DNA methylation analysis using bisulphite-based amplicon sequencing of individuals exposed to maternal tobacco use during pregnancy, and offspring conduct problems in childhood and adolescence†
Alexandra J. Noble
A * , John F. Pearson B , Alasdair D. Noble C , Joseph M. Boden D , L. John Horwood D , Martin A. Kennedy B and Amy J. Osborne A
+ Author Affiliations
- Author Affiliations
A School of Biological Sciences, University of Canterbury, Christchurch, New Zealand.
B Department of Pathology and Biomedical Sciences, University of Otago, Christchurch, New Zealand.
C AgResearch, Lincoln Research Centre, Christchurch, New Zealand.
D Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.
Reproduction, Fertility and Development 34(7) 540-548 https://doi.org/10.1071/RD21108
Published online: 8 February 2022
© 2022 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)
Abstract
Maternal tobacco smoking during pregnancy is a large driver of health inequalities and a higher prevalence of conduct problem (CP) has been observed in exposed offspring. Further, maternal tobacco use during pregnancy can also alter offspring DNA methylation. However, currently, limited molecular evidence has been found to support this observation. Thus we aim to examine the association between maternal tobacco use in pregnancy and offspring CP, to determine whether offspring CP is mediated by tobacco exposure-induced DNA methylation differences. Understanding the etiology of the association between maternal tobacco use and offspring CP will be crucial in the early identification and treatment of CP in children and adolescents. Here, a sub group of N = 96 individuals was sourced from the Christchurch Health and Development Study, a longitudinal birth cohort studied for over 40 years in New Zealand. Whole blood samples underwent bisulphite-based amplicon sequencing at 10 loci known to play a role in neurodevelopment, or which had associations with CP phenotypes. We identified significant (P < 0.05) differential DNA methylation at specific CpG sites in CYP1A1, ASH2L and MEF2C in individuals with CP who were exposed to tobacco in utero. We conclude that environmentally-induced DNA methylation differences could play a role in the observed link between maternal tobacco use during pregnancy and childhood/adolescent CP. However, larger sample sizes are needed to produce an adequate amount of power to investigate this interaction further.
Keywords: conduct disorder, developmental biology, DNA, DNA methylation, environmental epigenetics, epigenetics, pregnancy, tobacco exposure.
References
Acosta, MT, Arcos-Burgos, M, and Muenke, M (2004). Attention deficit/hyperactivity disorder (ADHD): complex phenotype, simple genotype? Genetics in Medicine 6, 1–15.| Attention deficit/hyperactivity disorder (ADHD): complex phenotype, simple genotype?Crossref | GoogleScholarGoogle Scholar | 14726804PubMed |
Beaver, KM, Wright, JP, DeLisi, M, Walsh, A, Vaughn, MG, Boisvert, D, and Vaske, J (2007). A gene × gene interaction between DRD2 and DRD4 is associated with conduct disorder and antisocial behavior in males. Behavioral and Brain Functions 3, 30.
| A gene × gene interaction between DRD2 and DRD4 is associated with conduct disorder and antisocial behavior in males.Crossref | GoogleScholarGoogle Scholar | 17587443PubMed |
Carter, S, Paterson, J, Gao, W, and Iusitini, L (2008). Maternal smoking during pregnancy and behaviour problems in a birth cohort of 2-year-old Pacific children in New Zealand. Early Human Development 84, 59–66.
| Maternal smoking during pregnancy and behaviour problems in a birth cohort of 2-year-old Pacific children in New Zealand.Crossref | GoogleScholarGoogle Scholar | 17499944PubMed |
Chen, Y, Pal, B, Visvader, JE, and Smyth, GK (2017). Differential methylation analysis of reduced representation bisulfite sequencing experiments using edger. F1000Res 6, 2055–55.
| Differential methylation analysis of reduced representation bisulfite sequencing experiments using edger.Crossref | GoogleScholarGoogle Scholar | 29333247PubMed |
Conners, CK (1969). A teacher rating scale for use in drug studies with children. American Journal of Psychiatry 126, 884–888.
| A teacher rating scale for use in drug studies with children.Crossref | GoogleScholarGoogle Scholar |
Conners, CK (1970). Symptom patterns in hyperkinetic, neurotic, and normal children. Child Development 41, 667–82.
| Symptom patterns in hyperkinetic, neurotic, and normal children.Crossref | GoogleScholarGoogle Scholar |
Cox, MP, Peterson, DA, and Biggs, PJ (2010). SolexaQA: at-a-glance quality assessment of Illumina second-generation sequencing data. BMC Bioinformatics 11, 485.
| SolexaQA: at-a-glance quality assessment of Illumina second-generation sequencing data.Crossref | GoogleScholarGoogle Scholar | 20875133PubMed |
De Vocht, F, Simpkin, AJ, Richmond, RC, Relton, C, and Tilling, K (2015). Assessment of offspring DNA methylation across the lifecourse associated with prenatal maternal smoking using Bayesian mixture modelling. International Journal of Environmental Research and Public Health 12, 14461–14476.
| Assessment of offspring DNA methylation across the lifecourse associated with prenatal maternal smoking using Bayesian mixture modelling.Crossref | GoogleScholarGoogle Scholar | 26580635PubMed |
Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Bækvad-Hansen, M, and Cerrato, F (2019). Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics 51, 63–75.
| Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.Crossref | GoogleScholarGoogle Scholar | 30478444PubMed |
Fergusson, DM, Horwood, LJ, and Lloyd, M (1991). Confirmatory factor models of attention deficit and conduct disorder. Journal of Child Psychology and Psychiatry, and Allied Disciplines 32, 257–274.
| Confirmatory factor models of attention deficit and conduct disorder.Crossref | GoogleScholarGoogle Scholar | 2033107PubMed |
Fergusson, DM, John Horwood, L, and Ridder, EM (2005). Show me the child at seven: the consequences of conduct problems in childhood for psychosocial functioning in adulthood. Journal of Child Psychology and Psychiatry, and Allied Disciplines 46, 837–849.
| Show me the child at seven: the consequences of conduct problems in childhood for psychosocial functioning in adulthood.Crossref | GoogleScholarGoogle Scholar | 16033632PubMed |
Harrington, AJ, Raissi, A, Rajkovich, K, Berto, S, Kumar, J, Molinaro, G, Raduazzo, J, Guo, Y, Loerwald, K, Konopka, G, Huber, KM, and Cowan, CW (2016). MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders. eLife 5, e20059.
| MEF2C regulates cortical inhibitory and excitatory synapses and behaviors relevant to neurodevelopmental disorders.Crossref | GoogleScholarGoogle Scholar | 27779093PubMed |
Hsieh, C-J, Jeng, S-F, Su, Y-N, Liao, H-F, Hsieh, W-S, Wu, K-Y, and Chen, P-C (2010). CYP1A1 modifies the effect of maternal exposure to environmental tobacco smoke on child behavior. Nicotine & Tobacco Research 12, 1108–1117.
| CYP1A1 modifies the effect of maternal exposure to environmental tobacco smoke on child behavior.Crossref | GoogleScholarGoogle Scholar |
Jiao, S-S, Shen, L-L, Zhu, C, Bu, X-L, Liu, Y-H, Liu, C-H, Yao, X-Q, Zhang, L-L, Zhou, H-D, Walker, DG, Tan, J, Götz, J, Zhou, X-F, and Wang, Y-J (2016). Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease. Translational Psychiatry 6, e907.
| Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease.Crossref | GoogleScholarGoogle Scholar | 27701410PubMed |
Joelsson, P, Chudal, R, Talati, A, Suominen, A, Brown, AS, and Sourander, A (2016). Prenatal smoking exposure and neuropsychiatric comorbidity of ADHD: a finnish nationwide population-based cohort study. BMC Psychiatry 16, 306.
| Prenatal smoking exposure and neuropsychiatric comorbidity of ADHD: a finnish nationwide population-based cohort study.Crossref | GoogleScholarGoogle Scholar | 27581195PubMed |
Joubert, BR, Håberg, SE, Nilsen, RM, Wang, X, Vollset, SE, Murphy, SK, Huang, Z, Hoyo, C, Midttun, Ø, Cupul-Uicab, LA, Ueland, PM, Wu, MC, Nystad, W, Bell, DA, Peddada, SD, and London, SJ (2012). 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environmental Health Perspectives 120, 1425–1431.
| 450K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy.Crossref | GoogleScholarGoogle Scholar | 22851337PubMed |
Joubert, BR, Felix, JF, Yousefi, P, Bakulski, KM, Just, AC, Breton, C, Reese, SE, Markunas, CA, Richmond, RC, and Xu, C-J (2016). DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. The American Journal of Human Genetics 98, 680–696.
| DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis.Crossref | GoogleScholarGoogle Scholar | 27040690PubMed |
Jung, Y, Hsieh, LS, Lee, AM, Zhou, Z, Coman, D, Heath, CJ, Hyder, F, Mineur, YS, Yuan, Q, Goldman, D, Bordey, A, and Picciotto, MR (2016). An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior. Nature Neuroscience 19, 905–914.
| An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior.Crossref | GoogleScholarGoogle Scholar | 27239938PubMed |
Kosfeld, M, Heinrichs, M, Zak, PJ, Fischbacher, U, and Fehr, E (2005). Oxytocin increases trust in humans. Nature 435, 673–676.
| Oxytocin increases trust in humans.Crossref | GoogleScholarGoogle Scholar | 15931222PubMed |
Krueger, F, and Andrews, SR (2011). Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics 27, 1571–1572.
| Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications.Crossref | GoogleScholarGoogle Scholar | 21493656PubMed |
Lantz, PM, House, JS, Lepkowski, JM, Williams, DR, Mero, RP, and Chen, J (1998). Socioeconomic factors, health behaviors, and mortality results from a nationally representative prospective study of US Adults’. JAMA 279, 1703–08.
| Socioeconomic factors, health behaviors, and mortality results from a nationally representative prospective study of US Adults’.Crossref | GoogleScholarGoogle Scholar | 9624022PubMed |
Lee, KWK, Richmond, R, Hu, P, French, L, Shin, J, Bourdon, C, Reischl, E, Waldenberger, M, Zeilinger, S, Gaunt, T, McArdle, W, Ring, S, Woodward, G, Bouchard, L, Gaudet, D, Smith, GD, Relton, C, Paus, T, and Pausova, Z (2015). Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environmental Health Perspectives 123, 193–199.
| Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age.Crossref | GoogleScholarGoogle Scholar |
Li, L, Ruan, X, Wen, C, Chen, P, Liu, W, Zhu, L, Xiang, P, Zhang, X, Wei, Q, Hou, L, Yin, B, Yuan, J, Qiang, B, Shu, P, and Peng, X (2019). The COMPASS family protein ASH2L mediates corticogenesis via transcriptional regulation of wnt signaling. Cell Reports 28, 698–711.e5.
| The COMPASS family protein ASH2L mediates corticogenesis via transcriptional regulation of wnt signaling.Crossref | GoogleScholarGoogle Scholar | 31315048PubMed |
Meyer, M, Berger, I, Winter, J, and Jurek, B (2018). Oxytocin alters the morphology of hypothalamic neurons via the transcription factor myocyte enhancer factor 2A (MEF-2A). Molecular and Cellular Endocrinology 477, 156–162.
| Oxytocin alters the morphology of hypothalamic neurons via the transcription factor myocyte enhancer factor 2A (MEF-2A).Crossref | GoogleScholarGoogle Scholar | 29928931PubMed |
Meyer, M, Kuffner, K, Winter, J, Neumann, ID, Wetzel, CH, and Jurek, B (2020). Myocyte Enhancer Factor 2A (MEF2A) defines oxytocin-induced morphological effects and regulates mitochondrial function in neurons. International Journal of Molecular Sciences 21, 2200.
| Myocyte Enhancer Factor 2A (MEF2A) defines oxytocin-induced morphological effects and regulates mitochondrial function in neurons.Crossref | GoogleScholarGoogle Scholar |
Mick, E, Biederman, J, Faraone, SV, Sayer, J, and Kleinman, S (2002). Case-control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy. Journal of the American Academy of Child & Adolescent Psychiatry 41, 378–385.
| Case-control study of attention-deficit hyperactivity disorder and maternal smoking, alcohol use, and drug use during pregnancy.Crossref | GoogleScholarGoogle Scholar |
Noble, AJ, Pearson, JF, Boden, JM, Horwood, LJ, Gemmell, NJ, Kennedy, MA, and Osborne, AJ (2021). A validation of Illumina EPIC array system with bisulfite-based amplicon sequencing. PeerJ 9, e10762.
| A validation of Illumina EPIC array system with bisulfite-based amplicon sequencing.Crossref | GoogleScholarGoogle Scholar | 33614276PubMed |
Rauschert, S, Melton, PE, Burdge, G, Craig, JM, Godfrey, KM, Holbrook, JD, Lillycrop, K, Mori, TA, Beilin, LJ, Oddy, WH, Pennell, C, and Huang, R-C (2019). Maternal smoking during pregnancy induces persistent epigenetic changes into adolescence, independent of postnatal smoke exposure and is associated with cardiometabolic risk. Frontiers in Genetics 10, 770.
| Maternal smoking during pregnancy induces persistent epigenetic changes into adolescence, independent of postnatal smoke exposure and is associated with cardiometabolic risk.Crossref | GoogleScholarGoogle Scholar | 31616461PubMed |
Richmond, RC, Simpkin, AJ, Woodward, G, Gaunt, TR, Lyttleton, O, McArdle, WL, Ring, SM, Smith, ADAC, Timpson, NJ, Tilling, K, Davey Smith, G, and Relton, CL (2015). Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). Human Molecular Genetics 24, 2201–2217.
| Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC).Crossref | GoogleScholarGoogle Scholar | 25552657PubMed |
Richmond, RC, Suderman, M, Langdon, R, Relton, CL, and Davey Smith, G (2018). DNA methylation as a marker for prenatal smoke exposure in adults. International Journal of Epidemiology 47, 1120–1130.
| DNA methylation as a marker for prenatal smoke exposure in adults.Crossref | GoogleScholarGoogle Scholar | 29860346PubMed |
Riva, V, Battaglia, M, Nobile, M, Cattaneo, F, Lazazzera, C, Mascheretti, S, Giorda, R, Mérette, C, Émond, C, Maziade, M, and Marino, C (2015). GRIN2B predicts attention problems among disadvantaged children. European Child & Adolescent Psychiatry 24, 827–836.
| GRIN2B predicts attention problems among disadvantaged children.Crossref | GoogleScholarGoogle Scholar |
Rotroff, DM, Joubert, BR, Marvel, SW, Håberg, SE, Wu, MC, Nilsen, RM, Ueland, PM, Nystad, W, London, SJ, and Motsinger-Reif, A (2016). Maternal smoking impacts key biological pathways in newborns through epigenetic modification in utero. BMC Genomics 17, 976.
| Maternal smoking impacts key biological pathways in newborns through epigenetic modification in utero.Crossref | GoogleScholarGoogle Scholar | 27887572PubMed |
Rutter M, Tizard J, Whitmore K (1970) ‘Education, health and behavior.’ (Longmans: London)
Rzehak, P, Saffery, R, Reischl, E, Covic, M, Wahl, S, Grote, V, Xhonneux, A, Langhendries, J-P, Ferre, N, Closa-Monasterolo, R, Verduci, E, Riva, E, Socha, P, Gruszfeld, D, and Koletzko, B Rzehak, P, Saffery, R, Reischl, E, Covic, M, Wahl, S, Grote, V, Xhonneux, A, Langhendries, J-P, Ferre, N, Closa-Monasterolo, R, Verduci, E, Riva, E, Socha, P, Gruszfeld, D, and Koletzko, B (2016). Maternal smoking during pregnancy and DNA-methylation in children at age 5.5 years: epigenome-wide-analysis in the European Childhood Obesity Project (CHOP)-study. PLoS ONE 11, e0155554.
| Maternal smoking during pregnancy and DNA-methylation in children at age 5.5 years: epigenome-wide-analysis in the European Childhood Obesity Project (CHOP)-study.Crossref | GoogleScholarGoogle Scholar | 27171005PubMed |
Salvatore, JE, and Dick, DM (2018). Genetic influences on conduct disorder. Neuroscience & Biobehavioral Reviews 91, 91–101.
| Genetic influences on conduct disorder.Crossref | GoogleScholarGoogle Scholar |
Sengupta, SM, Smith, AK, Grizenko, N, and Joober, R (2017). Locus-specific DNA methylation changes and phenotypic variability in children with attention-deficit hyperactivity disorder. Psychiatry Research 256, 298–304.
| Locus-specific DNA methylation changes and phenotypic variability in children with attention-deficit hyperactivity disorder.Crossref | GoogleScholarGoogle Scholar | 28662467PubMed |
Skogstrand, K, Hagen, CM, Borbye-Lorenzen, N, Christiansen, M, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Werge, T, Børglum, A, Mors, O, Nordentoft, M, Mortensen, PB, and Hougaard, DM (2019). Reduced neonatal brain-derived neurotrophic factor is associated with autism spectrum disorders. Translational Psychiatry 9, 252.
| Reduced neonatal brain-derived neurotrophic factor is associated with autism spectrum disorders.Crossref | GoogleScholarGoogle Scholar | 31591381PubMed |
Suter, M, Abramovici, A, Showalter, L, Hu, M, Shope, CD, Varner, M, and Aagaard-Tillery, K (2010). In utero tobacco exposure epigenetically modifies placental CYP1A1 expression. Metabolism-Clinical and Experimental 59, 1481–1490.
| In utero tobacco exposure epigenetically modifies placental CYP1A1 expression.Crossref | GoogleScholarGoogle Scholar | 20462615PubMed |
Tehranifar, P, Wu, H-C, McDonald, JA, Jasmine, F, Santella, RM, Gurvich, I, Flom, JD, and Terry, MB (2018). Maternal cigarette smoking during pregnancy and offspring DNA methylation in midlife. Epigenetics 13, 129–134.
| Maternal cigarette smoking during pregnancy and offspring DNA methylation in midlife.Crossref | GoogleScholarGoogle Scholar | 28494218PubMed |
van Otterdijk, SD, Binder, AM, and Michels, KB (2017). Locus-specific DNA methylation in the placenta is associated with levels of pro-inflammatory proteins in cord blood and they are both independently affected by maternal smoking during pregnancy. Epigenetics 12, 875–885.
| Locus-specific DNA methylation in the placenta is associated with levels of pro-inflammatory proteins in cord blood and they are both independently affected by maternal smoking during pregnancy.Crossref | GoogleScholarGoogle Scholar | 28820654PubMed |
Verzi, MP, Agarwal, P, Brown, C, McCulley, DJ, Schwarz, JJ, and Black, BL (2007). The transcription factor MEF2C is required for craniofacial development. Developmental Cell 12, 645–652.
| The transcription factor MEF2C is required for craniofacial development.Crossref | GoogleScholarGoogle Scholar | 17420000PubMed |
Wakschlag, LS, Lahey, BB, Loeber, R, Green, SM, Gordon, RA, and Leventhal, BL (1997). Maternal smoking during pregnancy and the risk of conduct disorder in boys. Archives of General Psychiatry 54, 670–676.
| Maternal smoking during pregnancy and the risk of conduct disorder in boys.Crossref | GoogleScholarGoogle Scholar | 9236551PubMed |
Zak, PJ, Stanton, AA, and Ahmadi, S (2007). Oxytocin increases generosity in humans. PLoS ONE 2, e1128.
| Oxytocin increases generosity in humans.Crossref | GoogleScholarGoogle Scholar | 17987115PubMed |
