Plasma per- and polyfluoroalkyl substance (PFAS) concentrations in mid-childhood and associations with DNA methylation and epigenetic aging through early adolescence.

Background

Per- and polyfluoroalkyl substances (PFAS) are widespread synthetic chemicals. PFAS exposure in early life has previously been associated with DNA methylation (DNAm) variation. However, limited studies have examined associations of childhood PFAS exposure with DNAm in childhood or adolescence.

Objective

We examined associations of mid-childhood plasma PFAS concentrations with mid-childhood leukocyte DNAm and epigenetic age acceleration, and whether associations were similar in early adolescence.

Methods

In participants from the Project Viva prospective cohort in eastern Massachusetts, we measured six PFAS in mid-childhood plasma and leukocyte DNAm in mid-childhood [n=403; mean (range) 7.87 years (6.67, 10.52 years), HumanMethylation450 BeadChip] and early adolescence [n=376; mean (range) 13.04 years (12.01, 16.59 years), Infinium HumanMethylationEPIC BeadChip]. There were 263 participants that overlapped in each analysis. For each mid-childhood PFAS, we tested for differentially methylated positions (DMPs) using robust linear models and performed sex-stratified analyses. Bonferroni-significant DMPs in mid-childhood were evaluated in early adolescence. We also calculated epigenetic age acceleration (EAA) for the Horvath pan-tissue, intrinsic, and skin and blood clocks at both timepoints. We examined associations of each PFAS with EAA in mid-childhood and early adolescence using adjusted linear models.

Results

PFOS was associated with lower methylation of cg02852436 (located in FAM113A and VPS16) and PFDA was associated with higher methylation of cg26619099. PFHxS was associated with lower methylation of cg04462567 (located in PITPNM3) and cg20386705 (located in BTBD9) and higher methylation of cg07527909 (located in LMF1). Associations between PFHxS and cg04462567 were also observed in early adolescence. In sex-stratified analyses, 28 CpG sites in females and 22 CpG sites in males passed Bonferroni significance, with no overlap. Higher PFOS and PFHxS concentrations were associated with lower skin and blood EAA [β= -0.02 years, 95% confidence interval (CI)= -0.04, -0.00 for both] in mid-childhood.

Conclusions

Mid-childhood exposures to PFAS were associated with few DNAm and epigenetic age variation in mid-childhood, with limited evidence of similar associations in early adolescence. Future work should focus on longitudinal analyses examining associations between PFAS and epigenetic differences at different time points of development.