title: Genotoxic signature in cord blood cells of newborns exposed in utero to a Zidovudine-based antiretroviral combination.
abstract: BACKGROUND
  The genotoxicity of zidovudine has been established in experimental models. The objective of the study was to identify genotoxicity markers in cord blood cells from newborns exposed in utero to antiretroviral (ARV) combinations containing zidovudine.
  
  
  METHODS
  Cells were investigated by karyotyping and gene expression analysis of the CD34(+) hematopoietic stem/progenitor cell (HPC) compartment.
  
  
  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, 18.8% [interquartile range, 10.0%-26.7%] vs 6.6% [interquartile range, 3.1%-11.7%]; P < .001). All chromosomes were involved, with a random distribution of these alterations. Gene expression profiling of CD34(+) HPCs from 7 ARV-exposed and 6 control newborns revealed that >300 genes were significantly upregulated or downregulated by at least 1.5-fold in the exposed group (P < .05 for all comparisons). Significant alterations of genes involved in cell cycle control, mitotic checkpoints, and DNA repair were identified. Although this study does not allow discrimination between the roles of each of the 3 drugs, both cytogenetic and transcriptional findings are similar to those in cellular experiments that used zidovudine alone.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U768, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine.
authors.forename: Isabelle
authors.initials: I
authors.lastname: André-Schmutz
authors.forename: Liliane
authors.initials: L
authors.lastname: Dal-Cortivo
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Six
authors.forename: Sophie
authors.initials: S
authors.lastname: Kaltenbach
authors.forename: Fabienne
authors.initials: F
authors.lastname: Cocchiarella
authors.forename: Jerome
authors.initials: J
authors.lastname: Le Chenadec
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cagnard
authors.forename: Anne-Gael
authors.initials: AG
authors.lastname: Cordier
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benachi
authors.forename: Laurent
authors.initials: L
authors.lastname: Mandelbrot
authors.forename: Elie
authors.initials: E
authors.lastname: Azria
authors.forename: Naima
authors.initials: N
authors.lastname: Bouallag
authors.forename: Sonia
authors.initials: S
authors.lastname: Luce
authors.forename: Brigitte
authors.initials: B
authors.lastname: Ternaux
authors.forename: Christian
authors.initials: C
authors.lastname: Reimann
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford-Weiss
authors.forename: Cristina
authors.initials: C
authors.lastname: Leschi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Recchia
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004338:Drug Combinations; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D007621:Karyotyping / Q000379:methods; D008431:Maternal-Fetal Exchange / Q000502:physiology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D011297:Prenatal Exposure Delayed Effects; D013234:Stem Cells / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D055815:Young Adult; D015215:Zidovudine / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D018952:Antigens, CD34; D004338:Drug Combinations; D015215:Zidovudine
keywords: aneuploidy; genotoxicity; pregnancy; transcriptome; zidovudine