Genotoxic signature in cord blood cells of newborns exposed in utero to a zidovudine-based antiretroviral combination

Background: Zidovudine experimental genotoxicity has been established. Objective of the study was to identify genotoxicity markers in cord blood cells from newborns exposed in utero to ARV combinations containing zidovudine. Methods: Cells were investigated by karyotyping and gene expression analysis of the CD34+ hematopoietic stem/progenitor cell compartment (HPC). Results: Karyotyping of the cord blood cells from 15 ARV-exposed newborns and 12 controls revealed a higher proportion of aneuploid cells in the exposed group (median [IQR]: 18.8% [10.0-26.7] vs. 6.6 % [3.1-11.7], p<0.001). All chromosomes were involved with a random distribution of these alterations. Gene expression profiling of CD34+ HPCs from seven ARV-exposed and six control newborns revealed >300 genes significantly up- or down-regulated (p<0.05) by at least 1.5-fold in the exposed group. Significant alterations of genes involved in the control of cell cycle, mitotic check-points and DNA repair were identified. Although this study does not allow discrimination between the roles of each of the three drugs, both cytogenetic and transcriptional findings are similar to those in cellular experiments using zidovudine alone. Conclusion: The cord blood cells —including hematopoietic stem cells— from newborns exposed in utero to a zidovudine-based ARV combination present cytogenetic and transcriptional abnormalities compatible with DNA damage.