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PFAS Biotransformation Products: AFFF, AFFF-fed mice liver and urine, PFAS Chemical standards, and Mouse enzyme treated PFAS chemical standards

ABSTRACT: This Agilent QTOF data consists of urine and liver of mice fed AFFF, as well as PFAS chemical standards treated with mouse enzymes for biotransformation. Data acquired by Sheng Liu and David A. Dukes. It goes alongside the manuscript: "Expanding PFAS Identification with Transformation Product Libraries: Non-Targeted Analysis Reveals Biotransformation Products in Mice" published in Environmental Science & Technology An interactive dataset after FluoroMatch annotation for the urine data can be found here: https://innovativeomics.com/datasets/non-targeted-pfas-dataset-from-urine-of-afff-fed-mice/ Software with the biotransformation libraries can also be found at: https://innovativeomics.com Per- and polyfluoroalkyl substances (PFAS) are widely used persistent synthetic chemicals that have been linked to adverse health effects. While the behavior of PFAS has been evaluated in the environment, our understanding of reaction products in mammalian systems is limited. This study identified biological PFAS transformation products and generated mass spectral libraries to facilitate automated search and identification. The biological transformation products of 27 PFAS, spanning 5 chemical subclasses (alcohols, sulfonamides, carboxylic acids, ethers, and esters), were evaluated following enzymatic reaction with mouse liver S9 fractions. Four major pathways were identified by liquid chromatography-high resolution mass spectrometry: glucuronidation; sulfation; dealkylation and oxidation. Class-based fragmentation rules and associated PFAS transformation product libraries were generated and integrated into an automated non-targeted PFAS data analysis software (FluoroMatch). Fragmentation was additionally predicted for the potential transformation products of more than 2,500 PFAS in the EPA CompTox Chemicals Dashboard PFASSTRUCTv4. Generated mass spectral libraries were validated by applying FluoroMatch to a dataset of urine from aqueous film-forming foam (AFFF)-dosed mice. Toxicity predictions showed identified PFAS transformation products as potential developmental and mutagenic toxicants. This research enables more comprehensive PFAS characterization in biological systems which will improve assessment of exposures and evaluation of the associated health impacts.

INSTRUMENT(S): 6545 Q-TOF LC/MS

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Krystal G. Pollitt Jeremy Koelmel David Dukes Sheng Liu Carrie A McDonough

PROVIDER: MSV000095980 | MassIVE |

REPOSITORIES: MassIVE

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Project description:This Agilent QTOF data consists of urine and liver of mice fed AFFF, as well as PFAS chemical standards treated with mouse enzymes for biotransformation. Data acquired by Sheng Liu and David A. Dukes. It goes alongside the manuscript: "Expanding PFAS Identification with Transformation Product Libraries: Non-Targeted Analysis Reveals Biotransformation Products in Mice" published in Environmental Science & Technology An interactive dataset after FluoroMatch annotation for the urine data can be found here: https://innovativeomics.com/datasets/non-targeted-pfas-dataset-from-urine-of-afff-fed-mice/ Software with the biotransformation libraries can also be found at: https://innovativeomics.com Per- and polyfluoroalkyl substances (PFAS) are widely used persistent synthetic chemicals that have been linked to adverse health effects. While the behavior of PFAS has been evaluated in the environment, our understanding of reaction products in mammalian systems is limited. This study identified biological PFAS transformation products and generated mass spectral libraries to facilitate automated search and identification. The biological transformation products of 27 PFAS, spanning 5 chemical subclasses (alcohols, sulfonamides, carboxylic acids, ethers, and esters), were evaluated following enzymatic reaction with mouse liver S9 fractions. Four major pathways were identified by liquid chromatography-high resolution mass spectrometry: glucuronidation; sulfation; dealkylation and oxidation. Class-based fragmentation rules and associated PFAS transformation product libraries were generated and integrated into an automated non-targeted PFAS data analysis software (FluoroMatch). Fragmentation was additionally predicted for the potential transformation products of more than 2,500 PFAS in the EPA CompTox Chemicals Dashboard PFASSTRUCTv4. Generated mass spectral libraries were validated by applying FluoroMatch to a dataset of urine from aqueous film-forming foam (AFFF)-dosed mice. Toxicity predictions showed identified PFAS transformation products as potential developmental and mutagenic toxicants. This research enables more comprehensive PFAS characterization in biological systems which will improve assessment of exposures and evaluation of the associated health impacts.

Project description:This is the GC Orbitrap data accompanying the FluoroMatch GC Library manuscript. References and software are available here: https://innovativeomics.com/software/fluoromatch-gc-modular-pfas-annotation/ Despite thousands of documented PFAS, approaches to characterize volatile and semi-volatile PFAS are limited. To address this gap, we developed a non-targeted gas chromatography high-resolution mass spectrometry (GC-HRMS) workflow to extend coverage of volatile and semi-volatile PFAS. This workflow includes new FlouroMatch GC mass spectral libraries (>1900 EI and PCI predicted and experimental spectra) and characterization of thousands of PFAS specific EI fragments for fragment screening. Liquid chromatography (LC) and GC-HRMS approaches were highly complementary, with GC-HRMS revealing diverse PFAS profiles in 8 different environmental and biological matrices distinct from PFAS detected in LC approaches. For example, we detected a previously unreported PFAS, 2-(perfluorohexyl)ethanethiol in multiple firefighting foam (AFFF) formulations and a novel feature tentatively annotated as N-methyl-N-(2-hydroxyethyl) perfluorooctanesulfonamide (MeFOSE alcohol) that was consistently detected in various matrices related to point and non-point PFAS exposures including dried blood spots, leachate, industrial effluent, and settled dust collected from homes, which were not detected in corresponding LC approaches. Personal exposure to volatile and semi-volatile PFAS was found to vary significantly across individuals. In a cohort of 48 children in Connecticut wearing wristband passive samplers, GC-HRMS fragment screening revealed that 46% of 40 unique airborne PFAS detected only occurred in a single child, and 58% of 47 unique PFAS detected in settled dust collected from 11 households were only detected in a single home. Findings highlight the importance of personal monitoring using a combination of non-targeted GC and LC-HRMS approaches to comprehensively characterize PFAS exposures. The novel methods that we have established will allow the health burden PFAS to be rigorously evaluated, ultimately informing regulatory policies and public health interventions.

Project description:Per- and polyfluoroalkyl substances (PFAS) are a very large (thousands of chemicals) category; these substances have important industrial and consumer product applications. PFAS are highly persistent in the environment, and some are known to pose human health hazard. Regulatory agencies worldwide are considering restrictions and outright bans of PFAS; however, little data exists to make informed decisions. Therefore, a prioritization strategy is urgently needed for evaluation of potential hazards of PFAS. Structure-based grouping could expedite selection of PFAS for testing; still, the hypothesis that structure-effect relationships exist requires confirmation. We tested 26 structurally diverse PFAS from 8 groups in two human cell types from organs that are thought to be targets for PFAS. We used human induced pluripotent stem cell-derived hepatocytes and cardiomyocytes and tested concentration-response effects on both cell function and gene expression. Few phenotypic effects were observed in hepatocytes, but negative chronotropy was observed for 8 of 26 PFAS. Substance- and cell-dependent transcriptomic changes were more pronounced; however, little evidence of group-specific effects was observed. In hepatocytes, we found up-regulation of stress-related and extracellular matrix organization pathways, and down-regulation of fat metabolism. In cardiomyocytes, contractility-related pathways were most affected. Using these data, we derived phenotypic and transcriptomic point of departure estimates and compared them to predicted PFAS exposures. The conservative estimates for bioactivity and exposure were used to derive margin-of-exposure (MOE) for each PFAS. We found that most (23 of 26) PFAS had MOE>1. Overall, our data suggests that chemical structure-based grouping of PFAS may not be an appropriate strategy to predict their biological effects. This means that testing of the individual PFAS would be needed for confident decision-making. Our proposed strategy of using two human cell types and considering both phenotypic and transcriptomic effects, combined with dose-response analysis, may be used for prioritization of PFAS.

Project description:Background: Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced changes of enterohepatic circulation may play a critical role in cardiovascular risk. Objectives: Using a mouse model with high LDL-VLDL cholesterol and aortic lesion development similar to humans, the current study investigates mechanisms linking exposure to a PFAS mixture with increased cholesterol. Methods: Male and female Ldlr-/- mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFNA, PFHxS, GenX), each at a concentration of 2 mg/L, for 7 weeks. Blood was collected longitudinally for cholesterol measurements and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA-sequencing. Results: After 7 weeks of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and 1.5 µg/mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7 µg/mL in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. PFAS exposure led to elevated circulating cholesterol levels after 7 weeks compared to vehicle mice, with females increasing 18% and males increasing 24%. Total circulating bile acid levels were elevated in PFAS-exposed mice by 230% in males and 290% in females compared to vehicle. PFAS decreased fecal bile acid levels by 62% in females and 59% in males. In the ileum, expression levels of the bile acid reuptake transporter ASBT were increased due to PFAS exposure. Discussion: Mice exposed to a PFAS mixture display increased circulating cholesterol and bile acids perhaps due to changes in enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk due to PFAS.

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PFAS Biotransformation Products: AFFF, AFFF-fed mice liver and urine, PFAS Chemical standards, and Mouse enzyme treated PFAS chemical standards

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