Metabolic Signatures of Youth Exposure to Mixtures of Per- and Polyfluoroalkyl Substances: A Multi-Cohort Study
- PMID: 36821578
- PMCID: PMC9945578
- DOI: 10.1289/EHP11372
Metabolic Signatures of Youth Exposure to Mixtures of Per- and Polyfluoroalkyl Substances: A Multi-Cohort Study
Abstract
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.
Figures
![Figure is a dot graph with three columns titled Study of Latino Adolescents at Risk, Children’s Health Study, and Meta-analysis. There are five groups of pathways, named Other, which includes Nitrogen metabolism and Drug metabolism-cytochrome P 450; Metabolism of cofactors and vitamins, including Vitamin B6 (pyridoxine) metabolism and Porphyrin metabolism; Lipid metabolism, including Linoleate metabolism, Fatty acid metabolism, anti-inflammatory metabolism from Eicosapentaenoic acid, Prostaglandin formation from Arachidonate, and De novo fatty acid biosynthesis; Nonaromatic amino acid metabolism, including Lysine metabolism, Arginine and Proline metabolism, Urea cycle or amino group metabolism, and Glutathione metabolism; and Aromatic amino acid metabolism, including Tyrosine metabolism (y-axis) across negative log uppercase p, ranging from 0 to 6 in increments of 2 (x-axis) for analysis, individual cohort analysis, and meta-analysis, respectively.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9945578/bin/ehp11372_f1.gif)
![Figure 2A is a coefficient plot titled Study of Latino Adolescents at Risk, plotting Thyroid hormone biosynthesis, including Thyroxine; Phenylalanine metabolism, including Phenylacetylglutamine, Phenylacetaldehyde, and Hippuric acid; Tyrosine metabolism and degradation, including Acetoacetic acid, 4-Hydroxyphenylacetaldehyde, Pyruvic acid, L-Glutamic acid, and Tyramine-O-sulfate; Catecholamine biosynthesis and degradation, including Homovanillin, Vanylglycol, 1,2-Dehydrosalsolinol, 3-O-Methyldopa, 3-Methoxytyramine, Norepinephrine, Norepinephrine sulfate, Metanephrine, and ascorbate (y-axis) across Per- and polyfluoroalkyl substances mixture effect uppercase psi (95 percent Bayesian credible interval), ranging from negative 1 to 3 in unit increments (x-axis) for Same direction of association in Study of Latino Adolescents at Risk and Children’s Health Study, Only significant in one cohort, and Opposite direction of association in Study of Latino Adolescents at Risk versus Children’s Health Study. Figure 2B is a coefficient plot titled Children’s Health Study, plotting Melanin biosynthesis, including Dopaquinone; Thyroid hormone biosynthesis, including Thyroxine; Phenylalnine metabolism, including Hippuric acid; Tyrosine metabolism and degradation, including L-Glutamic acid and Acetoacetic acid; and Catecholamine biosynthesis and degradation, including Vanylglycol and Homovanillic acid (y-axis) across Per- and polyfluoroalkyl substances mixture effect uppercase psi (95 percent Bayesian credible interval), ranging from negative 1 to 3 in unit increments (x-axis) for Same direction of association in Study of Latino Adolescents at Risk and Children’s Health Study, Only significant in one cohort, and Opposite direction of association in Study of Latino Adolescents at Risk versus Children’s Health Study.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9945578/bin/ehp11372_f2.gif)
![Figure 3A is a coefficient plot titled Study of Latino Adolescents at Risk, plotting Putative anti-inflammatory metabolites formation from Eicosapentaenoic acid, including Leukotriene C 5 and 15 Keto-prostaglandin E 2; Prostaglandin formation from Arachidonate, including Arachidonic acid and Prostaglandin E 2; Linoleate metabolism, including (E)-4-Hyfroxynon-2-enal, 12,13-Epoxy-9-alkoxy-10 E-octadecenoate, Lysophosphatidylcholines (18 to 1(9 Z)), Pelargonic acid, 13(S)-Hydroperoxyoctadecatrienoic acid, 13-Octadecanienoic acid, and Linoleic acid; Fatty acid metabolism, including Glycerol; and De novo fatty acid biosynthesis, including Elaidic acid and Dodecanoic acid (y-axis) across Per- and polyfluoroalkyl substances mixture effect uppercase psi (95 percent Bayesian credible interval), ranging from negative 1 to 2 in unit increments (x-axis) for Same direction of association in Study of Latino Adolescents at Risk and Children’s Health Study and Only significant in one cohort. Figure 3B is a coefficient plot titled Children’s Health Study, plotting Prostaglandin formation from Arachidonate, including Arachidonic acid and 11-Hydroxyeicosatetraenoate glyceryl ester, and De novo fatty acid biosynthesis, including Docosahexaenoic acid and Behenic acid (y-axis) across per- and polyfluoroalkyl substances mixture effect uppercase psi (95 percent Bayesian credible interval), ranging from negative 1 to 2 in unit increments (x-axis) for Same direction of association in Study of Latino Adolescents at Risk and Children’s Health Study and Only significant in one cohort.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9945578/bin/ehp11372_f3.gif)
![Figure 4A is a coefficient plot titled Study of Latino Adolescents at Risk, plotting Urea cycle, including N-acetylornithine; Lysine metabolism, including L-Carnitine, Aminoadipic acid, 6-Amino-2-oxohexanoate; and Arginine and proline metabolism, including Aspartic acid, 5-Amino-2-oxopentanoic acid, Citrulline, and N-Acetylputrescine (y-axis) across Per- and polyfluoroalkyl substances mixture effect uppercase psi (95 percent Bayesian credible interval), ranging from negative 1 to 2 in unit increments (x-axis) for Same direction of association in Study of Latino Adolescents at Risk and Children’s Health Study and Only significant in one cohort. Figure 4B is a coefficient plot titled Children’s Health Study, plotting Lysine metabolism, including 3-Dehydroxycarnitine and Aminoadipic acid; and Arginine and proline metabolism, including 5 prime-Methylthioadenosine (y-axis) across Per- and polyfluoroalkyl substances mixture effect uppercase psi (95 percent Bayesian credible interval), ranging from negative 1 to 2 in unit increments (x-axis) for Same direction of association in Study of Latino Adolescents at Risk and Children’s Health Study and Only significant in one cohort.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9945578/bin/ehp11372_f4.gif)
![Figure 5 is a coefficient plot, plotting Vitamin B 6 (pyridoxine) metabolism, including 4-Pyridoxic acid and Pyridoxamine and porphyrin metabolism, including Biliverdin and Bilirubin (y-axis) across Per- and polyfluoroalkyl substances mixture effect uppercase psi (95 percent Bayesian credible interval), ranging from negative 1 to 2 in unit increments (x-axis) for Only significant in one cohort.](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/9945578/bin/ehp11372_f5.gif)
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