Persistent environmental pollutants and risk of cardiovascular disease

Persistent chemicals emitted in the environment can have a considerable impact on ecosystems and human health, now and in the future. One notorious group of persistent organic pollutants (POPs) is the per- and polyfluoroalkyl substances (PFAS). Since their production in 1940s for household and consumer products, they have accumulated in the environment and in humans via consumption of contaminated drinking water and food. They are hypothesized to induce metabolic disturbances, due to shared chemical similarities with fatty acids. Consequently, PFAS may have high societal and economic impact by increasing risk of obesity, type 2 diabetes (T2D) and cardiovascular disease (CVD). However, reports on these associations are scarce, and the underlying molecular pathways are still unclear. Therefore, in this PhD project, we aimed to i) investigate associations between PFAS and risk of several cardiometabolic diseases and ii) explore potential underlying pathways.

In Paper I, we investigated cross-sectional associations between PFAS mixtures and body mass index (BMI) in European teenagers using meta-regression. Results showed a tendency for inverse associations between PFAS and BMI and indicated a potential for diverging contributions between PFAS compounds. In Paper II, using a nested casecontrol study on T2D including metabolomics data in Swedish adults, we found that PFAS correlated positively with glycerophospholipids and diacylglycerols. But whilst glycerophospholipids associated with lower T2D risk, diacylglycerols associated with higher T2D risk. This indicates a potential for diverging effects on disease risk. In Paper III, we investigated whether genetic polymorphisms in peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), which encodes a master regulator of pathways potentially disrupted by PFAS exposure, associated with secondary cardiovascular events in a large consortium study. However, we did not find clear evidence for such associations. In Paper IV, we assessed associations of PFAS with blood lipids and incident CVD using case-control studies nested in two Swedish adult cohorts. We observed overall null associations with stroke, but a tendency for inverse associations with myocardial infarction as well as associations with higher HDL-cholesterol and lower triglycerides, but also with higher LDL-cholesterol. In Paper V, we included OMICs data (metabolites, proteins and genes), which linked PFAS to lower myocardial infarction risk via lipid and inflammatory pathways. Likewise, a group of ‘old POPs’, the organochlorine compounds (OCs), were linked to higher myocardial infarction risk via the same pathways and to higher stroke risk via mitochondrial pathways.

Thus, although we found no evidence for associations between PFAS and increased cardiometabolic disease risk, the overall findings indicate associations of PFAS with metabolic disturbances, particularly lipid metabolism. This is a potential adverse effect on human physiology and warrants further attention.

List of scientific papers

I. Schillemans T, Iszatt N, Remy S, Schoeters G, Fernández MF, D’Cruz SC, […], Åkesson A. Cross-sectional associations between exposure to perand polyfluoroalkyl substances and body mass index among European teenagers in the HBM4EU aligned studies. Environmental Pollution. 2022 Nov;316(Pt 1):120566.
https://doi.org/10.1016/j.envpol.2022.120566

II. Schillemans T, Shi L, Donat-Vargas C, Hanhineva K, Tornevi A, Johansson I, Koponen J, Kiviranta H, Rolandsson O, Bergdahl IA, Landberg R, Åkesson A, Brunius C. Plasma metabolites associated with exposure to perfluoroalkyl substances and risk of type 2 diabetes – A nested case-control study. Environment International. 2021 Jan;146:106180.
https://doi.org/10.1016/j.envint.2020.106180

III. Schillemans T, Tragante V, Maitusong B, Gigante B, Cresci S, Laguzzi F, […], Leander K. Associations of polymorphisms in the peroxisome proliferatoractivated receptor gamma coactivator-1 alpha gene with subsequent coronary heart disease: an individual-level meta-analysis. Frontiers of Physiology. 2022 Jun 23;13:909870.
https://doi.org/10.3389/fphys.2022.909870

IV. Schillemans T, Donat-Vargas C, Lindh CH, de Faire U, Wolk A, Leander K, Åkesson A. Per- and Polyfluoroalkyl Substances and Risk of Myocardial Infarction and Stroke: A Nested Case–Control Study in Sweden. Environmental Health Perspectives. 2022 Mar;130(3):37007.
https://doi.org/10.1289/EHP9791

V. Schillemans T, Yan Y, Ribbenstedt A, Donat-Vargas C, Lindh CH, Kivirante H, Wolk A, Landberg R, Åkesson A, Brunius C. OMICs signatures linking persistent organic pollutants to cardiovascular disease in the Swedish Mammography Cohort. [Manuscript]