Mediation Effects of DNA Methylation and Hydroxymethylation on Birth Outcomes After Prenatal Per- and Polyfluoroalkyl Substances (PFAS) Exposure in the Michigan Mother-infant Pairs Cohort

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2023 Mar 25

PMID 36964604

Authors

Rebekah L Petroff

Raymond G Cavalcante

Elizabeth S Langen

Dana C Dolinoy

Vasantha Padmanabhan

Jaclyn M Goodrich

Affiliations

Soon will be listed here.

Abstract

Background: Per- and polyfluoroalkyl substances (PFAS) are chemicals that are resistant to degradation and ubiquitous in our environments. PFAS may impact the developing epigenome, but current human evidence is limited to assessments of total DNA methylation. We assessed associations between first trimester PFAS exposures with newborn DNA methylation, including 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC). DNA methylation mediation of associations between PFAS and birth outcomes were explored in the Michigan Mother Infant Pairs cohort. Nine PFAS were measured in maternal first trimester blood. Seven were highly detected and included for analysis: PFHxS, PFOA, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA. Bisulfite-converted cord blood DNA (n = 141) and oxidative-bisulfite-converted cord blood (n = 70) were assayed on Illumina MethylationEPIC BeadChips to measure total DNA methylation (5-mC + 5-hmC) and 5-mC/5-hmC. Correcting for multiple comparisons, beta regressions were used to assess associations between levels of PFAS and total methylation, 5-mC, or 5-hmC. Nonlinear mediation analyses were used to assess the epigenetic meditation effect between PFAS and birth outcomes.

Results: PFAS was significantly associated with total methylation (q < 0.05: PFHxS-12 sites; PFOS-19 sites; PFOA-2 sites; PFNA-3 sites; PFDA-4 sites). In 72 female infants and 69 male infants, there were sex-specific associations between five PFAS and DNA methylation. 5-mC and 5-hmC were each significantly associated with thousands of sites for PFHxS, PFOS, PFNA, PFDA, PFUnDA, and MeFOSAA (q < 0.05). Clusters of 5-mC and 5-hmC sites were significant mediators between PFNA and PFUnDA and decreased gestational age (q < 0.05).

Conclusions: This study demonstrates the mediation role of specific types of DNA methylation on the relationship between PFAS exposure and birth outcomes. These results suggest that 5-mC and 5-hmC may be more sensitive to the developmental impacts of PFAS than total DNA methylation.

Citing Articles

Parkinson's disease-associated alterations in DNA methylation and hydroxymethylation in human brain.

Choza J, Virani M, Kuhn N, Adams M, Kochmanski J, Bernstein A bioRxiv. 2025; .

PMID: 39975085 PMC: 11838189. DOI: 10.1101/2024.05.21.595193.

Lifetime Postnatal Exposure to Perfluoroalkyl Substance Mixture and DNA Methylation at Twelve Years of Age.

Liu Y, Gairola R, Kuiper J, Papandonatos G, Kelsey K, Langevin S Environ Sci Technol Lett. 2025; 10(10):824-830.

PMID: 39831111 PMC: 11741666. DOI: 10.1021/acs.estlett.3c00410.

PFAS Exposure and Male Reproductive Health: Implications for Sperm Epigenetics.

Maxwell D, Petriello M, Pilsner J Semin Reprod Med. 2025; 42(4):288-301.

PMID: 39788533 PMC: 11893235. DOI: 10.1055/s-0044-1801363.

Characterizing DNA Methylation and Hydroxymethylation in Cord Blood and Identifying Sex-Specific Differences using the Illumina EPIC Array.

Petroff R, Dolinoy D, Padmanabhan V, Goodrich J Epigenet Rep. 2024; 2(1):1-7.

PMID: 39610770 PMC: 11600988. DOI: 10.1080/28361512.2024.2427955.

Early pregnancy serum PFAS are associated with alterations in the maternal lipidome.

Rabotnick M, Haidari A, Dolinoy D, Meijer J, Harris S, Burant C Environ Res. 2024; 263(Pt 3):120183.

PMID: 39426451 PMC: 11639123. DOI: 10.1016/j.envres.2024.120183.

References

Leijon I, Ingemansson F, Nelson N, Wadsby M, Samuelsson S . Reading deficits in very low birthweight children are associated with vocabulary and attention issues at the age of seven. Acta Paediatr. 2015; 105(1):60-8. PMC: 4758409. DOI: 10.1111/apa.13094. View

Teschendorff A, Zhuang J, Widschwendter M . Independent surrogate variable analysis to deconvolve confounding factors in large-scale microarray profiling studies. Bioinformatics. 2011; 27(11):1496-505. DOI: 10.1093/bioinformatics/btr171. View

Dong H, Curran I, Williams A, Bondy G, Yauk C, Wade M . Hepatic miRNA profiles and thyroid hormone homeostasis in rats exposed to dietary potassium perfluorooctanesulfonate (PFOS). Environ Toxicol Pharmacol. 2016; 41:201-10. DOI: 10.1016/j.etap.2015.12.009. View

Kuklenyik Z, Needham L, Calafat A . Measurement of 18 perfluorinated organic acids and amides in human serum using on-line solid-phase extraction. Anal Chem. 2005; 77(18):6085-91. DOI: 10.1021/ac050671l. View

Ahmad S, Wen Y, Irudayaraj J . PFOA induces alteration in DNA methylation regulators and SARS-CoV-2 targets and in mouse lung tissues. Toxicol Rep. 2021; 8:1892-1898. PMC: 8620096. DOI: 10.1016/j.toxrep.2021.11.014. View

Boronow K, Brody J, Schaider L, Peaslee G, Havas L, Cohn B . Serum concentrations of PFASs and exposure-related behaviors in African American and non-Hispanic white women. J Expo Sci Environ Epidemiol. 2019; 29(2):206-217. PMC: 6380931. DOI: 10.1038/s41370-018-0109-y. View

Kingsley S, Kelsey K, Butler R, Chen A, Eliot M, Romano M . Maternal serum PFOA concentration and DNA methylation in cord blood: A pilot study. Environ Res. 2017; 158:174-178. PMC: 5554452. DOI: 10.1016/j.envres.2017.06.013. View

Ojo A, Peng C, Annamalai P, Megharaj M, Ng J . Toxicity assessment of historical aqueous film-forming foams (AFFFs) using cell-based assays. Environ Pollut. 2022; 310:119806. DOI: 10.1016/j.envpol.2022.119806. View

Leung Y, Ouyang B, Niu L, Xie C, Ying J, Medvedovic M . Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort. Epigenetics. 2018; 13(3):290-300. PMC: 5997167. DOI: 10.1080/15592294.2018.1445901. View

10.

Omoike O, Pack R, Mamudu H, Liu Y, Strasser S, Zheng S . Association between per and polyfluoroalkyl substances and markers of inflammation and oxidative stress. Environ Res. 2020; 196:110361. DOI: 10.1016/j.envres.2020.110361. View

11.

Kim S, Thapar I, Brooks B . Epigenetic changes by per- and polyfluoroalkyl substances (PFAS). Environ Pollut. 2021; 279:116929. DOI: 10.1016/j.envpol.2021.116929. View

12.

Xu Z, Niu L, Li L, Taylor J . ENmix: a novel background correction method for Illumina HumanMethylation450 BeadChip. Nucleic Acids Res. 2015; 44(3):e20. PMC: 4756845. DOI: 10.1093/nar/gkv907. View

13.

Goodrich J, Ingle M, Domino S, Treadwell M, Dolinoy D, Burant C . First trimester maternal exposures to endocrine disrupting chemicals and metals and fetal size in the Michigan Mother-Infant Pairs study. J Dev Orig Health Dis. 2019; 10(4):447-458. PMC: 6660406. DOI: 10.1017/S204017441800106X. View

14.

Ojo A, Peng C, Ng J . Combined effects and toxicological interactions of perfluoroalkyl and polyfluoroalkyl substances mixtures in human liver cells (HepG2). Environ Pollut. 2020; 263(Pt B):114182. DOI: 10.1016/j.envpol.2020.114182. View

15.

Sonkar R, Kay M, Choudhury M . PFOS Modulates Interactive Epigenetic Regulation in First-Trimester Human Trophoblast Cell Line HTR-8/SV. Chem Res Toxicol. 2019; 32(10):2016-2027. DOI: 10.1021/acs.chemrestox.9b00198. View

16.

Aryee M, Jaffe A, Corrada-Bravo H, Ladd-Acosta C, Feinberg A, Hansen K . Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014; 30(10):1363-9. PMC: 4016708. DOI: 10.1093/bioinformatics/btu049. View

17.

Valeri L, VanderWeele T . Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013; 18(2):137-50. PMC: 3659198. DOI: 10.1037/a0031034. View

18.

Szwagierczak A, Bultmann S, Schmidt C, Spada F, Leonhardt H . Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res. 2010; 38(19):e181. PMC: 2965258. DOI: 10.1093/nar/gkq684. View

19.

Miura R, Araki A, Miyashita C, Kobayashi S, Kobayashi S, Wang S . An epigenome-wide study of cord blood DNA methylations in relation to prenatal perfluoroalkyl substance exposure: The Hokkaido study. Environ Int. 2018; 115:21-28. DOI: 10.1016/j.envint.2018.03.004. View

20.

Wu H, DAlessio A, Ito S, Wang Z, Cui K, Zhao K . Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 2011; 25(7):679-84. PMC: 3070931. DOI: 10.1101/gad.2036011. View