Associations between Serum Perfluoroalkyl Acids and LINE-1 DNA Methylation in a Highly Exposed Population

Abstract

Background: Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been associated with cardiovascular risk factors, as well as changes in gene expression and DNA methylation in animal and cellular systems. LINE-1 methylation, a measure of global DNA methylation, is also associated with cardiovascular risk factors and disease. Aims: To evaluate associations between serum perfluoroalkyl acids (PFAAs) and LINE-1 DNA methylation in a population highly exposed to PFOA. Methods: We measured serum PFAAs in a subset of adult participants in a community population highly exposed to industrial contaminants in Ohio/West Virginia at study enrollment (2005-2006) and during participation in two follow-up studies (2010-2011). Quantitative bisulfite pyrosequencing was used to measure LINE-1 DNA methylation in peripheral blood leukocytes at follow-up. Associations were expressed as predicted absolute differences in LINE-1 methylation for an interquartile shift in PFAA serum levels at enrollment and follow-up, stratified by gender. Results: Consistent with previous research, women had on average 0.47% lower LINE-1 methylation compared to men (p=<0.0001). Serum PFOA, PFNA, and PFHxS measured at enrollment were not associated with LINE-1 methylation after adjustment for covariates. Among men, an IQR difference in serum PFOA at follow-up was marginally associated with 0.09% lower LINE-1 methylation (p=0.06). In contrast, an IQR difference in serum PFOS at follow-up was associated with 0.42% and 0.31% higher LINE-1 methylation among men and women respectively (p=0.03; p=0.04). Associations with PFOS measured at enrollment were weaker (men 0.16%, p=0.02; women 0.07%, p=0.33). Conclusions: Exposure to PFOS and possibly PFOA is associated with changes in LINE-1 methylation, suggesting that these compounds may be epigenetically active. More research is needed to replicate these findings and to more precisely determine the role of epigenetics in the etiology of PFAA -related outcomes.