Infant peripheral blood repetitive element hypomethylation associated with antiretroviral therapy in utero

Carmen J Marsit, Sean S Brummel, Deborah Kacanek, George R Seage 3rd, Stephen A Spector, David A Armstrong, Barry M Lester, Kenneth Rich, Pediatric HIV/AIDS Cohort Studies Network, Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter, William Shearer, Mary Paul, Norma Cooper, Lynnette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Patricia Garvie, James Blood, William Borkowsky, Sandra Deygoo, Helen Rozelman, Arry Dieudonne, Linda Bettica, Susan Adubato, Katherine Knapp, Kim Allison, Megan Wilkins, Midnela Acevedo-Flores, Lourdes Angeli- Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Chi Dola, Robert Maupin, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Jenna Wallace, Carrie Chambers, Christine Reed, Mobeen Rathore, Kristi Stowers, Ann Usitalo, Kenneth Rich, Lourdes Richardson, Renee Smith, Gwendolyn Scott, Claudia Florez, Elizabeth Willen, Toni Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio, Carmen J Marsit, Sean S Brummel, Deborah Kacanek, George R Seage 3rd, Stephen A Spector, David A Armstrong, Barry M Lester, Kenneth Rich, Pediatric HIV/AIDS Cohort Studies Network, Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter, William Shearer, Mary Paul, Norma Cooper, Lynnette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Patricia Garvie, James Blood, William Borkowsky, Sandra Deygoo, Helen Rozelman, Arry Dieudonne, Linda Bettica, Susan Adubato, Katherine Knapp, Kim Allison, Megan Wilkins, Midnela Acevedo-Flores, Lourdes Angeli- Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Chi Dola, Robert Maupin, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Jenna Wallace, Carrie Chambers, Christine Reed, Mobeen Rathore, Kristi Stowers, Ann Usitalo, Kenneth Rich, Lourdes Richardson, Renee Smith, Gwendolyn Scott, Claudia Florez, Elizabeth Willen, Toni Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio

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.

Keywords: DNA methylation; HIV; anti-retroviral; atazanavir; developmental origins; newborn; pediatrics; pharmaceuticals; prenatal; repetitive elements.

Figures

Figure 1.
Figure 1.
Distributions of (A) LINE-1 and (B) AluYb8 methylation extent at individual CpG sites, and the mean across the sequenced regions with and without batch adjustment

References

    1. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, et al.. Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine Treatment. Pediatric Aids Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331:1173–80; PMID:7935654;
    1. Hurst SA, Appelgren KE, Kourtis AP. Prevention of Mother-to-Child Transmission of Hiv Type 1: The Role of Neonatal and Infant Prophylaxis. Expert Rev Anti Infect Ther 2015; 13:169–81; PMID:25578882;
    1. Stevens J, Lyall H. Mother to Child Transmission of Hiv: What Works and How Much Is Enough? J Infect 2014; 69 Suppl 1:S56–62; PMID:25438711;
    1. Ciaranello AL, Seage GR 3rd, Freedberg KA, Weinstein MC, Lockman S, Walensky RP. Antiretroviral Drugs for Preventing Mother-to-Child Transmission of Hiv in Sub-Saharan Africa: Balancing Efficacy and Infant Toxicity. AIDS 2008; 22:2359–69; PMID:18981776;
    1. Culnane M, Fowler M, Lee SS, McSherry G, Brady M, O'Donnell K, Mofenson L, Gortmaker SL, Shapiro DE, Scott G, et al.. Lack of Long-Term Effects of in Utero Exposure to Zidovudine among Uninfected Children Born to Hiv-Infected Women. Pediatric Aids Clinical Trials Group Protocol 219/076 Teams. JAMA 1999; 281:151–7; PMID:9917118;
    1. Ahmed S, Kim MH, Abrams EJ. Risks and Benefits of Lifelong Antiretroviral Treatment for Pregnant and Breastfeeding Women: A Review of the Evidence for the Option B+ Approach. Curr Opin HIV AIDS 2013; 8:474–89; PMID:23925003;
    1. Brogly SB, Ylitalo N, Mofenson LM, Oleske J, Van Dyke R, Crain MJ, Abzug MJ, Brady M, Jean-Philippe P, Hughes MD, et al.. In Utero Nucleoside Reverse Transcriptase Inhibitor Exposure and Signs of Possible Mitochondrial Dysfunction in Hiv-Uninfected Children. AIDS 2007; 21:929–38; PMID:17457086;
    1. Stek AM. Antiretroviral Treatment in Pregnancy. Curr Opin HIV AIDS 2008; 3:155–60; PMID:19372959;
    1. Blanche S, Tardieu M, Benhammou V, Warszawski J, Rustin P. Mitochondrial Dysfunction Following Perinatal Exposure to Nucleoside Analogues. AIDS 2006; 20:1685–90; PMID:16931932;
    1. Cossarizza A, Troiano L, Mussini C. Mitochondria and Hiv Infection: The First Decade. J Biol Regul Homeost Agents 2002; 16:18–24; PMID:12003168
    1. Barret B, Tardieu M, Rustin P, Lacroix C, Chabrol B, Desguerre I, Dollfus C, Mayaux MJ, Blanche S, French Perinatal Cohort Study G . Persistent Mitochondrial Dysfunction in Hiv-1-Exposed but Uninfected Infants: Clinical Screening in a Large Prospective Cohort. AIDS 2003; 17:1769–85; PMID:12891063;
    1. Heidari S, Mofenson L, Cotton MF, Marlink R, Cahn P, Katabira E. Antiretroviral Drugs for Preventing Mother-to-Child Transmission of Hiv: A Review of Potential Effects on Hiv-Exposed but Uninfected Children. J Acquir Immune Defic Syndr 2011; 57:290–6; PMID:21602695;
    1. Mofenson LM, Munderi P. Safety of Antiretroviral Prophylaxis of Perinatal Transmission for Hiv-Infected Pregnant Women and Their Infants. J Acquir Immune Defic Syndr 2002; 30:200–15; PMID:12045684;
    1. Cutfield WS, Hofman PL, Mitchell M, Morison IM. Could Epigenetics Play a Role in the Developmental Origins of Health and Disease? Pediatr Res 2007; 61:68R–75R; PMID:17413843;
    1. Kiser DP, Rivero O, Lesch KP. Annual Research Review: The (Epi)Genetics of Neurodevelopmental Disorders in the Era of Whole-Genome Sequencing - Unveiling the Dark Matter. J Child Psychol Psychiatry 2015; 56:278–95; PMID:25677560;
    1. Isles AR. Neural and Behavioral Epigenetics; What It Is, and What Is Hype. Genes Brain Behav 2015; 14:64–72; PMID:25346298;
    1. Desplats PA. Perinatal Programming of Neurodevelopment: Epigenetic Mechanisms and the Prenatal Shaping of the Brain. Adv Neurobiol 2015; 10:335–61; PMID:25287548
    1. Lester BM, Marsit CJ, Conradt E, Bromer C, Padbury JF. Behavioral Epigenetics and the Developmental Origins of Child Mental Health Disorders. J Dev Orig Health Dis 2012; 3:395–408; PMID:25084292;
    1. Lester BM, Tronick E, Nestler E, Abel T, Kosofsky B, Kuzawa CW, Marsit CJ, Maze I, Meaney MJ, Monteggia LM, et al.. Behavioral Epigenetics. Ann N Y Acad Sci 2011; 1226:14–33; PMID:21615751;
    1. Desai M, Jellyman JK, Ross MG. Epigenomics, Gestational Programming and Risk of Metabolic Syndrome. Int J Obes (Lond) 2015; 39(4):633–41; PMID:25640766
    1. Ruchat SM, Hivert MF, Bouchard L. Epigenetic Programming of Obesity and Diabetes by in Utero Exposure to Gestational Diabetes Mellitus. Nutr Rev 2013; 71 Suppl 1:S88–94; PMID:24147929;
    1. Heerwagen MJ, Miller MR, Barbour LA, Friedman JE. Maternal Obesity and Fetal Metabolic Programming: A Fertile Epigenetic Soil. Am J Physiol Regul Integr Comp Physiol 2010; 299:R711–22; PMID:20631295;
    1. Schulz WA, Steinhoff C, Florl AR. Methylation of Endogenous Human Retroelements in Health and Disease. Curr Top Microbiol Immunol 2006; 310:211–50; PMID:16909913
    1. Baccarelli A, Tarantini L, Wright RO, Bollati V, Litonjua AA, Zanobetti A, Sparrow D, Vokonas P, Schwartz J. Repetitive Element DNA Methylation and Circulating Endothelial and Inflammation Markers in the Va Normative Aging Study. Epigenetics 2010; 5:222–8; PMID:20305373;
    1. Baccarelli A, Wright R, Bollati V, Litonjua A, Zanobetti A, Tarantini L, Sparrow D, Vokonas P, Schwartz J. Ischemic Heart Disease and Stroke in Relation to Blood DNA Methylation. Epidemiology 2010; 21:819–28; PMID:20805753;
    1. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A. Decline in Genomic DNA Methylation through Aging in a Cohort of Elderly Subjects. Mech Ageing Dev 2009; 130:234–9; PMID:19150625;
    1. Wilhelm CS, Kelsey KT, Butler R, Plaza S, Gagne L, Zens MS, Andrew AS, Morris S, Nelson HH, Schned AR, et al.. Implications of Line1 Methylation for Bladder Cancer Risk in Women. Clin Cancer Res 2010; 16:1682–9; PMID:20179218;
    1. Nelson HH, Marsit CJ, Kelsey KT. Global Methylation in Exposure Biology and Translational Medical Science. Environ Health Perspect 2011; 119:1528–33; PMID:21669556;
    1. Blanche S, Tardieu M, Rustin P, Slama A, Barret B, Firtion G, Ciraru-Vigneron N, Lacroix C, Rouzioux C, Mandelbrot L, et al.. Persistent Mitochondrial Dysfunction and Perinatal Exposure to Antiretroviral Nucleoside Analogues. Lancet 1999; 354:1084–9; PMID:10509500;
    1. Christensen BC, Smith AA, Zheng S, Koestler DC, Houseman EA, Marsit CJ, Wiemels JL, Nelson HH, Karagas MR, Wrensch MR, et al.. DNA Methylation, Isocitrate Dehydrogenase Mutation, and Survival in Glioma. J Natl Cancer Inst 2011; 103:143–53; PMID:21163902;
    1. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, et al.. Identification of a Cpg Island Methylator Phenotype That Defines a Distinct Subgroup of Glioma. Cancer Cell 2010; 17:510–22; PMID:20399149;
    1. Wallace DC, Fan W. Energetics, Epigenetics, Mitochondrial Genetics. Mitochondrion 2010; 10:12–31; PMID:19796712;
    1. DiMauro S, Schon EA. Mitochondrial DNA Mutations in Human Disease. Am J Med Genet 2001; 106:18–26; PMID:11579421;
    1. Funk MJ, Belinson SE, Pimenta JM, Morsheimer M, Gibbons DC. Mitochondrial Disorders among Infants Exposed to Hiv and Antiretroviral Therapy. Drug Saf 2007; 30:845–59; PMID:17867723;
    1. Jitratkosol MH, Sattha B, Maan EJ, Gadawski I, Harrigan PR, Forbes JC, Alimenti A, van Schalkwyk J, Money DM, Cote HC, et al.. Blood Mitochondrial DNA Mutations in Hiv-Infected Women and Their Infants Exposed to Haart During Pregnancy. AIDS 2012; 26:675–83; PMID:22436539;
    1. Jao J, Abrams EJ. Metabolic Complications of in Utero Maternal Hiv and Antiretroviral Exposure in Hiv-Exposed Infants. Pediatr Infect Dis J 2014; 33:734–40; PMID:24378947;
    1. Pilsner JR, Hall MN, Liu X, Ilievski V, Slavkovich V, Levy D, Factor-Litvak P, Yunus M, Rahman M, Graziano JH, et al.. Influence of Prenatal Arsenic Exposure and Newborn Sex on Global Methylation of Cord Blood DNA. PLoS One 2012; 7:e37147; PMID:22662134;
    1. Kile ML, Baccarelli A, Hoffman E, Tarantini L, Quamruzzaman Q, Rahman M, Mahiuddin G, Mostofa G, Hsueh YM, Wright RO, et al.. Prenatal Arsenic Exposure and DNA Methylation in Maternal and Umbilical Cord Blood Leukocytes. Environ Health Perspect 2012; 120:1061–6; PMID:22466225;
    1. Intarasunanont P, Navasumrit P, Waraprasit S, Chaisatra K, Suk WA, Mahidol C, Ruchirawat M. Effects of Arsenic Exposure on DNA Methylation in Cord Blood Samples from Newborn Babies and in a Human Lymphoblast Cell Line. Environ Health 2012; 11:31; PMID:22551203;
    1. Pilsner JR, Hu H, Ettinger A, Sanchez BN, Wright RO, Cantonwine D, Lazarus A, Lamadrid-Figueroa H, Mercado-Garcia A, Tellez-Rojo MM, et al.. Influence of Prenatal Lead Exposure on Genomic Methylation of Cord Blood DNA. Environ Health Perspect 2009; 117:1466–71; PMID:19750115;
    1. Huen K, Yousefi P, Bradman A, Yan L, Harley KG, Kogut K, Eskenazi B, Holland N. Effects of Age, Sex, and Persistent Organic Pollutants on DNA Methylation in Children. Environ Mol Mutagen 2014; 55:209–22; PMID:24375655;
    1. Haggarty P, Hoad G, Campbell DM, Horgan GW, Piyathilake C, McNeill G. Folate in Pregnancy and Imprinted Gene and Repeat Element Methylation in the Offspring. Am J Clin Nutr 2013; 97:94–9; PMID:23151531;
    1. Boeke CE, Baccarelli A, Kleinman KP, Burris HH, Litonjua AA, Rifas-Shiman SL, Tarantini L, Gillman M. Gestational Intake of Methyl Donors and Global Line-1 DNA Methylation in Maternal and Cord Blood: Prospective Results from a Folate-Replete Population. Epigenetics 2012; 7:253–60; PMID:22430801;
    1. Lee HS, Barraza-Villarreal A, Hernandez-Vargas H, Sly PD, Biessy C, Ramakrishnan U, Romieu I, Herceg Z. Modulation of DNA Methylation States and Infant Immune System by Dietary Supplementation with Omega-3 Pufa During Pregnancy in an Intervention Study. Am J Clin Nutr 2013; 98:480–7; PMID:23761484;
    1. Smith AK, Conneely KN, Newport DJ, Kilaru V, Schroeder JW, Pennell PB, Knight BT, Cubells JC, Stowe ZN, Brennan PA. Prenatal Antiepileptic Exposure Associates with Neonatal DNA Methylation Differences. Epigenetics 2012; 7:458–63; PMID:22419127;
    1. Mandelbrot L, Mazy F, Floch-Tudal C, Meier F, Azria E, Crenn-Hebert C, Treluyer JM, Herinomenzanahary E, Ferreira C, Peytavin G. Atazanavir in Pregnancy: Impact on Neonatal Hyperbilirubinemia. Eur J Obstet Gynecol Reprod Biol 2011; 157:18–21; PMID:21492993;
    1. Williams PL, Crain MJ, Yildirim C, Hazra R, Van Dyke RB, Rich K, Read JS, Stuard E, Rathore M, Mendez HA, et al.. Congenital Anomalies and in Utero Antiretroviral Exposure in Human Immunodeficiency Virus-Exposed Uninfected Infants. JAMA Pediatr 2015; 169:48–55; PMID:25383770;
    1. Zhou H, Gurley EC, Jarujaron S, Ding H, Fang Y, Xu Z, Pandak WM Jr., Hylemon PB. Hiv Protease Inhibitors Activate the Unfolded Protein Response and Disrupt Lipid Metabolism in Primary Hepatocytes. Am J Physiol Gastrointest Liver Physiol 2006; 291:G1071–80; PMID:16861219;
    1. Zhou H, Jarujaron S, Gurley EC, Chen L, Ding H, Studer E, Pandak WM Jr., Hu W, Zou T, Wang JY, et al.. Hiv Protease Inhibitors Increase Tnf-Alpha and Il-6 Expression in Macrophages: Involvement of the Rna-Binding Protein Hur. Atherosclerosis 2007; 195:e134–43; PMID:17531241;
    1. Caso G, Mileva I, McNurlan MA, Mynarcik DC, Darras F, Gelato MC. Effect of Ritonavir and Atazanavir on Human Subcutaneous Preadipocyte Proliferation and Differentiation. Antiviral Res 2010; 86:137–43; PMID:20153378;
    1. Gibellini L, De Biasi S, Pinti M, Nasi M, Riccio M, Carnevale G, Cavallini GM, Sala de Oyanguren FJ, O'Connor JE, Mussini C, et al.. The Protease Inhibitor Atazanavir Triggers Autophagy and Mitophagy in Human Preadipocytes. AIDS 2012; 26:2017–26; PMID:22948272;
    1. Smith ZD, Chan MM, Humm KC, Karnik R, Mekhoubad S, Regev A, Eggan K, Meissner A. DNA Methylation Dynamics of the Human Preimplantation Embryo. Nature 2014; 511:611–5; PMID:25079558;
    1. El Hajj N, Pliushch G, Schneider E, Dittrich M, Muller T, Korenkov M, Aretz M, Zechner U, Lehnen H, Haaf T. Metabolic Programming of Mest DNA Methylation by Intrauterine Exposure to Gestational Diabetes Mellitus. Diabetes 2013; 62:1320–8; PMID:23209187;
    1. Michels KB, Harris HR, Barault L. Birthweight, Maternal Weight Trajectories and Global DNA Methylation of Line-1 Repetitive Elements. PLoS One 2011; 6:e25254; PMID:21980406;
    1. Griner R, Williams PL, Read JS, Seage GR 3rd, Crain M, Yogev R, Hazra R, Rich K, Pediatric HIVACS . In utero and postnatal exposure to antiretrovirals among Hiv-Exposed but Uninfected Children in the United States. AIDS Patient Care STDS 2011; 25:385–94; PMID:21992592;
    1. Rodriguez EM, Mendez H, Rich K, Sheon A, Fox H, Green K, Diaz C, Brambilla D, Mofenson L. Maternal Drug Use in Perinatal Hiv Studies. The Women and Infants Transmission Study. Ann N Y Acad Sci 1993; 693:245–8; PMID:8267268;
    1. Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D, Byun HM, Jiang J, Marinelli B, Pesatori AC, et al.. Changes in DNA Methylation Patterns in Subjects Exposed to Low-Dose Benzene. Cancer Res 2007; 67:876–80; PMID:17283117;
    1. Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP. A Simple Method for Estimating Global DNA Methylation Using Bisulfite Pcr of Repetitive DNA Elements. Nucleic Acids Res 2004; 32:e38; PMID:14973332;
    1. Wilhelm-Benartzi CS, Houseman EA, Maccani MA, Poage GM, Koestler DC, Langevin SM, Gagne LA, Banister CE, Padbury JF, Marsit CJ. In Utero Exposures, Infant Growth, and DNA Methylation of Repetitive Elements and Developmentally Related Genes in Human Placenta. Environ Health Perspect 2012; 120:296–302; PMID:22005006;
    1. Giordan M. A Two-Stage Procedure for the Removal of Batch Effect in Microarray Studies. Statistics in Bioscience 2014; 6.1:73–84;

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