Abstract
Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (β = 2.28 × 10-4, p-value = 5.87 × 10-5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (β = 0.004, p-value = 4.97 × 10-5), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (β = 0.002, p-value = 4.81 × 10-7) in GRK1 and cg02212000 (β = -0.001, p-value = 8.13 × 10-7) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.
| Original language | English |
|---|---|
| Article number | 112093 |
| Number of pages | 11 |
| Journal | Environmental Research |
| Volume | 204 |
| Issue number | Pt B |
| Early online date | 22 Sept 2021 |
| DOIs | |
| Publication status | Published - 1 Mar 2022 |
Bibliographical note
Funding Information:The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research , NIH/NIEHS (contract no N01-ES-75558 ), NIH/NINDS (grant no. 1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537–06A1 ). MoBa1 and MoBa 2 are supported by the Intramural Research Program of the NIH , National Institute of Environmental Health Sciences ( Z01-ES-49019 ) and Norwegian Research Council /BIOBANK (grant no 221097 ). The work in MoBa3 was supported in part by a Postdoctoral Fellowship grant from the Ulleval Hospitals Research Council (now under Oslo University Hospital) and travel grants from the Unger-Vetlesens foundation and the Norwegian American Womens Club , all to M.C.M.K. MoBa3 epigenomics data analyses were funded by INCA/Plan Cancer-EVA-INSERM, France, and the International Childhood Cancer Cohort Consortium (I4C), and performed by the Epigenetics Group at the International Agency for Research on Cancer (IARC, Lyon, France), A.G. was supported by the grant from INCA /Plan Cancer-EVA-INSERM (France, 2015) to Z.H. and also by the IARC Postdoctoral Fellowship, partially supported by the EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND).
Funding Information:
ALSPAC study was funded by the UK Medical Research Council and the Wellcome Trust (grant ref: 102215/2/13/2 ) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, PY and CR, who will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). The Accessible Resource for Integrated Epigenomics Studies (ARIES), was funded by the UK Biotechnology and Biological Sciences Research Council ( BB/I025751/1 and BB/I025263/1 ). Additional epigenetic profiling of ALSPAC was supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit and the University of Bristol ( MC_UU_12013_1 , MC_UU_12013_2 , MC_UU_12013_5 and MC_UU_12013_8 ), the Wellcome Trust ( WT088806 ) and the United States National Institute of Diabetes and Digestive and Kidney Diseases ( R01 DK10324 ). PY and CR are supported by the UK MRC Integrative Epidemiology Unit ( MC_UU_00011/5 ).
Funding Information:
The Project Viva cohort is funded by NIH grants R01HL111108 , R01NR013945 , and R37 HD034568 .
Funding Information:
The Hokkaido-Sapporo Study is supported by Grant-in-Aid for Scientific Research from the Japanese Ministry of Health , Labour and Welfare ( JPMH14427175 , JPMH19189425 , JPMH17932352 ); the Japan Society for the Promotion of Science ; the Ministry of Education, Culture, Sports, Science and Technology ( JP16H02645 , JP19H01071 , JP18H03035 , JP15H04780 , JP19K10576 , JP19K10636 , JP18K10042 , JP18K10022 , JP19K22730 , JP19K20457 ); and an Environment Research and Technology Development fund ( JPMEERF20145054 , JPMEERF20175053 , JPMEERF20205002 ); AMED ( JPMH19188595 , JPMH18950314 ); and Ministry of Internal Affairs and Communications ( JPMI10001 ).
Funding Information:
ALSPAC. ALSPAC study is extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We would like to acknowledge Oliver Lyttleton, Hashem Shihab, Nabila Kazmi and Geoff Woodward for their earlier contribution to the generation of ARIES data (ALSPAC methylation data). INMA, The authors would like to thank all the participants for their generous collaboration. full roster of the INMA project investigators can be found at http://www.proyectoinma.org/presentacion-inma/listado-investigadores/en_listado-investigadores.html. MoBa, The authors would also like to thank Ingvild Essen for thorough field work, Heidi Marie Nordheim for biological sample management and the MoBa administrative unit (MoBa). The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. Project Viva, Project Viva researchers would like to thank all mothers, children and families for their ongoing participation. RHEA, The authors would like to thank Georgia Chalkiadaki and Danai Feida for biological sample management, to Eirini Michalaki, Mariza Kampouri, Anny Kyriklaki and Minas Iakovidis for field study performance and to Maria Fasoulaki for administrative assistance. SAPPORO-HOKKAIDO, We would like to express our appreciation to all of the study participants of the Hokkaido Study on Environment and Children’ Health. We also express our profound gratitude to all personnel in the hospitals and clinics that collaborated with the study, including Sapporo Toho Hospital, Keiai Hospital, Endo Kikyo Maternity Clinic, Shiroishi Hospital, Memuro Municipal Hospital, Aoba Ladies Clinic, Obihiro-Kyokai Hospital, Akiyama Memorial Hospital, Sapporo Medical University Hospital, Hokkaido University Hospital, Kitami Red Cross Hospital, Hoyukai Sapporo Hospital, Gorinbashi Hospital, Hashimoto Clinic, Asahikawa Medical College Hospital, Hakodate Central General Hospital, Ohji General Hospital, Nakashibetsu Municipal Hospital, Sapporo Tokushukai Hospital, Asahikawa Red Cross Hospital, Wakkanai City Hospital, Kushiro Rosai Hospital, Sapporo-Kosei General Hospital, Shibetsu City General Hospital, Nikko Memorial Hospital, Sapporo City General Hospital, Kohnan Hospital, Hakodate City Hospital, Hokkaido Monbetsu Hospital, Tenshi Hospital, Hakodate Goryoukaku Hospital, Nakamura Hospital, Kin-ikyo Sapporo Hospital, Kitami Lady's Clinic, Engaru-Kosei General Hospital, Kushiro Red Cross Hospital, Nayoro City General Hospital, and Obihiro-Kosei General Hospital. We also deeply express our gratitude to the staff of The Hokkaido Study on Environment and Children's Health for their considerable efforts to support our study, including N. Goto, O. Hayashi, T. Hikichi, N. Kanda, K. Kunita, K. Miura, Y. Shibasaki, K. Sugawara, K. Tanaka, E. Toyama, and T. Yoshikawa. Special thanks to Ms. Mimi Takahashi on her effort to support writing this manuscript.ALSPAC study was funded by the UK Medical Research Council and the Wellcome Trust (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, PY and CR, who will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Accessible Resource for Integrated Epigenomics Studies (ARIES), was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling of ALSPAC was supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). PY and CR are supported by the UK MRC Integrative Epidemiology Unit (MC_UU_00011/5).Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03–1615, FIS-FEDER PI16/1288, FIS-FEDER PI19/1338; Miguel Servet FEDER 15/0025 and 20/0006; FIS-FSE: 17/00260), Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat Valenciana BEST/2020/059, Fundacio ́ La Marato ́ de TV3 (090,430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: Brain dEvelopment and Air polluTion ultrafine particles in school childrEn).This study was supported by the Korean Environment Industry & Technology Institute (KEITI) through “the Environmental Health Action Program”, funded by Korea Ministry of Environment (2017001360005).The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537–06A1). MoBa1 and MoBa 2 are supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and Norwegian Research Council/BIOBANK (grant no 221097). The work in MoBa3 was supported in part by a Postdoctoral Fellowship grant from the Ulleval Hospitals Research Council (now under Oslo University Hospital) and travel grants from the Unger-Vetlesens foundation and the Norwegian American Womens Club, all to M.C.M.K. MoBa3 epigenomics data analyses were funded by INCA/Plan Cancer-EVA-INSERM, France, and the International Childhood Cancer Cohort Consortium (I4C), and performed by the Epigenetics Group at the International Agency for Research on Cancer (IARC, Lyon, France), A.G. was supported by the grant from INCA/Plan Cancer-EVA-INSERM (France, 2015) to Z.H. and also by the IARC Postdoctoral Fellowship, partially supported by the EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND).The Project Viva cohort is funded by NIH grants R01HL111108, R01NR013945, and R37 HD034568.The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; ‘Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN (MTM2015-68140-R), Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII, the H2020-EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583) (ATHLETE project), and from the European Union's Horizon 2020 research and innovation programme (grant Agreement number: 733206) (Early Life stressors and Lifecycle Health (LIFECYCLE)).The Hokkaido-Sapporo Study is supported by Grant-in-Aid for Scientific Research from the Japanese Ministry of Health, Labour and Welfare (JPMH14427175, JPMH19189425, JPMH17932352); the Japan Society for the Promotion of Science; the Ministry of Education, Culture, Sports, Science and Technology (JP16H02645, JP19H01071, JP18H03035, JP15H04780, JP19K10576, JP19K10636, JP18K10042, JP18K10022, JP19K22730, JP19K20457); and an Environment Research and Technology Development fund (JPMEERF20145054, JPMEERF20175053, JPMEERF20205002); AMED (JPMH19188595, JPMH18950314); and Ministry of Internal Affairs and Communications (JPMI10001).
Funding Information:
Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III ( Red INMA G03/176 , CB06/02/0041 ), Spanish Ministry of Health ( FIS-PI04/1436 , FIS-PI08/1151 including FEDER funds, FIS-PI11/00610 , FIS-FEDER-PI06/0867 , FIS-FEDER-PI03–1615 , FIS-FEDER PI16/1288 , FIS-FEDER PI19/1338 ; Miguel Servet FEDER 15/0025 and 20/0006 ; FIS-FSE : 17/00260 ), Generalitat de Catalunya-CIRIT 1999SGR 00241 , Generalitat Valenciana BEST/2020/059 , Fundacio ́ La Marato ́ de TV3 ( 090,430 ), EU Commission ( 261357 -MeDALL: Mechanisms of the Development of ALLergy), and European Research Council ( 268479 -BREATHE: Brain dEvelopment and Air polluTion ultrafine particles in school childrEn).
Funding Information:
The authors would also like to thank Ingvild Essen for thorough field work, Heidi Marie Nordheim for biological sample management and the MoBa administrative unit (MoBa). The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research . We are grateful to all the participating families in Norway who take part in this on-going cohort study.
Funding Information:
The Rhea project was financially supported by European projects , and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; ‘Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN ( MTM2015-68140-R ), Centro Nacional de Genotipado - CEGEN-PRB2-ISCIII, the H2020 -EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583 ) (ATHLETE project), and from the European Union's Horizon 2020 research and innovation programme (grant Agreement number: 733206 ) (Early Life stressors and Lifecycle Health (LIFECYCLE)).
Funding Information:
This study was supported by the Korean Environment Industry & Technology Institute ( KEITI ) through “the Environmental Health Action Program”, funded by Korea Ministry of Environment ( 2017001360005 ).
Publisher Copyright:
© 2021 The Authors
Keywords
- DNA methylation
- Mercury
- Methylmercury
- Prenatal exposure
- PACE
- HELIX study
- ALSPAC