Internal Exposure to Legacy Per- and Polyfluoroalkyl Substances (PFAS) and Changes in Blood Lipoprotein Profiles in the General Population: A Systematic Review and Meta-Analysis

Per- and polyfluoroalkyl substances (PFASs) may be linked with increased human blood lipid levels. However, associations are inconsistent, which could be due to spatiotemporal changes in the exposure-response association. This meta-analysis summarized associations between PFAS and blood lipids stratified by region-specific regulatory phase-outs. PubMed and Scopus were searched for articles published through December 31, 2025, investigating associations between four legacy PFAS (PFOA, PFOS, PFHxS, and PFNA) and blood lipids (total cholesterol (TC), HDL, LDL, TG, TC/HDL). Secondary outcomes included hypercholesterolemia, hypertriglyceridemia, and above-threshold lipid levels. Estimates were re-expressed as mg/dL changes per 1 ng/mL PFAS increase and pooled via the generic inverse variance method. Subgroup analyses included age group, general versus high, pre- versus postnatal exposure, and region-specific regulatory phases, complemented by temporal meta-regressions using the study sampling midpoint year. Of 133 studies selected via systematic review, 89 were included in the meta-analysis. In the pooled analysis, all four PFAS compounds showed statistically significant associations with increased levels of TC, HDL, and LDL. Effect sizes decreased over time for PFOA but increased for PFOS, a trend confirmed by a significantly positive meta-regression slope for PFOS and LDL. PFOS, PFHxS, and PFNA were associated with increased odds of hypercholesterolemia and above-threshold LDL levels. PFNA, showing the strongest overall effects on blood lipids, was also linked to increased odds of below-threshold HDL levels. Legacy PFAS exposure is associated with altered blood lipid profiles, but temporal variation suggests that pooling estimates may not fully reflect contemporary exposure-response relationships. These findings warrant further investigation of time-sensitive exposure-response dynamics.