Abstract
Despite increased awareness, maternal cigarette smoking during pregnancy continues to be a common habit causing risk for numerous documented negative health consequences in the exposed children. It has been proposed that epigenetic mechanisms constitute the link between prenatal exposure to maternal cigarette smoking (PEMCS) and the diverse pathologies arising in later life. We here review the current literature, focusing on DNA methylation. Alterations in the global DNA methylation patterns were observed after exposure to maternal smoking during pregnancy in placenta, cord blood and buccal epithelium tissue. Further, a number of specific genes exemplified by CYP1A1, AhRR, FOXP3, TSLP, IGF2, AXL, PTPRO, C11orf52, FRMD4A and BDNF are shown to have altered DNA methylation patterns in at least one of these tissue types due to PEMCS. Investigations showing persistence and indications of trans-generational inheritance of DNA methylation alterations induced by smoking exposure are also described. Further, smoking-induced epigenetic manifestations can be both tissue-dependent and gender-specific which show the importance of addressing the relevant sex, tissue and cell types in the future studies linking specific epigenetic alterations to disease development. Moreover, the effect of paternal cigarette smoking and second-hand smoke exposure is documented and accordingly not to be neglected in future investigations and data evaluations. We also outline possible directions for the future research to address how DNA methylation alterations induced by maternal lifestyle, exemplified by smoking, have direct consequences for fetal development and later in life health and behavior of the child.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barker DJ (2007) The origins of the developmental origins theory. J Intern Med 261:412–417. doi:10.1111/j.1365-2796.2007.01809.x
Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD (2009) Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 180:462–467. doi:10.1164/rccm.200901-0135OC
Breton CV, Salam MT, Gilliland FD (2011) Heritability and role for the environment in DNA methylation in AXL receptor tyrosine kinase. Epigenetics 6:895–898
Breton CV et al (2014) Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation. PLoS One 9:e99716. doi:10.1371/journal.pone.0099716
Curley JP, Mashoodh R, Champagne FA (2011) Epigenetics and the origins of paternal effects. Horm Behav 59:306–314. doi:10.1016/j.yhbeh.2010.06.018
Dietz PM, Homa D, England LJ, Burley K, Tong VT, Dube SR, Bernert JT (2011) Estimates of nondisclosure of cigarette smoking among pregnant and nonpregnant women of reproductive age in the United States. Am J Epidemiol 173:355–359. doi:10.1093/aje/kwq381
Doherty SP, Grabowski J, Hoffman C, Ng SP, Zelikoff JT (2009) Early life insult from cigarette smoke may be predictive of chronic diseases later in life. Biomarkers 14(Suppl 1):97–101. doi:10.1080/13547500902965898
Duijts L (2012) Fetal and infant origins of asthma. Eur J Epidemiol 27:5–14. doi:10.1007/s10654-012-9657-y
Flom JD et al (2011) Prenatal smoke exposure and genomic DNA methylation in a multiethnic birth cohort. Cancer Epidemiol Biomark Prev 20:2518–2523. doi:10.1158/1055-9965.epi-11-0553
Ganu RS, Harris RA, Collins K, Aagaard KM (2012) Early origins of adult disease: approaches for investigating the programmable epigenome in humans, nonhuman primates, and rodents. ILAR J 53:306–321. doi:10.1093/ilar.53.3-4.306
Guerrero-Preston R et al (2010) Global DNA hypomethylation is associated with in utero exposure to cotinine and perfluorinated alkyl compounds. Epigenetics 5:539–546
Hahn ME, Allan LL, Sherr DH (2009) Regulation of constitutive and inducible AHR signaling: complex interactions involving the AHR repressor. Biochem Pharmacol 77:485–497. doi:10.1016/j.bcp.2008.09.016
Hao N, Whitelaw ML (2013) The emerging roles of AhR in physiology and immunity. Biochem Pharmacol 86:561–570. doi:10.1016/j.bcp.2013.07.004
Herberth G et al (2014) Maternal and cord blood miR-223 expression associates with prenatal tobacco smoke exposure and low regulatory T-cell numbers. J Allergy Clin Immunol 133:543–550. doi:10.1016/j.jaci.2013.06.036
Hinz D et al (2012) Cord blood Tregs with stable FOXP3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year. Allergy 67:380–389. doi:10.1111/j.1398-9995.2011.02767.x
Jaenisch R (1997) DNA methylation and imprinting: why bother? Trends Genet 13:323–329
Jorde L, Carey J, Bamshad M (2009) Medical genetics, 4th edn. Elsevier, Amsterdam
Joubert BR et al (2012) 450 K epigenome-wide scan identifies differential DNA methylation in newborns related to maternal smoking during pregnancy. Environ Health Perspect 120:1425–1431. doi:10.1289/ehp.1205412
Joubert BR et al (2014) Maternal smoking and DNA methylation in newborns: in utero effect or epigenetic inheritance? Cancer Epidemiol Biomark Prev 23:1007–1017. doi:10.1158/1055-9965.epi-13-1256
Kinney SR, Pradhan S (2013) Ten eleven translocation enzymes and 5-hydroxymethylation in mammalian development and cancer. Adv Exp Med Biol 754:57–79. doi:10.1007/978-1-4419-9967-2_3
Kishi R, Sata F, Yoshioka E, Ban S, Sasaki S, Konishi K, Washino N (2008) Exploiting gene-environment interaction to detect adverse health effects of environmental chemicals on the next generation. Basic Clin Pharmacol Toxicol 102:191–203. doi:10.1111/j.1742-7843.2007.00201.x
Knopik VS, Maccani MA, Francazio S, McGeary JE (2012) The epigenetics of maternal cigarette smoking during pregnancy and effects on child development. Dev Psychopathol 24:1377–1390. doi:10.1017/s0954579412000776
Lee SA, Ding C (2012) The dysfunctional placenta epigenome: causes and consequences. Epigenomics 4:561–569. doi:10.2217/epi.12.49
Lillycrop KA, Hoile SP, Grenfell L, Burdge GC (2014) DNA methylation, ageing and the influence of early life nutrition. Proc Nutr Soc 73:413–421. doi:10.1017/s0029665114000081
Lim JP, Brunet A (2013) Bridging the transgenerational gap with epigenetic memory. Trend genet 29:176–186. doi:10.1016/j.tig.2012.12.008
Maccani MA, Marsit CJ (2009) Epigenetics in the placenta. Am J Reprod Immunol Microbiol 62:78–89. doi:10.1111/j.1600-0897.2009.00716.x
Maccani MA, Avissar-Whiting M, Banister CE, McGonnigal B, Padbury JF, Marsit CJ (2010) Maternal cigarette smoking during pregnancy is associated with downregulation of miR-16, miR-21, and miR-146a in the placenta. Epigenetics 5:583–589
Michels KB, Harris HR, Barault L (2011) Birthweight, maternal weight trajectories and global DNA methylation of LINE-1 repetitive elements. PLoS One 6:e25254. doi:10.1371/journal.pone.0025254
Morris CV, DiNieri JA, Szutorisz H, Hurd YL (2011) Molecular mechanisms of maternal cannabis and cigarette use on human neurodevelopment. Eur J Neurosci 34:1574–1583. doi:10.1111/j.1460-9568.2011.07884.x
Murphy SK et al (2012) Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke. Gene 494:36–43. doi:10.1016/j.gene.2011.11.062
Ng SP, Zelikoff JT (2007) Smoking during pregnancy: subsequent effects on offspring immune competence and disease vulnerability in later life. Reprod Toxicol 23:428–437. doi:10.1016/j.reprotox.2006.11.008
Novakovic B, Ryan J, Pereira N, Boughton B, Craig JM, Saffery R (2013) Postnatal stability, tissue, and time specific effects of methylation change in response to maternal smoking in pregnancy. Epigenetics 9:377–386. doi:10.4161/epi.27248
Pembrey ME, Bygren LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, Golding J (2006) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14:159–166. doi:10.1038/sj.ejhg.5201538
Sen B, Mahadevan B, DeMarini DM (2007) Transcriptional responses to complex mixtures: a review. Mutat Res 636:144–177. doi:10.1016/j.mrrev.2007.08.002
Shipton D, Tappin DM, Vadiveloo T, Crossley JA, Aitken DA, Chalmers J (2009) Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study. BMJ 339:b4347. doi:10.1136/bmj.b4347
Soubry A, Hoyo C, Jirtle RL, Murphy SK (2014) A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line. Bioessays 36:359–371. doi:10.1002/bies.201300113
Suter MA, Aagaard K (2012) What changes in DNA methylation take place in individuals exposed to maternal smoking in utero? Epigenomics 4:115–118. doi:10.2217/epi.12.7
Suter M, Abramovici A, Showalter L, Hu M, Shope CD, Varner M, Aagaard-Tillery K (2010) In utero tobacco exposure epigenetically modifies placental CYP1A1 expression. Metabolism 59:1481–1490. doi:10.1016/j.metabol.2010.01.013
Suter M et al (2011) Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression. Epigenetics 6:1284–1294. doi:10.4161/epi.6.11.17819
Suter MA, Anders AM, Aagaard KM (2013) Maternal smoking as a model for environmental epigenetic changes affecting birthweight and fetal programming. Mol Hum Reprod 19:1–6. doi:10.1093/molehr/gas050
Swanson JM, Entringer S, Buss C, Wadhwa PD (2009) Developmental origins of health and disease: environmental exposures. Semin Reprod Med 27:391–402. doi:10.1055/s-0029-1237427
Szyf M, Bick J (2013) DNA methylation: a mechanism for embedding early life experiences in the genome. Child Dev 84:49–57. doi:10.1111/j.1467-8624.2012.01793.x
Szyf M, McGowan P, Meaney MJ (2008) The social environment and the epigenome. Environ Mol Mutagen 49:46–60. doi:10.1002/em.20357
Toledo-Rodriguez M et al (2010) Maternal smoking during pregnancy is associated with epigenetic modifications of the brain-derived neurotrophic factor-6 exon in adolescent offspring. Am Med Genet Part B, Neuropsychiatr Genet 153b:1350–1354. doi:10.1002/ajmg.b.31109
Tollefsbol TO (2011) Advances in epigenetic technology. Methods Mol Biol 791:1–10. doi:10.1007/978-1-61779-316-5_1
Wadhwa PD, Buss C, Entringer S, Swanson JM (2009) Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med 27:358–368. doi:10.1055/s-0029-1237424
Wang IJ, Chen SL, Lu TP, Chuang EY, Chen PC (2013) Prenatal smoke exposure DNA methylation, and childhood atopic dermatitis. Clin Exp Allergy 43:535–543. doi:10.1111/cea.12108
Weisenberger DJ VDBD, Pan F, Berman BP, Laird PW, (2008) Comprehensive DNA methylation analysis on the Illumina Infinium assay platform. University of Southern California, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles
Wilhelm-Benartzi CS et al (2012) In utero exposures, infant growth, and DNA methylation of repetitive elements and developmentally related genes in human placenta. Environ Health Perspect 120:296–302. doi:10.1289/ehp.1103927
Zeilinger S et al (2013) Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One 8:e63812. doi:10.1371/journal.pone.0063812
Acknowledgments
This work was supported by The Lundbeck Foundation, Dines Hansens Legat, and Læge Sofus Carl Emil Friis og hustru Olga Doris Friis Legat.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nielsen, C.H., Larsen, A. & Nielsen, A.L. DNA methylation alterations in response to prenatal exposure of maternal cigarette smoking: A persistent epigenetic impact on health from maternal lifestyle?. Arch Toxicol 90, 231–245 (2016). https://doi.org/10.1007/s00204-014-1426-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-014-1426-0