Angeline Ajit

Background:  Tobacco use during pregnancy remains a significant public health concern, contributing to adverse birth outcomes such as intrauterine growth restriction, preeclampsia, and preterm birth.¹ The placenta, a vital organ for nutrient exchange and maternal-fetal immune tolerance, is particularly sensitive to environmental exposures.² While the toxicological effects of cigarette smoke have been well documented, recent research has shifted focus toward epigenetic mechanisms as critical mediators of tobacco-related placental dysfunction.² Environmental exposures such as nicotine can influence DNA methylation in key regulatory regions, including enhancers and imprinted genes, which in turn affects gene expression.² Disruptions in the expression of immune checkpoint genes like Human Leukocyte Antigen-G (HLA-G) may impair immune tolerance at the maternal-fetal interface.¹ Understanding these epigenetic changes is essential for developing biomarkers and potential interventions to improve pregnancy outcomes in populations exposed to tobacco.⁵

Objective:  This literature review examines how prenatal tobacco smoke and nicotine exposure affect placental immune regulation through epigenetic mechanisms, with an emphasis on DNA methylation and gene expression related to immune tolerance and fetal development.¹⁻⁵

Search Methods:  Relevant literature published between 2017 and 2023 was identified through searches in PubMed and Google Scholar.¹⁻⁵ Keywords and MeSH terms included “tobacco smoke,” “nicotine,” “placenta,” “DNA methylation,” “HLA-G,” “immune regulation,” and “fetal development.”¹⁻⁵ The search yielded studies including epigenome-wide association studies (EWAS), cohort studies, and randomized controlled trials.¹⁻⁵

Results:  Rousseaux et al. identified 203 differentially methylated regions (DMRs) in placentas from smokers, enriched in enhancer and imprinted gene regions such as H19 and NNAT, with some changes persisting even in former smokers, indicating a potential epigenetic memory of prior exposure.² Janssen et al. demonstrated that smoking decreases placental mitochondrial DNA content and increases methylation of CYP1A1, contributing to oxidative stress and reduced fetal growth.³ Dunk et al. found altered expression of HLA-C, HLA-G, HLA-F, and HLA-E in placentas from pregnancies complicated by preeclampsia and chorioamnionitis, suggesting immune dysregulation at the maternal-fetal interface.¹ Cardenas et al. identified several CpG sites, including one in PBX1, that mediated the association between smoking and birth weight reduction, with methylation at this site correlating with a 301-gram decrease in birth weight.⁴ Shorey-Kendrick et al. showed that vitamin C supplementation normalized 69 percent of smoking-associated methylation changes across placental, cord blood, and buccal tissues, supporting its potential role in mitigating epigenetic damage.⁵

Conclusion:  Prenatal tobacco exposure contributes to immune dysfunction and fetal growth impairment through placental epigenetic alterations, including DNA methylation changes in enhancer elements and immune-related genes.¹⁻⁵ These disruptions impair mitochondrial function and maternal immune tolerance.¹⁻³ Identification of methylation biomarkers such as cg22638236 in PBX1 may enable earlier risk assessment for adverse outcomes.⁴ Interventions like vitamin C supplementation may offer protective effects against tobacco-induced epigenetic damage.⁵ Further research should investigate the roles of histone-modifying enzymes, non-coding RNAs, and inflammatory signaling pathways in regulating immune gene expression in tobacco-exposed pregnancies.¹⁻⁵

Works Cited

1. Dunk CE, Bucher M, Zhang J, et al. Human leukocyte antigen HLA-C, HLA-G, HLA-F, and HLA-E placental profiles are altered in early severe preeclampsia and preterm birth with chorioamnionitis. Am J Obstet Gynecol. 2022;227(4):641.e1-641.e13. doi:10.1016/j.ajog.2022.07.021
2. Rousseaux S, Seyve E, Chuffart F, et al. Immediate and durable effects of maternal tobacco consumption alter placental DNA methylation in enhancer and imprinted gene-containing regions. BMC Med. 2020;18(1):1-20. doi:10.1186/s12916-020-01736-1
3. Janssen BG, Gyselaers W, Byun HM, et al. Placental mitochondrial DNA and CYP1A1 gene methylation as molecular signatures for tobacco smoke exposure in pregnant women and the relevance for birth weight. J Transl Med. 2017;15(1):5. doi:10.1186/s12967-016-1113-4
4. Cardenas A, Lutz SM, Everson TM, et al. Mediation by placental DNA methylation of the association of prenatal maternal smoking and birth weight. Am J Epidemiol. 2019;188(11):1878-1886. doi:10.1093/aje/kwz184
5. Shorey-Kendrick LE, McEvoy CT, Ferguson B, et al. Vitamin C prevents offspring DNA methylation changes associated with maternal smoking in pregnancy. Am J Respir Crit Care Med. 2017;196(6):745-755. doi:10.1164/rccm.201610-2141OC