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SRM PFAS NTA Data Agilent Revident Q-TOF: Expanding PFAS Coverage in Non-Targeted Analysis Using Data-Independent Analysis and IonDecon with FluoroMatch Suite

ABSTRACT: non-targeted analysis PFAS data acquired on the state-of-the-art Revident LC Q-TOF for estuarine sediment (BCR667), sewage sludge (ERMCC144), dried sediment from Milwaukee Bay, WI, USA (SRM1936), freeze-dried sediment (SRM1941b), human plasma (SRM1950), organic contaminants in house dust (SRM2585), and domestic sludge (SRM 2781). For SRM 2781 the data goes alongside a manuscript describing the following: All Ions with deconvolution using IonDecon is a complementary approach to use with DDA or intelligent acquisition methods. All Ions improves coverage in complex matrices by providing fragmentation for every feature where fragments can be correlated with precursor ions. It provides coverage of low abundance intensity ions not selected by DDA. Furthermore, it provides isotopic ratios in the fragmentation spectra, which can be used for aiding characterization of unknowns. While IonDecon and All Ions can reduce false negatives, it was also shown to increase false positives, and therefore some issues of All Ions should be understood by the user and accounted for when annotating using All Ions. These include retaining fragments which do not belong to precursor ions, but rather belong to other adducts, dimers, and other correlating compounds. Furthermore, fragment ions may be retained due to false positives, thousands of MS/MS peaks are often included in All Ions spectra, and hence the random chance for a fragment to correlate with a precursor is high. To obtain better spectral quality, more stringent thresholds can be used but these will also increase false negatives. IonDecon also can be used for QRAI data, which may further reduce these issues and can be used in any workflow which requires MS/MS files. As part of an overall workflow, All Ions and IonDecon will improve MS/MS coverage of PFAS molecules. IonDecon will aid in discovering more PFAS present in the environment which will enable the associated health burden to be investigated. This understanding can be used for developing regulations and mitigation strategies for legacy PFAS as well as newly discovered PFAS.

INSTRUMENT(S): Revident Q-TOF (Agilent Technologies), 6546 Q-TOF (Agilent Technologies)

ORGANISM(S): Na

SUBMITTER: Krystal G. Pollitt Jeremy Koelmel Olivier Chevallier John A. Bowden

PROVIDER: MSV000092698 | MassIVE | Sat Aug 19 09:05:00 BST 2023

REPOSITORIES: MassIVE

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Project description:Per- and polyfluoroalkyl substances (PFAS) are some of the most prominent organic contaminants in human blood that have the potential to disrupt biological processes and pathways in the liver. Although the toxicological implications from human exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are well established, data on other, lesser-understood PFAS are limited. A challenge for regulatory authorities is to determine acceptable levels of human exposure to large, diverse classes of environmental contaminants. New approach methodologies (NAMs) that apply bioinformatics tools to interpret biological data are being increasingly considered to inform risk assessment when traditional toxicology methodologies are not amenable. The aim of the current investigation was to identify the biological responses relevant to PFAS mode of action as the concentration (benchmark dose) that these effects take place in order to utililze this information to inform/facilitate read-across for risk assessment of data-poor PFAS. A TempO-Seq platform (BioSpyder) measured gene expression changes in human liver microtissues (i.e., spheroids) after 1-day and 10-day exposures to increasing concentrations of PFAS. A bioinformatics framework was applied to 23 PFAS sub-classed into carboxylates (PFCAs), sulfonates (PFSAs), or PFAS precursors that were analyzed for the total altered transcripts, the concentration where effects take place, and identifying target genes of interest. Both PFCAs and PFSAs exhibited a trend toward increased transcriptional changes with carbon chain-length. Specifically, longer-chain compounds (7 to 10 carbons) were more likely to surpass liver-toxic transcriptomic thresholds established from previous studies than shorter chain PFAS. Longer-chain PFAS were also more potent, inducing transcriptional effects at lower concentrations. However, PFOS was the most potent PFAS and of all precursors, only PFOSA (a PFOS precursor) induced a response. The combined high-throughput transcriptomic and bioinformatics analyses revealed the capability of NAMs to assess the effects of PFAS in liver microtissues; such data improves our understanding of PFAS-related effects in humans and facilitates the use of read-across in human health risk assessment for other data-poor chemicals.

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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SRM PFAS NTA Data Agilent Revident Q-TOF: Expanding PFAS Coverage in Non-Targeted Analysis Using Data-Independent Analysis and IonDecon with FluoroMatch Suite

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