Background: Exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous and has been associated with an increased risk of several cardiometabolic diseases. However, the metabolic pathways linking PFAS exposure and human disease are unclear. Objective: We examined associations of PFAS mixtures with alterations in metabolic pathways in independent cohorts of adolescents and young adults. Methods: Three hundred twelve overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) and 137 young adults from the Southern California Children’s Health Study (CHS) were included in the analysis. Plasma PFAS and the metabolome were determined using liquid-chromatography/high-resolution mass spectrometry. A metabolome-wide association study was performed on log-transformed metabolites using Bayesian regression with a g-prior specification and g-computation for modeling exposure mixtures to estimate the impact of exposure to a mixture of six ubiquitous PFAS (PFOS, PFHxS, PFHpS, PFOA, PFNA, and PFDA). Pathway enrichment analysis was performed using Mummichog and Gene Set Enrichment Analysis. Significance across cohorts was determined using weighted -tests. Results: In the SOLAR and CHS cohorts, PFAS exposure was associated with alterations in tyrosine metabolism (meta-analysis ) and de novo fatty acid biosynthesis ( ), among others. For example, when increasing all PFAS in the mixture from low ( th percentile) to high ( th percentile), thyroxine (T4), a thyroid hormone related to tyrosine metabolism, increased by 0.72 standard deviations (SDs; equivalent to a standardized mean difference) in the SOLAR cohort (95% Bayesian credible interval (BCI): 0.00, 1.20) and 1.60 SD in the CHS cohort (95% BCI: 0.39, 2.80). Similarly, when going from low to high PFAS exposure, arachidonic acid increased by 0.81 SD in the SOLAR cohort (95% BCI: 0.37, 1.30) and 0.67 SD in the CHS cohort (95% BCI: 0.00, 1.50). In general, no individual PFAS appeared to drive the observed associations. Discussion: Exposure to PFAS is associated with alterations in amino acid metabolism and lipid metabolism in adolescents and young adults. https://doi.org/10.1289/EHP11372
The exposome, which is defined as the cumulative effect of environmental exposures and corresponding biological responses, aims to provide a comprehensive measure for evaluating non-genetic causes of disease. Operationalization of the exposome for environmental health and precision medicine has been limited by the lack of a universal approach for characterizing complex exposures, particularly as they vary temporally and geographically. To overcome these challenges, passive sampling devices (PSDs) provide a key measurement strategy for deep exposome phenotyping, which aims to provide comprehensive chemical assessment using untargeted high-resolution mass spectrometry for exposome-wide association studies. To highlight the advantages of silicone PSDs, we review their use in population studies and evaluate the broad range of applications and chemical classes characterized using these samplers. We assess key aspects of incorporating PSDs within observational studies, including the need to preclean samplers prior to use to remove impurities that interfere with compound detection, analytical considerations, and cost. We close with strategies on how to incorporate measures of the external exposome using PSDs, and their advantages for reducing variability in exposure measures and providing a more thorough accounting of the exposome. Continued development and application of silicone PSDs will facilitate greater understanding of how environmental exposures drive disease risk, while providing a feasible strategy for incorporating untargeted, high-resolution characterization of the external exposome in human studies.
Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of Alzheimer's disease (AD), a disease also associated with hyperphosphorylated tau (p-tau) protein aggregation. We investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans using a transgenic strain that expresses human tau protein prone to aggregation by measuring changes in size, swim behavior, respiration, lifespan, learning, and metabolism. In addition, we examined the association between cerebrospinal fluid (CSF) p-tau protein – as a marker of post-mortem tau burden – and global metabolism in both a human population study and in C. elegans, using the same p-tau transgenic strain. From the human population study, plasma and CSF-derived metabolic features associated with p-tau levels were related to drug, amino acid, fatty acid and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of p-tau protein on growth and basal respiration. In the presence of p-tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Our findings in C. elegans indicate that DDT exposure and p-tau aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of p-tau aggregation. Further, biological pathways associated with exposure to DDT and the pathogenic Alzheimer's protein appear to be conserved between species.
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