Dataset Information

Can Blood Proteome Diversity Among Fish Species Help Explain Perfluoroalkyl Acid Trophodynamics in Aquatic Food Webs?

ABSTRACT: Per- and polyfluoroalkyl substances (PFAS) are a diverse family of industrially significant synthetic chemicals infamous for extreme environmental persistence and global environmental distribution. Many PFAS are bioaccumulative and biologically active mainly due to their tendency to bind with various proteins. These protein interactions may be the most important element in determining the accumulation potential and tissue distribution of individual PFAS. Trophodynamics studies including aquatic food webs present inconsistent evidence for PFAS biomagnification. This study strives to identify whether the observed variability in PFAS bioaccumulation potential among species could correspond with interspecies protein composition differences. Specifically, this work compares the perfluorooctane sulfonate (PFOS) serum protein binding potential and the tissue distribution of ten perfluoroalkyl acids (PFAAs) detected in alewife (Alosa pseudoharengus), deepwater sculpin (Myoxocephalus thompsonii), and lake trout (Salvelinus namaycush) of the Lake Ontario aquatic piscivorous food web. To identify interspecies differences in PFAS-binding serum proteins, fish sera were pre-equilibrated with PFOS, fractionated by serial molecular weight cut-off filter fractionation, followed by liquid chromatography–tandem mass spectrometry analysis of the tryptic protein digests and the PFOS extracts of each fraction. This workflow identified similar serum proteins for all fish species. However, serum albumin was only identified in lake trout, suggesting apolipoproteins are likely the primary PFAA transporters in alewife and deepwater sculpin sera. PFAA tissue distribution analysis provided supporting evidence for interspecies variations in lipid transport and storage, which may also contribute to the varied PFAA accumulation in these species.

INSTRUMENT(S): Xevo G2 Q-Tof

ORGANISM(S): Alosa Pseudoharengus Salvelinus Namaycush Myoxocephalus Thompsonii

TISSUE(S): Blood Serum

SUBMITTER: Adam Point

LAB HEAD: Costel C. Darie

PROVIDER: PXD039145 | Pride | 2023-03-11

REPOSITORIES: Pride

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Publications

Can blood proteome diversity among fish species help explain perfluoroalkyl acid trophodynamics in aquatic food webs?

Point Adam D AD Crimmins Bernard S BS Holsen Thomas M TM Fernando Sujan S Hopke Philip K PK Darie Costel C CC

The Science of the total environment 20230226

Per- and polyfluoroalkyl substances (PFAS) are a diverse family of industrially significant synthetic chemicals infamous for extreme environmental persistence and global environmental distribution. Many PFAS are bioaccumulative and biologically active mainly due to their tendency to bind with various proteins. These protein interactions are important in determining the accumulation potential and tissue distribution of individual PFAS. Trophodynamics studies including aquatic food webs present in ...[more]

PMID: 36848995

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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:The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recent human and environmental health concern. There is a persistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is a relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, there have been no mechanistic studies to date cancerning PFAS and TGCTs. In this report, the effects of the legacy PFAS, perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS, lithium bis(trifluoromethylsulfonyl)imide (LiTFSi and called HQ-115) on TGCT tumorigenicity, survival, metabolism, and gene regulation were investigated. In vitro, proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide concentration range of PFOS and HQ-115. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistenet with human exposure but had minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptiomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression altersations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways were previously shown to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar pattersn of PFOS-mediated gene expression occured in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associiated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acied based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, this first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.

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.

Dataset Information

Can Blood Proteome Diversity Among Fish Species Help Explain Perfluoroalkyl Acid Trophodynamics in Aquatic Food Webs?

Publications

Can blood proteome diversity among fish species help explain perfluoroalkyl acid trophodynamics in aquatic food webs?

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