Effects of Per- and Polyfluoroalkyl Substances (PFAS) Exposure Reduction on Serum Lipids in the Copenhagen City Heart Study: A Protocol for an Observational Cohort Study Emulating a Target Trial
Aug 2026· Toxics· Vol 14, pp. 722· 0 citations· 32 references
Medicine
TL;DR
This protocol explores applying the target trial emulation framework to improve causal inference in environmental epidemiology by emulating a target trial of a hypothetical PFAS-reduction intervention using observational data from the Copenhagen City Heart Study.
Abstract
Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants associated with higher serum lipids, although primarily in cross-sectional studies, limiting causal inference. We aim to determine whether there is a causal relationship between PFAS and serum lipid levels by emulating a target trial of a hypothetical PFAS-reduction intervention using observational data. The target trial would enroll adults aged ≥20 years without prior cardiovascular, kidney, or liver disease, diabetes, or use of related medications. Participants would be randomly assigned to either PFAS-reduction counseling or no counseling, with adherence evaluated after 10 years, and then followed up after 10 years to assess effects on serum lipids. To emulate the target trial, we will use data from the Copenhagen City Heart Study on three successive clinical visits: baseline, follow-up, and outcome assessment visit, 10 years apart. Eligible participants meet the target trial criteria, have available blood samples for PFAS quantification at follow-up, and information on serum lipids at the outcome assessment. Intervention strategies will be evaluated based on observed reductions in PFAS concentrations between baseline and follow-up visit. Serum lipids are assessed at the outcome assessment visit. The emulation assumes exchangeability by adjusting for baseline and time-varying confounders using G-computation. This protocol explores applying the target trial emulation framework to improve causal inference in environmental epidemiology.
The findings suggest that exposure to low levels of some alternative and precursor PFAS may be widespread in Canada and reinforce the role of pregnancy and breastfeeding as excretion pathways for legacy PFAS and support previous investigations demonstrating that exposure to some PFAS may be lower amongst financially disadvantaged populations.
M. Borghese, Rebecca Lelievre, Sara Packull-McCormick et al.· Environmental Health· 0 citations
It is suggested that mixed PFAS exposure, particularly to PFOA and PFHpA, may induce impaired renal function, with increased blood lipids playing an important mediating role.
Dandan Xu, Z. Mo, Jie Xiang et al.· Environmental Pollution· 0 citations
Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals detected in populations, including children, through exposure from food, drinking water, and consumer products. Although growing evidence links PFAS exposure to altered pediatric lipid profiles, few longitudinal studies have determined whether developmental timing during early childhood is more strongly associated with lipid alterations than exposure magnitude.
Serum PFAS concentrations and lipid levels, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), were measured in 212 children from the Environment and Development of Children cohort at ages 2, 4, 6, and 8 years. Generalized additive mixed models (GAMMs) characterized longitudinal dose–response relationships, tested whether associations varied by exposure age, and whether baseline concentrations at age 2 years were associated with lipid trajectories from ages 2 to 8 years. Age-specific linear regression models (lagged and concurrent) and quantile-based g-computation (q-gcomp) were used to estimate age-specific associations and joint effects of the PFAS mixture on lipid levels at age 8 years.
In age-pooled GAMMs at ages 2, 4, 6, and 8 years, exposure-response relationships varied in both shape and direction across PFAS compounds for all lipid outcomes, including linear, non-linear and inverse patterns. Baseline PFAS concentrations at age 2 years were not associated with the rate of age-related change in any lipid outcome from ages 2 to 8 years. By contrast, in age-specific regression models evaluating lipid levels at age 8 years, higher HDL-C was associated with PFAS exposure at ages 6 and 8 years, and most associations remained significant after false discovery rate correction. In q-gcomp analyses, the PFAS mixture was positively associated with HDL-C at age 8 years for exposures measured at ages 6 and 8 years.
In age-specific analysis, childhood PFAS exposure was associated with higher HDL-C concentrations, and the strength of this association varied by exposure age rather than corresponding directly to exposure magnitude. These findings suggest that developmental timing should be considered when evaluating the effects of childhood PFAS exposure on blood lipids, and require confirmation in larger longitudinal cohort studies.
Ji-Eun Lee, Dong-Wook Lee, Youn-Hee Lim et al.· Lipids in Health and Disease· 0 citations
Background: This study aimed to assess the effects of a combined vitamin D3 (VD3) and docosahexaenoic acid (DHA) intervention on cognitive function and blood pyroptotic biomarkers in older adults with mild cognitive impairment (MCI). Methods: In total, 360 participants with MCI were recruited, and randomly assigned into four groups: VD3 (800 IU/day), DHA (1 g/day), VD3+DHA (VD3 800 IU/day+DHA 1 g/day), and placebo. Cognitive function was evaluated by the Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC), and blood biomarkers were measured by ELISA and Western blot at baseline, 6 months and 12 months. Linear mixed-effects models (LMMs) were employed to analyze longitudinal interaction effects on cognitive function and blood biomarkers. Structural equation modeling (SEM) was conducted to evaluate the parallel mediation effects of blood biomarkers on cognitive improvements. Results: A total of 355 participants completed the trial. Over the 12-month intervention, all intervention groups demonstrated significant improvements in cognitive function and reductions in five blood biomarkers (IL-1β, IL-18, NLRP3, Gasdermin D (GSDMD), cleaved caspase-1) compared to the placebo group (p < 0.05). Compared to each single intervention, the combined VD3 and DHA intervention yielded superior cognitive improvements in scores for full-scale IQ (FIQ), performance IQ (PIQ), verbal IQ (VIQ) and several subtests (information, comprehension, digit span, vocabulary, picture completion, block design, and picture arrangement), and significantly reduced five blood pyroptotic biomarkers (all p < 0.05). Path analysis revealed that longitudinal GSDMD reduction mediated the improvements in FIQ. Conclusions: A 12-month intervention with VD3, DHA, or their combination significantly improves cognitive function and mitigates pyroptosis, and the combined intervention showed superior benefits, potentially mediated by downregulating the protein GSDMD.
