Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis

Background: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes.

Objectives: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children.

Methods: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression.

Results: Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns.

Conclusions: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.

Citing Articles

Developmental air pollution exposure augments airway hyperreactivity, alters transcriptome, and DNA methylation in female adult progeny.

Zakarya R, Chan Y, Wang B, Thorpe A, Xenaki D, Ho K Commun Biol. 2025; 8(1):400.

PMID: 40057553 PMC: 11890619. DOI: 10.1038/s42003-025-07835-0.

Air pollution exposure is associated with gene expression in children.

Das S, Rundblad A, Marques I, Goncalves Soares A, Jaddoe V, Vrijheid M Environ Epigenet. 2024; 10(1):dvae025.

PMID: 39723337 PMC: 11668970. DOI: 10.1093/eep/dvae025.

Particulate matter-induced epigenetic modifications and lung complications.

Afthab M, Hambo S, Kim H, Alhamad A, Harb H Eur Respir Rev. 2024; 33(174).

PMID: 39537244 PMC: 11558539. DOI: 10.1183/16000617.0129-2024.

From womb to wellness: early environmental exposures, cord blood DNA methylation and disease origins.

Mirzakhani H Epigenomics. 2024; 16(17):1175-1183.

PMID: 39263926 PMC: 11457657. DOI: 10.1080/17501911.2024.2390823.

Modulatory Effects of Vitamin D: A Possible Approach to Mitigate Air Pollution Related Pregnancy Complications.

Singhal B, Chauhan S, Soni N, Gurjar V, Joshi V, Kaur P J Reprod Infertil. 2024; 25(2):79-101.

PMID: 39157803 PMC: 11327426. DOI: 10.18502/jri.v25i2.16004.

References

Vrijheid M, Slama R, Robinson O, Chatzi L, Coen M, van den Hazel P . The human early-life exposome (HELIX): project rationale and design. Environ Health Perspect. 2014; 122(6):535-44. PMC: 4048258. DOI: 10.1289/ehp.1307204. View

Relton C, Gaunt T, McArdle W, Ho K, Duggirala A, Shihab H . Data Resource Profile: Accessible Resource for Integrated Epigenomic Studies (ARIES). Int J Epidemiol. 2015; 44(4):1181-90. PMC: 5593097. DOI: 10.1093/ije/dyv072. View

Barouki R, Melen E, Herceg Z, Beckers J, Chen J, Karagas M . Epigenetics as a mechanism linking developmental exposures to long-term toxicity. Environ Int. 2018; 114:77-86. PMC: 5899930. DOI: 10.1016/j.envint.2018.02.014. View

Eeftens M, Beelen R, de Hoogh K, Bellander T, Cesaroni G, Cirach M . Development of Land Use Regression models for PM(2.5), PM(2.5) absorbance, PM(10) and PM(coarse) in 20 European study areas; results of the ESCAPE project. Environ Sci Technol. 2012; 46(20):11195-205. DOI: 10.1021/es301948k. View

Cassee F, Heroux M, Gerlofs-Nijland M, Kelly F . Particulate matter beyond mass: recent health evidence on the role of fractions, chemical constituents and sources of emission. Inhal Toxicol. 2013; 25(14):802-12. PMC: 3886392. DOI: 10.3109/08958378.2013.850127. View

Choi Y, Lee S, Lee W, Jeon H, Lee E, Lee H . RACK1 is a candidate gene associated with the prognosis of patients with early stage non-small cell lung cancer. Oncotarget. 2015; 6(6):4451-66. PMC: 4414203. DOI: 10.18632/oncotarget.2865. View

Strimmer K . fdrtool: a versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics. 2008; 24(12):1461-2. DOI: 10.1093/bioinformatics/btn209. View

Plusquin M, Chadeau-Hyam M, Ghantous A, Alfano R, Bustamante M, Chatzi L . DNA Methylome Marks of Exposure to Particulate Matter at Three Time Points in Early Life. Environ Sci Technol. 2018; 52(9):5427-5437. DOI: 10.1021/acs.est.7b06447. View

Qian Y, Huang X, Liang H, Zhang Z, Xu J, Chen J . Effects of maternal folic acid supplementation on gene methylation and being small for gestational age. J Hum Nutr Diet. 2016; 29(5):643-51. DOI: 10.1111/jhn.12369. View

10.

Verhein K, McCaw Z, Gladwell W, Trivedi S, Bushel P, Kleeberger S . Novel Roles for Notch3 and Notch4 Receptors in Gene Expression and Susceptibility to Ozone-Induced Lung Inflammation in Mice. Environ Health Perspect. 2015; 123(8):799-805. PMC: 4529014. DOI: 10.1289/ehp.1408852. View

11.

Jiang R, Jones M, Sava F, Kobor M, Carlsten C . Short-term diesel exhaust inhalation in a controlled human crossover study is associated with changes in DNA methylation of circulating mononuclear cells in asthmatics. Part Fibre Toxicol. 2014; 11:71. PMC: 4268899. DOI: 10.1186/s12989-014-0071-3. View

12.

Chen Y, Yang Q, Du M . Beyond brown adipogenesis the inheritance of imprinted H19. Noncoding RNA Investig. 2019; 2. PMC: 6559356. DOI: 10.21037/ncri.2018.11.05. View

13.

Packer A, Mailutha K, Ambrozewicz L, Wolgemuth D . Regulation of the Hoxa4 and Hoxa5 genes in the embryonic mouse lung by retinoic acid and TGFbeta1: implications for lung development and patterning. Dev Dyn. 2000; 217(1):62-74. DOI: 10.1002/(SICI)1097-0177(200001)217:1<62::AID-DVDY6>3.0.CO;2-U. View

14.

Wysocki K, Conley Y, Wenzel S . Epigenome variation in severe asthma. Biol Res Nurs. 2014; 17(3):263-9. PMC: 4387102. DOI: 10.1177/1099800414553463. View

15.

Peters T, Buckley M, Statham A, Pidsley R, Samaras K, Lord R . De novo identification of differentially methylated regions in the human genome. Epigenetics Chromatin. 2015; 8:6. PMC: 4429355. DOI: 10.1186/1756-8935-8-6. View

16.

Bakulski K, Daniele Fallin M . Epigenetic epidemiology: promises for public health research. Environ Mol Mutagen. 2014; 55(3):171-83. PMC: 4011487. DOI: 10.1002/em.21850. View

17.

Panni T, Mehta A, Schwartz J, Baccarelli A, Just A, Wolf K . Genome-Wide Analysis of DNA Methylation and Fine Particulate Matter Air Pollution in Three Study Populations: KORA F3, KORA F4, and the Normative Aging Study. Environ Health Perspect. 2016; 124(7):983-90. PMC: 4937859. DOI: 10.1289/ehp.1509966. View

18.

Bonder M, Luijk R, Zhernakova D, Moed M, Deelen P, Vermaat M . Disease variants alter transcription factor levels and methylation of their binding sites. Nat Genet. 2016; 49(1):131-138. DOI: 10.1038/ng.3721. View

19.

Reinius L, Acevedo N, Joerink M, Pershagen G, Dahlen S, Greco D . Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLoS One. 2012; 7(7):e41361. PMC: 3405143. DOI: 10.1371/journal.pone.0041361. View

20.

Felix J, Joubert B, Baccarelli A, Sharp G, Almqvist C, Annesi-Maesano I . Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol. 2017; 47(1):22-23u. PMC: 5837319. DOI: 10.1093/ije/dyx190. View