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ToxSci Advance Access published online on June 30, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh208
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received April 4, 2004
Accepted June 26, 2004

Systems Toxicology

Mitochondrial Damage Revealed by Morphometric and Semiquantitative Analysis of Mouse Pup Cardiomyocytes Following in Utero and Postnatal Exposure to Zidovudine and Lamivudine

Jack B. Bishop 1*, Yoshiro Tani 2, Kristine Witt 3, Jo Anne Johnson 2, Shyamal Peddada 4, June Dunnick 3, Abraham Nyska 2

1 Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
2 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
3 Toxicology Operations Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
4 Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709

* To whom correspondence should be addressed. E-mail: bishop{at}niehs.nih.gov.


  Abstract

Zidovudine (ZDV), an antiretroviral drug used alone or in combination with other antiretroviral agents to treat HIV-infected pregnant women and their newborn infants, effectively reduces mother-to-child transmission of the virus. That myopathy and cardiomyopathy, related to mitochondrial damage, develop in some adults chronically treated with ZDV has long been known; recently, reports have suggested that similar adverse effects may occur in some infants exposed perinatally. Using a mouse model of human neonatal exposure, we treated pregnant CD-1 mice twice daily with doses of 75 mg/kg ZDV plus 37.5 mg/kg lamivudine throughout gestation and lactation; pups were exposed by direct gavage beginning postnatal day (PND) 4 and sacrificed on PND 28. Hearts were removed rapidly, and ventricles were processed for electron microscopy. Morphometric and semiquantitative morphological analyses were performed on 3 micrographs from each of 3 blocks from each of 3 females and 3 males from the control and treated groups. Treated mice showed significant increases in the mean area and decreases in the mean number of cardiomyocytic mitochondria compared to controls. We observed clusters of damaged mitochondria more frequently in treated animals than in controls; damage included fragmentation and loss of cristae. These results, demonstrating alterations in cardiomyocytic mitochondria of mice exposed in utero and postnatally, may model cardiac damage reported in human infants similarly exposed to ZDV. Critical insights derived from animal-model data like these may be used to mitigate risks to thousands of human infants receiving essential lifesaving therapy with antiretroviral drugs.

Keywords: mitochondria; heart; AIDS drugs; transplacental exposure; mice; electron microscopy; morphometry.
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