Perfluoroalkyl substances, metabolomic profiling, and alterations in glucose homeostasis among overweight and obese Hispanic children: A proof-of-concept analysis

Abstract

Objective: To examine the prospective associations between exposure to perfluoroalkyl substances (PFASs) and longitudinal measurements of glucose metabolism in high-risk overweight and obese Hispanic children.

Methods: Forty overweight and obese Hispanic children (8-14 years) from urban Los Angeles underwent clinical measures and 2-hour oral glucose tolerance tests (OGTT) at baseline and a follow-up visit (range: 1-3 years after enrollment). Baseline plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and the plasma metabolome were measured by liquid-chromatography with high-resolution mass spectrometry. Multiple linear regression models were used to assess the association between baseline PFASs and changes in glucose homeostasis over follow-up. A metabolome-wide association study coupled with pathway enrichment analysis was performed to evaluate metabolic dysregulation associated with plasma PFASs concentrations. We performed a structural integrated analysis aiming to characterize the joint impact of all factors and to identify latent clusters of children with alterations in glucose homeostasis, based on their exposure and metabolomics profile.

Results: Each ln (ng/ml) increase in PFOA and PFHxS concentrations was associated with a 30.6 mg/dL (95% CI: 8.8-52.4) and 10.2 mg/dL (95% CI: 2.7-17.7) increase in 2-hour glucose levels, respectively. A ln (ng/ml) increase in PFHxS concentrations was also associated with 17.8 mg/dL increase in the glucose area under the curve (95% CI: 1.5-34.1). Pathway enrichment analysis showed significant alterations of lipids (e.g., glycosphingolipids, linoleic acid, and de novo lipogenesis), and amino acids (e.g., aspartate and asparagine, tyrosine, arginine and proline) in association to PFASs exposure. The integrated analysis identified a cluster of children with increased 2-h glucose levels over follow up, characterized by increased PFAS levels and altered metabolite patterns.

Conclusions: This proof-of-concept analysis shows that higher PFAS exposure was associated with dysregulation of several lipid and amino acid pathways and longitudinal alterations in glucose homeostasis in Hispanic youth. Larger studies are needed to confirm these findings and fully elucidate the underlying biological mechanisms.

Keywords: Children; Glucose metabolism; Metabolomics; Perfluoroalkyl substances; Type 2 diabetes.

Fig. 1.

Associations between plasma polyfluoroalkyl substances (PFASs) concentrations and change in measures of glucose homeostasis. Effect sizes (β) and p values shown were adjusted for sex, baseline social position (categorical), pubertal status (categorical), baseline outcome, as well as baseline and change in age and body fat percent at follow-up.

Fig. 2.

Metabolite features significantly altered in association with PFASs plasma concentrations. Y axis represents the negative log₁₀P for correlation of each metabolite feature with (A) PFOA, (B) PFOS and (C) PFHxS. X axis represents each metabolite in the function of retention time. Models adjusted for baseline age, sex, and social position (categorical). Metabolites above the dashed horizontal line and solid green line were significant at FDR < 20% and p < 0.05, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3.

Metabolic pathways associated with plasma PFASs concentrations. The vertical axis represents the pathways (blue circles) with circle radius representing the numbers of associated metabolite features, and horizontal axis represents the negative log₁₀ (p-value) of each pathway. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4.

Structural integrated analysis of PFASs plasma concentrations and individual metabolites for the identification of a subgroup of children with increased risk for developing type 2 diabetes. The thick blue line connecting “PFASs exposure” to “Cluster 2” indicates positive association, while thin blue line serves as the reference group. The blue lines connecting “Cluster” to metabolites suggest positive associations and grey lines suggest negative associations. The red line connecting “Cluster 2” and “Increased change in 2-hr glucose levels” represents that children in the latent “Cluster 2” were at higher risk for developing type 2 diabetes (OR = 8.63), compared to those in “Cluster 1” (reference). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)