title: Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapy in utero.
abstract: The use of combination antiretroviral therapy (cART) to prevent HIV mother-to-child transmission during pregnancy and delivery is generally considered safe. However, vigilant assessment of potential risks of these agents remains warranted. Epigenetic changes including DNA methylation are considered potential mechanisms linking the in utero environment with long-term health outcomes. Few studies have examined the epigenetic effects of prenatal exposure to pharmaceutical agents, including antiretroviral therapies, on children. In this study, we examined the methylation status of the LINE-1 and ALU-Yb8 repetitive elements as markers of global DNA methylation alteration in peripheral blood mononuclear cells obtained from newborns participating in the Pediatric HIV/AIDS Cohort Study SMARTT cohort of HIV-exposed, cART-exposed uninfected infants compared to a historical cohort of HIV-exposed, antiretroviral-unexposed infants from the Women and Infants Transmission Study Cohort. In linear regression models controlling for potential confounders, we found the adjusted mean difference of AluYb8 methylation of the cART-exposed compared to the -unexposed was -0.568 (95% CI: -1.023, -0.149) and for LINE-1 methylation was -1.359 (95% CI: -1.860, -0.857). Among those exposed to cART, subjects treated with atazanavir (ATV), compared to those on other treatments, had less AluYb8 methylation (-0.524, 95% CI: -0.025, -1.024). Overall, these results suggest a small but statistically significant reduction in the methylation of these repetitive elements in an HIV-exposed, cART-exposed cohort compared to an HIV-exposed, cART-unexposed historic cohort. The potential long-term implications of these differences are worthy of further examination.
authors.affiliation: a Departments of Pharmacology and Toxicology and of Epidemiology; Geisel School of Medicine at Dartmouth ; Hanover , NH USA.
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Sean S
authors.initials: SS
authors.lastname: Brummel
authors.forename: Deborah
authors.initials: D
authors.lastname: Kacanek
authors.forename: George R
authors.initials: GR
authors.lastname: Seage
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Spector
authors.forename: David A
authors.initials: DA
authors.lastname: Armstrong
authors.forename: Barry M
authors.initials: BM
authors.lastname: Lester
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rich
mesh_terms: D000328:Adult; D020087:Alu Elements / Q000187:drug effects / Q000235:genetics*; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate / Q000008:administration & dosage; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D006678:HIV / Q000235:genetics / Q000472:pathogenicity; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000635:transmission / Q000821:virology; D006801:Humans; D007231:Infant, Newborn; D020084:Long Interspersed Nucleotide Elements / Q000187:drug effects / Q000235:genetics*; D009034:Mother-Child Relations; D011247:Pregnancy
chemical_list: D000069446:Atazanavir Sulfate
keywords: DNA methylation; HIV; anti-retroviral; atazanavir; developmental origins; newborn; pediatrics; pharmaceuticals; prenatal; repetitive elements