Persistence of Mitochondrial Toxicity in Hearts of Female B6C3F1 Mice Exposed <I> In Utero</I> to 3'-Azido-3'-Deoxythymidine

Abstract

Cardiac toxicity has been associated with HIV infection and exposure to nucleoside reverse transcriptase inhibitors (NRTIs), but the role of the latter in the development of cardiac disease of HIV-infected patients is uncertain. To investigate the cardiotoxicity of transplacentally administered zidovudine (AZT) or AZT plus lamivudine (3TC) in the absence of HIV infection, we evaluated several biomarkers of cardiac mitochondrial structure and cardiac structure and function in a B6C3F1 mouse model. In utero exposure to AZT-3TC resulted in ultrastructural pathology, loss of mitochondria, and altered echocardiographic measurements in newborn mice. Cardiac pathology and dysfunction persisted into the adult life of female mice exposed in utero to AZT, as evidenced by significant dose-dependent heart enlargement, clusters of atypical mitochondria and myofibril alterations, significantly increased cytochrome c oxidase activity, and significantly higher numbers of mutations in mitochondrial tRNA genes compared with unexposed controls at 18 to 24 mo of age. These data led to the hypothesis that the long-term pathology of peri-natal exposure to these NRTIs is related to persistent mitochondrial DNA mutations in cardiac tissue; that is, the primary damage during drug treatment is mutational (as opposed to affecting polymerase gamma and/or other mitochondrial elements) and leads over time to delayed, progressive cardiotoxicity.

Effects of Zidovudine Treatment on Heart mRNA Expression and Mitochondrial DNA Copy Number Associated with Alterations in Deoxynucleoside Triphosphate Composition in a Neonatal Rat Model

“…Despite the past routine usage of AZT in mothers and the continuing use in neonates, the metabolism and mechanism(s) of toxicity of AZT or other analogues in the NRTI group have been poorly studied in neonates. Past studies have shown mitochondrial DNA depletion involving adult rat or mouse populations when treated with oral AZT (15,16,32). Our data show for the first time that AZT dramatically altered the size and composition of the dNTP pools during early neonatal growth (Fig.…”

“…Shortterm (7)(8)(9)(10)(11)(12)(13)(14) and long-term (15)(16)(17)(18) problems associated with AZT treatment in neonatal animal models and humans have been noted by others and are described in the introduction. It has been previously shown that alterations in dNTP composition are associated with mutagenesis in nuclear and mitochondrial DNA (23,26) and may account for the long-term problems (15)(16)(17)(18) and reports of AZT-induced carcinogenicity (15). While not a goal of this study, an examination of the implications of the AZT-induced cellular changes noted here on both short-term and long-term health of the animals is planned.…”

“…Significant reductions in oxidative phosphorylation and mitochondrial biogenesis were noted in cultured cardiomyocytes treated with AZT (12). In monkeys (13,14), rats (15), mice (15,16), and humans (17,18), AZT has been shown to be mutagenic during the in utero and neonatal period. Phosphorylated AZT has been shown to competitively and noncompetitively inhibit mitochondrial DNA (mtDNA) polymerase-gamma, the enzyme responsible for mitochondrial DNA synthesis (19).…”

An unusual phenotypic and genotypic expression in F2 generation following one stage zidovudine exposure during pregnancy and lactation- an experiment in mice

“…Secondly, ageing is also contributed by deficit in mitochondrial energy as a result of depletion of mitochondrial DNA (Shigenaga et al, 1994). ZDV is a drug linked to transplacental mitochondrial dysfunction in humans (Blanche et al, 1999;Poirier et al, 2003;Venhoff and Walker, 2006), in animal experiments (Gerschenson et al, 2004;Walker et al, 2004) as well as in vitro study (Cazzalini et al, 2001).…”

Special issue on health risks of perinatal exposure to nucleoside reverse transcriptase inhibitors

“…However, expanded use of multiple antiretroviral drugs during pregnancy has led to concerns regarding both short-term toxicities and long-term health risks to the drug-exposed infants, almost all of whom are born free of HIV-1-infection [Watts, 2006]. The theoretical longer-term effects, as evidenced in experimental models, include NRTI-induced carcinogenesis and mitochondrial abnormalities [Olivero et al, 1997;Diwan et al, 1999;Dagan et al, 2002;Poirier et al, 2004;Walker et al, 2004Walker et al, , 2007NTP, 2006], suggesting that monitoring of children exposed perinatally to antiretrovirals be recommended in order to intervene should adverse outcomes appear [Watts, 2006].…”