Altered heterochromatin organization after perinatal exposure to zidovudine.
BACKGROUND
Zidovudine (3'-azido-3'-deoxythymidine, AZT), administered to pregnant women alone or in combination with other antiretroviral drugs, greatly reduces the mother-to-child transmission of HIV-1. The potential genotoxicity of these molecules is underestimated and wide-ranging evaluation of its biological and clinical consequences is required.


METHODS
We investigated the nuclear organization of constitutive heterochromatin, a major domain participating in epigenetic regulation, in uninfected infants born to HIV-1-infected mothers treated with zidovudine and/or other nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy. We studied the organization of chromosome 1 heterochromatin (1q12) in peripheral leukocytes of 25 HIV-1-uninfected children (newborn to 9 years old): children born to HIV-1-infected mothers exposed to zidovudine and/or other NRTIs (n=15), children born to HIV-1-infected mothers not exposed to any NRTIs (n=6) and children born to HIV-1-uninfected mothers (n=4).


RESULTS
Results differed significantly between NRTI-exposed and -unexposed children. By contrast, there was no difference between NRTI-unexposed children born to HIV-1-infected mothers and children born to HIV-uninfected mothers. The anomaly persisted in lymphocytes cultured for 48 h. There was no evidence of abnormal DNA methylation, a major feature of constitutive heterochromatin and associated with the loss of its structure. In a complementary sample of children, analysis of chromosome 11 and 16 heterochromatin suggests that the defect affects most of the other heterochromatic sites of the human genome. The heterochromatin defect persists long after the end of the exposure and appears in leukocytes of both myeloid and lymphoid lineages, suggesting that haematopoietic stem cells are affected.
Senda
Sho
S
U741, INSERM, Paris, France.
Blanche
Stéphane
S
Costagliola
Dominique
D
Cibert
Christian
C
Nigon
Fabienne
F
Firtion
Ghilaine
G
Floch
Corinne
C
Parat
Sophie
S
Viegas-Péquignot
Evani
E
D000293:Adolescent; D019380:Anti-HIV Agents / Q000009:adverse effects*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D002878:Chromosomes, Human, Pair 1 / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11 / Q000187:drug effects; D002885:Chromosomes, Human, Pair 16 / Q000187:drug effects; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1; D006570:Heterochromatin / Q000187:drug effects*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D007962:Leukocytes / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D013997:Time Factors; D015215:Zidovudine / Q000009:adverse effects*
D019380:Anti-HIV Agents; D006570:Heterochromatin; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine