Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure

Houck, Keith A.; Patlewicz, Grace; Richard, Ann M.; Williams, Antony J.; Shobair, Mahmoud; Smeltz, Marci; Clifton, Matthew S.; Wetmore, Barbara A.; Medvedev, Alexander V.; Makarov, Sergei S.

doi:10.1016/j.tox.2021.152789

Cited by 76 publications

(80 citation statements)

References 83 publications

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“…In addition to enriched biological pathways, we investigated transcription factor enrichment and identified 43 transcription factors that were differentially expressed within our FBSA exposure dataset ( Table S6 ). Among these was Nuclear Factor erythroid-2 (NRF2), previously shown to be activated by various PFAS exposures in HepG2 cell assays ( Houck et al., 2021 ) and to modulate embryonic zebrafish response to PFOS exposure ( Sant et al., 2018 ). Our analysis also identified 191 enriched transcription factors predicted to regulate genes that were differentially expressed within our dataset.…”

Section: Resultsmentioning

confidence: 99%

“…Most notably within this list is Peroxisome Proliferator-Activated Receptor alpha (PPARα), predicted to regulate 36 of the genes disrupted by FBSA exposure. PPARα has been widely associated with PFAS toxicity in the literature, specifically related to the dysfunction of lipid metabolism and liver processes ( Fenton et al., 2021 ; Houck et al., 2021 ). Other transcription factors predicted to regulate FBSA-induced DE-Gs include Retinoid X Receptor alpha (RXRα, 56 DE-Gs) and Aryl Hydrocarbon Receptor (AHR, 54 DE-Gs).…”

Section: Resultsmentioning

confidence: 99%

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Sulfonamide functional head on short-chain perfluorinated substance drives developmental toxicity

et al. 2022

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Summary Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in environmental and biological samples and cause adverse health effects. Studies have predominately focused on long-chain PFAS, with far fewer addressing short-chain alternatives. This study leveraged embryonic zebrafish to investigate developmental toxicity of a short-chain series: perfluorobutane sulfonate (PFBS), perfluoropentanoic acid (PFPeA), perfluorobutane sulfonamide (FBSA), and 4:2 fluorotelomer sulfonic acid (4:2 FTS). Following static exposures at 8 h postfertilization (hpf) to each chemical (1–100 μM), morphological and behavioral endpoints were assessed at 24 and 120 hpf. Only FBSA induced abnormal morphology, while exposure to all chemicals caused aberrant larval behavior. RNA sequencing at 48 hpf following 47 μM exposures revealed only FBSA significantly disrupted normal gene expression. Measured tissue concentrations were FBSA > PFBS > 4:2 FTS > PFPeA. This study demonstrates functional head groups impact bioactivity and bioconcentration.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Sulfonamide functional head on short-chain perfluorinated substance drives developmental toxicity

et al. 2022

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“…To our knowledge, this work describes the first PFAS HTTS using a placental cell line, though prior work has leveraged other cell lines in PFAS HTTS efforts. A subclone of human hepatocellular carcinoma-derived HepG2 cells expressing elevated CYP have been used to test 142 unique PFAS for 81 different transcription factor activities ( Houck et al, 2021 ). This work similarly utilized a 24-h exposure period with exposure concentrations ranging from 0.137 to 300 µM and demonstrated nuclear receptor activation at concentrations lower than 1 µM in some cases ( Houck et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…A subclone of human hepatocellular carcinoma-derived HepG2 cells expressing elevated CYP have been used to test 142 unique PFAS for 81 different transcription factor activities ( Houck et al, 2021 ). This work similarly utilized a 24-h exposure period with exposure concentrations ranging from 0.137 to 300 µM and demonstrated nuclear receptor activation at concentrations lower than 1 µM in some cases ( Houck et al, 2021 ). Taken together with the gene expression results reported here at the 1 and 3 µM exposure level, these data suggest PFAS exposure can initiate molecular events at concentrations considerably lower than those required to perturb functional endpoints at the level of the cell (e.g., migration).…”

Section: Discussionmentioning

confidence: 99%

A High-Throughput Toxicity Screen of 42 Per- and Polyfluoroalkyl Substances (PFAS) and Functional Assessment of Migration and Gene Expression in Human Placental Trophoblast Cells

2022

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Per- and polyfluoroalkyl substances (PFAS) have become ubiquitous environmental contaminants that have been associated with adverse pregnancy outcomes in women and experimental research models. Adverse developmental and reproductive outcomes have been investigated for relatively few PFAS, and such studies are not scalable to address the thousands of unique chemical structures. As the placenta has been reported as a PFAS target tissue, the human placental trophoblast JEG-3 cell line was employed in a high-throughput toxicity screen (HTTS) to evaluate the effects of 42 unique PFAS on viability, proliferation, and mitochondrial membrane potential (MMP). HTTS concentration-response curve fitting determined EC50 values for 79% of tested compounds for at least one of the three endpoints. Trophoblast migratory potential was evaluated for a subset of six prioritized PFAS using a scratch wound assay. Migration, measured as the percent of wound closure after 72 h, was most severely inhibited by exposure to 100 µM perfluorooctanoic acid (PFOA; 72% closure), perfluorooctanesulfonic acid (PFOS; 57% closure), or ammonium perfluoro-2-methyl-3-oxahexanoate (GenX; 79% closure). PFOA and GenX were subsequently evaluated for disrupted expression of 46 genes reported to be vital to trophoblast health. Disrupted regulation of oxidative stress was suggested by altered expression of GPEX1 (300 µM GenX and 3 µM GenX), GPER1 (300 µM GenX), and SOD1 and altered cellular response to xenobiotic stress was indicated by upregulation of the placental efflux transporter, ABCG2 (300 µM GenX, 3 µM GenX, and 100 µM PFOA). These findings suggest the placenta is potentially a direct target of PFAS exposure and indicate that trophoblast cell gene expression and function are disrupted at PFAS levels well below the calculated cytotoxicity threshold (EC50). Future work is needed to determine the mechanism(s) of action of PFAS towards placental trophoblasts.

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“…The most commonly targeted processes include disruption of nuclear receptors including the Constitutive Androstane Receptor (CAR), Peroxisome Proliferator-Activated Receptor α (PPARα), and the Pregnane X Recptor (PXR), as well as pathways governing cell cycle regulation such as p53 signaling (reviewed in [ 33 ]). Other studies in vitro have shown PFAS have affinity for both PPARα and PPARγ, Estrogen Receptor α, and the antioxidant response pathway as regulated by Nrf2 [ 34 ]. Even with increased affinity for these nuclear receptor pathways, another in vitro study has shown that PFAS exposures to hepatic cells reduce expression of phase I and II detoxification enzymes, including cytochrome P450s (1A2, 2C19, and 3A4), glutathione-S-transferase (M1), and UDP-glucuronosyltransferase (1A1) [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Associations between Exposures to Perfluoroalkyl Substances and Diabetes, Hyperglycemia, or Insulin Resistance: A Scoping Review

Margolis

Sant

2021

JoX

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Per- and polyfluoroalkyl substances (PFASs) are persistent environmental pollutants that are commonly found in the human body due to exposures via drinking water, surfactants used in consumer materials, and aqueous film-forming foams (AFFFs). PFAS exposure has been linked to adverse health effects such as low infant birth weights, cancer, and endocrine disruption, though increasingly studies have demonstrated that they may perturb metabolic processes and contribute to dysfunction. This scoping review summarizes the chemistry of PFAS exposure and the epidemiologic evidence for associations between exposure to per- and polyfluoroalkyl substances and the development of diabetes, hyperglycemia, and/or insulin resistance. We identified 11 studies on gestational diabetes mellitus, 3 studies on type 1 diabetes, 7 studies on type 2 diabetes, 6 studies on prediabetes or unspecified diabetes, and 15 studies on insulin resistance or glucose tolerance using the SCOPUS and PubMed databases. Approximately 24 reported positive associations, 9 negative associations, 2 non-linear associations, and 2 inverse associations, and 8 reported no associations found between PFAS and all diabetes search terms. Cumulatively, these data indicate the need for further studies to better assess these associations between PFAS exposure and diabetes.

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Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure

Cited by 76 publications

References 83 publications

Sulfonamide functional head on short-chain perfluorinated substance drives developmental toxicity

Sulfonamide functional head on short-chain perfluorinated substance drives developmental toxicity

A High-Throughput Toxicity Screen of 42 Per- and Polyfluoroalkyl Substances (PFAS) and Functional Assessment of Migration and Gene Expression in Human Placental Trophoblast Cells

Associations between Exposures to Perfluoroalkyl Substances and Diabetes, Hyperglycemia, or Insulin Resistance: A Scoping Review

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