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Toxics
2024 Oct 10;1210:. doi: 10.3390/toxics12100732.
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Effects of Perfluorinated Alkyl Substances (PFAS) on Amphibian Body and Liver Conditions: Is Lipid Metabolism Being Perturbed throughout Metamorphosis?
Bushong A
,
Sepúlveda M
,
Scherer M
,
Valachovic AC
,
Neill CM
,
Horn S
,
Choi Y
,
Lee LS
,
Baloni P
,
Hoskins T
.
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Per- and polyfluoroalkyl substances (PFAS) may interact with peroxisome proliferator activated receptors (PPARs) and alter lipid homeostasis. Using Xenopus laevis, we investigated the effect of PFAS on (a) lipid homeostasis and whether this correlated to changes in body and hepatic condition; (b) the expression of hepatic genes regulated by PPAR; and (c) the hepatic lipidome. We chronically exposed tadpoles to 0.5 µg/L of either PFOS, PFHxS, PFOA, PFHxA, a binary mixture of PFOS and PFHxS (0.5 µg/L of each), or a control, from NF stage 52 through metamorphic climax. Growth, development, and survival were not affected, but we detected a sex-specific decrease in body condition at NF 66 (6.8%) and in hepatic condition (16.6%) across metamorphic climax for male tadpoles exposed to PFOS. We observed weak evidence for the transient downregulation of apolipoprotein-V (apoa5) at NF 62 in tadpoles exposed to PFHxA. Acyl-CoA oxidase 1 (acox1) was downregulated only in males exposed to PFHxS (Ln(Fold Change) = -0.54). We detected PFAS-specific downregulation of structural glycerophospholipids, while semi-quantitative profiling detected the upregulation in numerous glycerophospholipids, sphingomyelins, and diglycerides. Overall, our findings indicate that PFAS can induce sex-specific effects that change across larval development and metamorphosis. We demonstrate that PFAS alter lipid metabolism at environmentally relevant concentrations through divergent mechanisms that may not be related to PPARs, with an absence of effects on body condition, demonstrating the need for more molecular studies to elucidate mechanisms of PFAS-induced lipid dysregulation in amphibians and in other taxa.
Figure 1. Marginal mean ± 95% C.I. SHI and HSI for X. laevis exposed to different PFAS (control, PFHxA, PFHxS, PFOA, PFOS, Mix (PFHxS:PFOS)) across NF stages with raw data displayed in the background. Colors indicate NF stage and asterisks (*) indicates a significant difference between the mean of the pooled groups and the control. Moderate and extreme outliers (2 × IQR criterion) excluded. n = 33–36 per PFAS treatment (n = 3–9 per sex/NF stage/PFAS treatment).
Figure 2. Heat map displaying log2 fold change (logFC) for relative ion intensity of hepatic lipid species and signaling molecules by PFAS treatment, using LIMMA with covariate adjustment (spatial block, developmental stage, genetic sex). Shapes represent FDR-adjusted p-values: asterisks, p ≤ 0.05; circle, p ≤ 0.1; square, p ≤ 0.15). Faulty samples identified based on ionization of internal standards and visualization using heatmaps were excluded by lipid class for analysis. n = 22–24 per PFAS treatment (n = 7–8 per NF stage/PFAS treatment).
Figure 3. Heat map displaying log2 fold change (logFC) for semi-quantitative ion intensity (relative to internal standards) of hepatic structural lipid species by PFAS treatment, using LIMMA with covariate adjustment (spatial block, developmental stage, genetic sex). Shapes represent FDR-adjusted p-values: asterisks, p ≤ 0.05; no symbol, p ≤ 0.1). Faulty samples identified based on ionization of internal standards and visualization using heatmaps were excluded in analysis. n = 21–24 per PFAS treatment (n = 5–8 per NF stage/PFAS treatment).
Figure 4. Heat map displaying log2 fold change (logFC) for semi-quantitative ion intensity (relative to internal standards) of hepatic signaling and storage lipid species by PFAS treatment, using LIMMA with covariate adjustment (spatial block, developmental stage, genetic sex). Shapes represent FDR-adjusted p-values: asterisks, p ≤ 0.05; no symbol, p ≤ 0.1). Faulty samples identified based on ionization of internal standards and visualization using heatmaps were excluded in analysis. n = 21–24 per PFAS treatment (n = 6–8 per NF stage/PFAS treatment).
