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Comparative Metabolomics of Short-term Maternal Gestational Exposure of Rats to Emerging Perfluoroalkyl Ether Carboxylic Acids
Citation:
Macmillan, D., J. Ford, L. Gray, AND J. Conley. Comparative Metabolomics of Short-term Maternal Gestational Exposure of Rats to Emerging Perfluoroalkyl Ether Carboxylic Acids. Dioxin 2023, Maastricht, NETHERLANDS, September 10 - 14, 2023. https://doi.org/10.23645/epacomptox.24066012
Impact/Purpose:
These data are improving our understanding of metabolic impact of exposure to per- and polyfluoroalkyl ether carboxylic acids, enabling a more robust risk-based evaluation of a key emerging PFAS group.
Description:
Introduction: As manufacturers of per- and polyfluoroalkyl substances (PFAS) transition to greater use of per- and polyfluoroalkyl substance (PFAS) replacements, a concomitant increase in detection in human serum has occurred. Three emerging PFAS of note include perfluoroalkyl ether carboxylic acids (PFECA) hexafluoropropylene oxide dimer acid (HFPO-DA), perfluoro-3,5,7-butaoxadecanoic acid (PFO4DA), and perfluoro-3,5,7,9,11-pentaoxadecanoic acid (PFO5DoA). The U. S. Environmental Protection Agency (EPA) is conducting toxicity assessments to understand potential risks posed by replacement and legacy PFAS that may threaten human health, especially for vulnerable populations. We previously reported metabolomics of Nafion byproduct (NBP2) compared to HFPO-DA and perfluorooctane sulfonic acid (PFOS) (Conley et al., 2022). Here we report metabolomics results following short-term gestational exposure of rats to PFO4DA and PFO5DoA. Materials and Methods: Pregnant Sprague-Dawley rats were dosed with PFO4DA (0 - 62.5 mg/kg/day) or PFO5DoA (0 - 30 mg/kg/day) by oral gavage from gestational days (GD) 18-22. Maternal serum was collected on GD22, then prepared and analyzed using the Biocrates MxP Quant 500 kit (Biocrates Life Sciences AG, Innsbruck, Austria). Extracts were analyzed on a Sciex (Framingham, MA, USA) 6500+QTRAP. Raw data were processed using Sciex Analyst. Quality control validation was performed using Biocrates MetIDQ software. Data were further processed using MetaboAnalyst. Results: Gestational exposure to PFO5DoA yielded very different dam serum metabolomics results compared to PFO4DA. Statistical analysis of all dose levels using one-way ANOVA with a p value cut-off of 0.05 (False Discovery Rate) indicated no significant metabolite concentration changes for PFO4DA. For PFO5DoA, 181 metabolites were significantly different, including the antioxidant indole-3-propionic acid (3-IPA) (p = 3.09e-7), amino acids tryptophan (p = 0.000318) and 1-methylhistidine (p = 0.000318), bile acid taurochenodesoxycholic acid (TCDCA) (p = 0.00251), and multiple triacylglycerides and cholesterol esters. Significance testing (t test) of the highest dose for each PFECA versus controls showed no differences for PFO4DA and 130 significantly changed metabolite concentrations for PFO5DoA. Fold change analysis revealed greater than 2-fold increase in cholic acid compared to controls for PFO4DoA, with 25 metabolites, including tryptophan, 3-IPA, tauorocholic acid (TCA), and TCDCA decreasing more than 2-fold. Significant increases were observed for 43 metabolites, including cystine, cholic acid, and glycocholic acid, and multiple triglycerides for PFO5DoA high dose exposed serum. PFO5DoA exposure was related to concentration decreases for 81 metabolites, including 3-IPA, tryptophan, and several cholesterol esters and phosphatidylcholines. Discussion and Conclusion: The metabolic changes we observed after gestational exposure suggest biological interactions occur to a different extent for PFO4DA and PFO5DoA. Significant concentration changes were observed for many metabolites after PFO5DoA exposure, clearly differentiating exposed serum from controls. The data suggest dose-related impacts of PFO5DoA exposure on liver function, lipid homeostasis, and oxidative stress response, and less disruption after PFO4DA exposure. Similarly, we previously observed greater metabolic disturbance related to gestational exposure (GD 14-18) to HFPO-DA and PFOS than NBP2. For the PFECAs, the data suggest the rank order of metabolic disruption is PFO5DoA > HFPO-DA > PFO4DA. Disclaimer: The views expressed in this abstract are those of the authors and do not necessarily reflect the views or policies of the U.S. EPA. Mention of trade names is not a recommendation or endorsement.
URLs/Downloads:
DOI: Comparative Metabolomics of Short-term Maternal Gestational Exposure of Rats to Emerging Perfluoroalkyl Ether Carboxylic Acids
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