PMID- 33827680 OWN - NLM STAT- MEDLINE DCOM- 20220119 LR - 20221207 IS - 1868-7083 (Electronic) IS - 1868-7075 (Print) IS - 1868-7075 (Linking) VI - 13 IP - 1 DP - 2021 Apr 7 TI - DNA methylation of GFI1 as a mediator of the association between prenatal smoking exposure and ADHD symptoms at 6 years: the Hokkaido Study on Environment and Children's Health. PG - 74 LID - 10.1186/s13148-021-01063-z [doi] LID - 74 AB - BACKGROUND: Prenatal smoking exposure has been associated with childhood attention-deficit/hyperactivity disorder (ADHD). However, the mechanism underlying this relationship remains unclear. We assessed whether DNA methylation differences may mediate the association between prenatal smoking exposure and ADHD symptoms at the age of 6 years. RESULTS: We selected 1150 mother-infant pairs from the Hokkaido Study on the Environment and Children's Health. Mothers were categorized into three groups according to plasma cotinine levels at the third trimester: non-smokers (/= 11.49 ng/mL). The children's ADHD symptoms were determined by the ADHD-Rating Scale at the age of 6 years. Maternal active smoking during pregnancy was significantly associated with an increased risk of ADHD symptoms (odds ratio, 1.89; 95% confidence interval, 1.14-3.15) compared to non-smoking after adjusting for covariates. DNA methylation of the growth factor-independent 1 transcriptional repressor (GFI1) region, as determined by bisulfite next-generation sequencing of cord blood samples, mediated 48.4% of the total effect of the association between maternal active smoking during pregnancy and ADHD symptoms. DNA methylation patterns of other genes (aryl-hydrocarbon receptor repressor [AHRR], cytochrome P450 family 1 subfamily A member 1 [CYP1A1], estrogen receptor 1 [ESR1], and myosin IG [MYO1G]) regions did not exert a statistically significant mediation effect. CONCLUSIONS: Our findings demonstrated that DNA methylation of GFI1 mediated the association between maternal active smoking during pregnancy and ADHD symptoms at the age of 6 years. FAU - Miyake, Kunio AU - Miyake K AUID- ORCID: 0000-0001-9196-2229 AD - Departments of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. kmiyake@yamanashi.ac.jp. FAU - Miyashita, Chihiro AU - Miyashita C AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. FAU - Ikeda-Araki, Atsuko AU - Ikeda-Araki A AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. FAU - Miura, Ryu AU - Miura R AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. FAU - Itoh, Sachiko AU - Itoh S AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. FAU - Yamazaki, Keiko AU - Yamazaki K AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. FAU - Kobayashi, Sumitaka AU - Kobayashi S AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. FAU - Masuda, Hideyuki AU - Masuda H AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. FAU - Ooka, Tadao AU - Ooka T AD - Departments of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. FAU - Yamagata, Zentaro AU - Yamagata Z AD - Departments of Health Sciences, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan. FAU - Kishi, Reiko AU - Kishi R AD - Center for Environmental and Health Sciences, Hokkaido University, Hokkaido, Japan. LA - eng GR - JPMH17932352/Health Science Research from the Japanese Ministry of Health, Labor and Welfare/ GR - JP16H02645/Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology/ GR - JP19H01071/Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology/ GR - JP20H03928/Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology/ GR - JP20K21707/Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology/ GR - JPMEERF20145054/Environment Research and Technology Development Fund from the Ministry of the Environment, Japan./ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210407 PL - Germany TA - Clin Epigenetics JT - Clinical epigenetics JID - 101516977 RN - 0 (DNA-Binding Proteins) RN - 0 (GFI1 protein, human) RN - 0 (Transcription Factors) SB - IM MH - Adult MH - Asian People MH - Attention Deficit Disorder with Hyperactivity/*chemically induced MH - Child MH - *DNA Methylation MH - DNA-Binding Proteins/*genetics MH - Female MH - Gene Expression Regulation MH - Humans MH - Japan MH - Male MH - Maternal Exposure/*adverse effects MH - Pregnancy MH - Prenatal Exposure Delayed Effects/*genetics MH - Smoking/*adverse effects MH - Transcription Factors PMC - PMC8028116 OTO - NOTNLM OT - ADHD OT - Birth cohort OT - DNA methylation OT - DOHaD OT - GFI1 OT - Prenatal smoking exposure COIS- The authors declare that they have no competing interests. EDAT- 2021/04/09 06:00 MHDA- 2022/01/20 06:00 PMCR- 2021/04/07 CRDT- 2021/04/08 05:44 PHST- 2020/11/17 00:00 [received] PHST- 2021/03/25 00:00 [accepted] PHST- 2021/04/08 05:44 [entrez] PHST- 2021/04/09 06:00 [pubmed] PHST- 2022/01/20 06:00 [medline] PHST- 2021/04/07 00:00 [pmc-release] AID - 10.1186/s13148-021-01063-z [pii] AID - 1063 [pii] AID - 10.1186/s13148-021-01063-z [doi] PST - epublish SO - Clin Epigenetics. 2021 Apr 7;13(1):74. doi: 10.1186/s13148-021-01063-z.