What Happens In Utero Does Not Stay In Utero: a Review of Evidence for Prenatal Epigenetic Programming by Per- and Polyfluoroalkyl Substances (PFAS) in Infants, Children, and Adolescents.

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Review human literature on the relationship between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and epigenetic modifications in infants, children, and adolescents < 18years of age. Eleven studies were identified, with study populations located in the U.S., Taiwan, Japan, and the Kingdom of Denmark. Many studies (n = 5) were cross-sectional, with PFAS exposure and epigenetic outcomes measured in the same tissue collected at delivery via cord blood or dried newborn blood spots. The other six studies were prospective, with prenatal PFAS measured on maternal blood during pregnancy and DNA methylation (DNAm) assessed in cord blood and childhood peripheral leukocytes (n = 1 study). Epigenetic marks of interest included global DNAm measures (LINE-1, Alu, and an ELISA-based method), candidate genes (IFG2, H19, and MEST), and epigenome-wide DNA methylation via array-based methods (Infinium 450K and EPIC). Two studies using array-based methods employed discovery and validation paradigms, in which a small subset of loci (n = 6 and n = 4) were replicated in the discovery population. One site (TNXB) was a hit in two independent studies. Collectively, loci associated with PFAS were in regions involved in growth and development, lipid metabolism, and nutrient metabolism. There is moderate human evidence supporting associations of prenatal PFAS exposure on DNAm at birth, with one study suggesting sustained effects into childhood. Future studies are warranted to link PFAS-associated DNAm to health outcomes, as well as to investigate the role of other epigenetic marks such as hydroxymethylation, miRNA expression, and histone modifications.