Kelly M Bakulski1, HwaJin Lee2, Jason I Feinberg3, Ellen M Wells4, Shannon Brown1, Julie B Herbstman5, Frank R Witter2, Rolf U Halden6, Kathleen Caldwell7, Mary Ellen Mortensen7, Andrew E Jaffe8, John Moye9, Laura E Caulfield1, Yi Pan7, Lynn R Goldman10, Andrew P Feinberg3, M Daniele Fallin11. 1. Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA. 2. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 3. Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 4. Purdue University, School of Health Sciences, West Lafayette, Indiana, USA. 5. Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA, Columbia University Mailman School of Public Health, New York City, New York, USA. 6. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, Arizona State University, Fulton School of Engineering, Tempe, Arizona, USA. 7. National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. 8. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, Lieber Institute for Brain Development, Baltimore, Maryland, USA. 9. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA and. 10. Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA, George Washington University School of Public Health, Washington D.C., USA. 11. Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, dfallin@jhu.edu.
Abstract
BACKGROUND: Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. METHODS: A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. RESULTS: Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P < 0.05), and this association was diminished after adjusting for estimated cell proportions. CONCLUSIONS: Evidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed.
BACKGROUND:Human exposure to the widespread environmental contaminant mercury is a known risk factor for common diseases such as cancer, cardiovascular disease and neurological disorders through poorly characterized mechanisms. Evidence suggests mercury exposure may alter DNA methylation levels, but to date, the effects in early life on a genome-wide scale have not been investigated. METHODS: A study sample of 141 newborns was recruited in Baltimore, MD, USA and total mercury and methylmercury were measured in cord blood samples. We quantified genome-wide DNA methylation data using CHARM 2.0, an array-based method, and used region-finding analyses to identify concentration-associated differentially methylated regions (DMRs). To test for replication of these identified DMRs in the pilot, or Vanguard, phase of the National Children's Study (NCS), we compared bisulfite-pyrosequenced DNA at candidate regions from 85 whole cord blood samples with matched first trimester maternal mercury concentration measures. RESULTS: Total mercury concentration was associated with methylation at DMRs inside ANGPT2 and near PRPF18 genes [false discovery rate (FDR) < 0.05], as well as DMRs near FOXD2 and within TCEANC2 (FDR< 0.1) genes. Methylmercury concentration was associated with an overlapping DMR within TCEANC2 (FDR< 0.05). In NCS replication analyses, methylation levels at three of four cytosine-guanine DNA dinucleotides (CpG sites) within the TCEANC2 DMR were associated with total mercury concentration (P < 0.05), and this association was diminished after adjusting for estimated cell proportions. CONCLUSIONS: Evidence for an association between mercury and DNA methylation at the TCEANC2 region was found, which may represent a mercury-associated shift in cord blood cell composition or a change in methylation within blood cell types. Further confirmatory studies are needed.
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Authors: F Bakir; S F Damluji; L Amin-Zaki; M Murtadha; A Khalidi; N Y al-Rawi; S Tikriti; H I Dahahir; T W Clarkson; J C Smith; R A Doherty Journal: Science Date: 1973-07-20 Impact factor: 47.728
Authors: Mary E Mortensen; Samuel P Caudill; Kathleen L Caldwell; Cynthia D Ward; Robert L Jones Journal: Environ Res Date: 2014-08-29 Impact factor: 6.498
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Authors: S Hong Lee; Stephan Ripke; Benjamin M Neale; Stephen V Faraone; Shaun M Purcell; Roy H Perlis; Bryan J Mowry; Anita Thapar; Michael E Goddard; John S Witte; Devin Absher; Ingrid Agartz; Huda Akil; Farooq Amin; Ole A Andreassen; Adebayo Anjorin; Richard Anney; Verneri Anttila; Dan E Arking; Philip Asherson; Maria H Azevedo; Lena Backlund; Judith A Badner; Anthony J Bailey; Tobias Banaschewski; Jack D Barchas; Michael R Barnes; Thomas B Barrett; Nicholas Bass; Agatino Battaglia; Michael Bauer; Mònica Bayés; Frank Bellivier; Sarah E Bergen; Wade Berrettini; Catalina Betancur; Thomas Bettecken; Joseph Biederman; Elisabeth B Binder; Donald W Black; Douglas H R Blackwood; Cinnamon S Bloss; Michael Boehnke; Dorret I Boomsma; Gerome Breen; René Breuer; Richard Bruggeman; Paul Cormican; Nancy G Buccola; Jan K Buitelaar; William E Bunney; Joseph D Buxbaum; William F Byerley; Enda M Byrne; Sian Caesar; Wiepke Cahn; Rita M Cantor; Miguel Casas; Aravinda Chakravarti; Kimberly Chambert; Khalid Choudhury; Sven Cichon; C Robert Cloninger; David A Collier; Edwin H Cook; Hilary Coon; Bru Cormand; Aiden Corvin; William H Coryell; David W Craig; Ian W Craig; Jennifer Crosbie; Michael L Cuccaro; David Curtis; Darina Czamara; Susmita Datta; Geraldine Dawson; Richard Day; Eco J De Geus; Franziska Degenhardt; Srdjan Djurovic; Gary J Donohoe; Alysa E Doyle; Jubao Duan; Frank Dudbridge; Eftichia Duketis; Richard P Ebstein; Howard J Edenberg; Josephine Elia; Sean Ennis; Bruno Etain; Ayman Fanous; Anne E Farmer; I Nicol Ferrier; Matthew Flickinger; Eric Fombonne; Tatiana Foroud; Josef Frank; Barbara Franke; Christine Fraser; Robert Freedman; Nelson B Freimer; Christine M Freitag; Marion Friedl; Louise Frisén; Louise Gallagher; Pablo V Gejman; Lyudmila Georgieva; Elliot S Gershon; Daniel H Geschwind; Ina Giegling; Michael Gill; Scott D Gordon; Katherine Gordon-Smith; Elaine K Green; Tiffany A Greenwood; Dorothy E Grice; Magdalena Gross; Detelina Grozeva; Weihua Guan; Hugh Gurling; Lieuwe De Haan; Jonathan L Haines; Hakon Hakonarson; Joachim Hallmayer; Steven P Hamilton; Marian L Hamshere; Thomas F Hansen; Annette M Hartmann; Martin Hautzinger; Andrew C Heath; Anjali K Henders; Stefan Herms; Ian B Hickie; Maria Hipolito; Susanne Hoefels; Peter A Holmans; Florian Holsboer; Witte J Hoogendijk; Jouke-Jan Hottenga; Christina M Hultman; Vanessa Hus; Andrés Ingason; Marcus Ising; Stéphane Jamain; Edward G Jones; Ian Jones; Lisa Jones; Jung-Ying Tzeng; Anna K Kähler; René S Kahn; Radhika Kandaswamy; Matthew C Keller; James L Kennedy; Elaine Kenny; Lindsey Kent; Yunjung Kim; George K Kirov; Sabine M Klauck; Lambertus Klei; James A Knowles; Martin A Kohli; Daniel L Koller; Bettina Konte; Ania Korszun; Lydia Krabbendam; Robert Krasucki; Jonna Kuntsi; Phoenix Kwan; Mikael Landén; Niklas Långström; Mark Lathrop; Jacob Lawrence; William B Lawson; Marion Leboyer; David H Ledbetter; Phil H Lee; Todd Lencz; Klaus-Peter Lesch; Douglas F Levinson; Cathryn M Lewis; Jun Li; Paul Lichtenstein; Jeffrey A Lieberman; Dan-Yu Lin; Don H Linszen; Chunyu Liu; Falk W Lohoff; Sandra K Loo; Catherine Lord; Jennifer K Lowe; Susanne Lucae; Donald J MacIntyre; Pamela A F Madden; Elena Maestrini; Patrik K E Magnusson; Pamela B Mahon; Wolfgang Maier; Anil K Malhotra; Shrikant M Mane; Christa L Martin; Nicholas G Martin; Manuel Mattheisen; Keith Matthews; Morten Mattingsdal; Steven A McCarroll; Kevin A McGhee; James J McGough; Patrick J McGrath; Peter McGuffin; Melvin G McInnis; Andrew McIntosh; Rebecca McKinney; Alan W McLean; Francis J McMahon; William M McMahon; Andrew McQuillin; Helena Medeiros; Sarah E Medland; Sandra Meier; Ingrid Melle; Fan Meng; Jobst Meyer; Christel M Middeldorp; Lefkos Middleton; Vihra Milanova; Ana Miranda; Anthony P Monaco; Grant W Montgomery; Jennifer L Moran; Daniel Moreno-De-Luca; Gunnar Morken; Derek W Morris; Eric M Morrow; Valentina Moskvina; Pierandrea Muglia; Thomas W Mühleisen; Walter J Muir; Bertram Müller-Myhsok; Michael Murtha; Richard M Myers; Inez Myin-Germeys; Michael C Neale; Stan F Nelson; Caroline M Nievergelt; Ivan Nikolov; Vishwajit Nimgaonkar; Willem A Nolen; Markus M Nöthen; John I Nurnberger; Evaristus A Nwulia; Dale R Nyholt; Colm O'Dushlaine; Robert D Oades; Ann Olincy; Guiomar Oliveira; Line Olsen; Roel A Ophoff; Urban Osby; Michael J Owen; Aarno Palotie; Jeremy R Parr; Andrew D Paterson; Carlos N Pato; Michele T Pato; Brenda W Penninx; Michele L Pergadia; Margaret A Pericak-Vance; Benjamin S Pickard; Jonathan Pimm; Joseph Piven; Danielle Posthuma; James B Potash; Fritz Poustka; Peter Propping; Vinay Puri; Digby J Quested; Emma M Quinn; Josep Antoni Ramos-Quiroga; Henrik B Rasmussen; Soumya Raychaudhuri; Karola Rehnström; Andreas Reif; Marta Ribasés; John P Rice; Marcella Rietschel; Kathryn Roeder; Herbert Roeyers; Lizzy Rossin; Aribert Rothenberger; Guy Rouleau; Douglas Ruderfer; Dan Rujescu; Alan R Sanders; Stephan J Sanders; Susan L Santangelo; Joseph A Sergeant; Russell Schachar; Martin Schalling; Alan F Schatzberg; William A Scheftner; Gerard D Schellenberg; Stephen W Scherer; Nicholas J Schork; Thomas G Schulze; Johannes Schumacher; Markus Schwarz; Edward Scolnick; Laura J Scott; Jianxin Shi; Paul D Shilling; Stanley I Shyn; Jeremy M Silverman; Susan L Slager; Susan L Smalley; Johannes H Smit; Erin N Smith; Edmund J S Sonuga-Barke; David St Clair; Matthew State; Michael Steffens; Hans-Christoph Steinhausen; John S Strauss; Jana Strohmaier; T Scott Stroup; James S Sutcliffe; Peter Szatmari; Szabocls Szelinger; Srinivasa Thirumalai; Robert C Thompson; Alexandre A Todorov; Federica Tozzi; Jens Treutlein; Manfred Uhr; Edwin J C G van den Oord; Gerard Van Grootheest; Jim Van Os; Astrid M Vicente; Veronica J Vieland; John B Vincent; Peter M Visscher; Christopher A Walsh; Thomas H Wassink; Stanley J Watson; Myrna M Weissman; Thomas Werge; Thomas F Wienker; Ellen M Wijsman; Gonneke Willemsen; Nigel Williams; A Jeremy Willsey; Stephanie H Witt; Wei Xu; Allan H Young; Timothy W Yu; Stanley Zammit; Peter P Zandi; Peng Zhang; Frans G Zitman; Sebastian Zöllner; Bernie Devlin; John R Kelsoe; Pamela Sklar; Mark J Daly; Michael C O'Donovan; Nicholas Craddock; Patrick F Sullivan; Jordan W Smoller; Kenneth S Kendler; Naomi R Wray Journal: Nat Genet Date: 2013-08-11 Impact factor: 38.330
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