Effect of short-term exposure to zidovudine (AZT) on the expression of mitochondria-related genes in skeletal muscle of neonatal mice

Abstract

Zidovudine (3′-azido-3′-deoxythymidine; AZT) is the main anti-retroviral drug given to HIV-1-infected pregnant women during pregnancy and to their infants after birth to reduce mother-to-child transmission of the virus. In animal studies, however, a significant mitochondrial morphological damage has been reported in skeletal muscle as a consequence of transplacental or perinatal exposure to AZT. Because proper muscle function is highly dependent on efficient mitochondrial function and information on AZT-induced mitochondrial toxicity during neonatal exposure is limited, we investigated the effect of AZT on the expression of 542 mitochondria-related genes encoded by both nuclear and mitochondrial DNA in the skeletal muscle of infant male and female mice using microarray technology. Animals were treated orally by gavage with AZT at 0, 10, 50, 100, and 200 mg/kg body weight/day from postnatal day (PND) 1 through 8 and were sacrificed at 1- and 2-h following the last dose on PND 8. These doses in mice correspond to 0, 1.1, 5.5, 11.0, and 22.0 mg/kg AZT in human infants [Center for Drug Evaluation and Research (CDER) 2005. Pharmacology and Toxicology, Guidance for industry. Estimating the maximum safe dose in initial clinical trials for therapeutics in adult healthy volunteers, p. 7. http://www.fda.gov/cder/guidance/index.htm.]. Microarray data were analyzed for effects of time, sex, treatment, and their interactions using a fixed effect linear model. The results showed modest, but significant, dose-related responses in the expression level of genes associated with apoptosis, fatty acid metabolism, mitochondrial DNA maintenance, and various mitochondrial membrane transporters. The transcription levels were not significantly different at both time points and were not sex dependent. The results suggest that changes in expression of mitochondria-related genes in skeletal muscle may be an initial response to short-term AZT exposure in infant mice.