Journal
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
Volume 48, Issue 3-4, Pages 330-343Publisher
WILEY
DOI: 10.1002/em.20285
Keywords
AZT-DNA incorporation; Comet assay; glycophorin A mutations; lamivudine; transplacental mutagenicity; zidovudine
Categories
Funding
- NCI NIH HHS [R01 CA95741] Funding Source: Medline
- NICHD NIH HHS [R01 HD33648, R01 HD33016] Funding Source: Medline
Ask authors/readers for more resources
The genotoxicity of zidovudine (AZT) based treatments was investigated in human H9 lymphoblastoid cells in an in vitro study and in red blood cells (RBCs) from perinatally exposed HIV-1-infected mothers and their infants in an observational cohort study. Exposure of H9 cells for 24 hr to AZT produced dose-dependent increases in Comet assay tail moment (TM) when electrophoresed at pH 13.0, but not at pH 12.1 or pH 8.0, suggesting that DNA damage was via alkali-labile lesions and not double-stranded DNA strand breaks. The TM dose response at pH 13.0 correlated directly with AZT-DNA incorporation determined by AZT-radioimmunoassay. Levels of DNA damage in utero, measured by Comet assay TM, were similar in cord blood mononuclear cells of nucleoside analogexposed newborns (n=43) and unexposed controls (n=40). In contrast, the glycophorin A (GPA) somatic cell mutation assay (which screens for large-scale DNA damage in RBCs) showed clear evidence that GPA N/N variants, arising from chromosome loss and duplication, somatic recombination, and gene conversion, were significantly elevated in mother-child pairs receiving prepartum AZT plus lamivudine (3TC). Cord blood from newborns exposed to AZT-3TC had GPA N/ N variant frequencies of 4.7 +/- 0.7 (mean +/- SE) x 10(-6) RBCs (n=26 infants) compared with 2.2 +/- 0.3 x 10(-6) RBCs for unexposed controls (n= 30 infants; P < 0.001). Elevations in GPA N/N variants generally persisted through 1 year of age in nucleoside analog-exposed children. Overall, the mutagenic effects found in mother-child pairs receiving AZT-based treatments justify their surveillance for long-term genotoxic consequences. Environ. Mol. Mutagen. 48:330-343, 2007. (c) 2007Wiley-Liss, Inc.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available