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Background: Per-and polyfluoroalkyl substances (PFAS) contamination may disrupt sleep through disrupted metabolic and immune functions. The study aims to investigate the association and potential mechanism between PFAS and sleep. Methods: We included 136 young adults recruited between 2014-2018 and 76 were re-assessed between 2020-2022. Additional 8 participants only had complete data between 2020-2022. Plasma PFAS (PFOS, PFOA, PFHxS, PFHpS, PFPeS, PFNA, PFDA) were measured at both visits using liquid-chromatography high-resolution mass spectrometry. Plasma proteins were measured by Olink® Explore 384 Cardiometabolic and Inflammation Panel I. Sleep duration was self-reported at both visits along with follow-up sleep disturbance and sleep-related impairment using validated instruments. We utilized multiple linear regression to explore the association between individual PFAS (in tertile) and these sleep outcomes. PFAS associated with sleep outcomes were subjected to computational toxicology analysis using the Comparative Toxicogenomics Database and Toxicology in the 21st Century database to identify potential genetic links between them. Mediation analysis using proteomic data was then performed to confirm the findings from computational toxicology analysis. Results: At baseline, one tertile increase in PFDA was associated with 0.39 (95 % CI: 0.05, 0.73) hours of shorter nightly sleep duration, and, at follow-up, PFHxS and PFOA were associated with 0.39 (95 % CI: 0.05, 0.72) and 0.32 (95 % CI: 0.01, 0.63) hours shorter sleep duration, respectively. One tertile increase in PFOS exposure was associated with a 2.99-point increase in sleep disturbance scores (95 % CI: 0.67, 5.31) and a 3.35-point increase in sleep-related impairment scores (95 % CI: 0.51, 6.20). Computational toxicology and mediation analyses identified potential mediating roles for several proteins in the PFAS-sleep associations, including 11-beta-dehydrogenase isozyme 1 (HSD11B1), cathepsin B (CTSB) and several immune system-related proteins. Conclusion: Future large scale epidemiological and mechanistic studies should confirm our findings and test effect measure modification of the associations by age.

Background: Strong epidemiological evidence shows positive associations between exposure to per- and polyfluoroalkyl substances (PFAS) and adverse cardiometabolic outcomes (e.g., diabetes, hypertension, and dyslipidemia). However, the underlying cardiometabolic-relevant biological activities of PFAS in humans remain largely unclear. Aim: We evaluated the associations of PFAS exposure with high-throughput proteomics in Hispanic youth. Material and Methods: We included 312 overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) between 2001 and 2012, along with 137 young adults from the Metabolic and Asthma Incidence Research (Meta-AIR) between 2014 and 2018. Plasma PFAS (i.e., PFOS, PFOA, PFHxS, PFHpS, PFNA) were quantified using liquid-chromatography high-resolution mass spectrometry. Plasma proteins (n = 334) were measured utilizing the proximity extension assay using an Olink Explore Cardiometabolic Panel I. We conducted linear regression with covariate adjustment to identify PFAS-associated proteins. Ingenuity Pathway Analysis, protein-protein interaction network analysis, and protein annotation were used to investigate alterations in biological functions and protein clusters. Results: Results after adjusting for multiple comparisons showed 13 significant PFAS-associated proteins in SOLAR and six in Meta-AIR, sharing similar functions in inflammation, immunity, and oxidative stress. In SOLAR, PFNA demonstrated significant positive associations with the largest number of proteins, including ACP5, CLEC1A, HMOX1, LRP11, MCAM, SPARCL1, and SSC5D. After considering the mixture effect of PFAS, only SSC5D remained significant. In Meta-AIR, PFAS mixtures showed positive associations with GDF15 and IL6. Exploratory analysis showed similar findings. Specifically, pathway analysis in SOLAR showed PFOA- and PFNA-associated activation of immune-related pathways, and PFNA-associated activation of inflammatory response. In Meta-AIR, PFHxS-associated activation of dendric cell maturation was found. Moreover, PFAS was associated with common protein clusters of immunoregulatory interactions and JAK-STAT signaling in both cohorts. Conclusion: PFAS was associated with broad alterations of the proteomic profiles linked to pro-inflammation and immunoregulation. The biological functions of these proteins provide insight into potential molecular mechanisms of PFAS toxicity.