, National Institute of Environmental HealthSciences, National Institutes of Health, Research Triangle Park, North Carolina

*National Institute of Environmental Health Sciences, PO Box 12233, MD EC-01, Research Triangle Park, NC 27709, USA

  1. †

    This article is a US Government work and, as such, is in the public domain in the United States of America.

  2. ‡

    Invited article on the genotoxicity of perinatal NRTI therapy.

Publication History

  1. Issue published online: 19 MAR 2007
  2. Article first published online: 4 JAN 2006

Funded by

  • NIEHS/NTP. Grant Number: N01-ES-75409
  • NIEHS. Grant Number: P30ES012072
  • National Heart, Lung, and Blood Institute. Grant Number: R01 HL072727

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Keywords:

  • mitochondrial DNA;
  • mutations;
  • cardiomyopathy;
  • nucleoside reverse transcriptase inhibitors;
  • Combivir;
  • PCR

Abstract

Antiretroviral therapies based on nucleoside reverse transcriptase inhibitors (NRTIs), like zidovudine (3′-azido-3′-deoxythymidine; AZT) and lamivudine ((-)2′,3′-dideoxy-3′-thiacytidine; 3TC), markedly reduce mother-to-child transmission of the human immunodeficiency virus (HIV). However, AZT induces damage in nuclear DNA of mice exposed in utero and postnatally, and mitochondrial DNA (mtDNA) damage has been observed in both human and mouse neonates following perinatal exposure to AZT and AZT/3TC in combination. To provide animal data modeling the NRTI-induced heart damage reported in human infants, we treated pregnant CD-1 mice throughout gestation and treated their pups by direct gavage from postnatal day (PND) 4 through PND 28 with daily doses of 150 mg/kg body weight (bw)/day AZT, 75 mg/kg bw/day 3TC, 125/62.5 mg/kg bw/day AZT/3TC, or the vehicle control. Half the pups were euthanized on PND 28; the remainder received no further dosing, and were euthanized at week 10. Heart tissue was collected, total DNA was extracted, and mtDNA copy number relative to nuclear DNA copy number, mtDNA damage, and mtDNA mutation assays were performed using PCR-based methods. Analyses revealed increases in mtDNA lesions in 4-week-old males and females treated with AZT or 3TC, but not in 10-week-old mice, suggesting that the damage resolved after treatment ceased. Interestingly, 10-week-old females treated with AZT/3TC had significant increases in mtDNA damage. Point mutations were elevated in 10-week-old females treated with AZT or AZT/3TC, but not 3TC; no increases in mutations were seen in either gender at 4 weeks of age. Our data suggest that AZT/3TC combination treatment produces greater mtDNA damage than either agent individually, and that female mice are more sensitive than males to AZT/3TC-induced mtDNA damage. Environ. Mol. Mutagen., 2006. Published 2006 Wiley-Liss, Inc.

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