Comparative cytotoxicity of seven per- and polyfluoroalkyl substances (PFAS) in six human cell lines

Solan, Megan E.; Senthilkumar, Sanjanaa; Aquino, Grace V.; Bruce, Erica D.; Lavado, Ramón

doi:10.1016/j.tox.2022.153281

Cited by 22 publications

(7 citation statements)

References 90 publications

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“…Many forms of PFAS toxicity are chronic, taking place over years. 20 PFAS are commonly detected in human serum at low part per billion levels (ng/mL) or nanomolar concentrations, 45, 46 but do not exhibit toxicity in cultured cells up to 3∼100 μM 14, 47, 48 , consistent with our results. PFAS can reversibly bind to proteins which decreases bioavailability for uptake in vitro .…”

Section: Resultssupporting

confidence: 91%

“…21 PFAS are commonly detected in human serum at low part per billion levels (ng/mL) or nanomolar concentrations, 14, 41 but do not exhibit toxicity in cultured cells up to 3∼100 μM. 15, 42, 43 Another factor that should be considered is PFAS, specifically long-chain ionic PFAS, reversibly binds to proteins through complex interactions that decrease bioavailability non-linearly in protein-rich cellular media used for in vitro studies. 44 Based on these factors, exposure studies use much higher concentrations than environmentally relevant PFAS levels.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomics effects of per- and polyfluorinated alkyl substances in differentiated neuronal cells

Running,

Cristobal,

Karageorgiou

et al. 2024

Preprint

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Per- and polyfluorinated alkyl substances (PFAS) are ubiquitous in most environments, accumulate in several tissues, and can adversely affect human health. PFAS have been implicated in neurodegenerative and behavioral disorders. However, the mechanisms through which PFAS accumulation in neurons affects biological function remain unknown. In this study, SH-SY5Y neuroblastoma cells were used to investigate how perfluorooctanoic acid (PFOA), perfluorooctansulfonic acid (PFOS), perfluorodecanoic acid (PFDA) perfluorodecanesulfonic acid (PFDS), 8:2 fluorotelomer sulfate (8:2 FTS) and 8:2 fluorotelomer alcohol (8:2 FTOH) exposures influence neuronal health. After a 30 microM-, 24-hour exposure, cells accumulated up to 800 ng PFAS/mg protein. Transcriptomics analysis of control and PFAS-exposed cells revealed 721 genes were differentially expressed across six treatments (padj < 0.05). Eleven of these differentially expressed genes were observed for all treatments, suggesting that these genes are potential markers for neuronal PFAS exposure. In PFOA-treated cells, we observed multiple downregulated genes are enriched for functions related to synaptic growth and neural function. In contrast, upregulated genes in PFOS, PFDS, FTS, and FTOH-treated cells showed enrichment in functions related to response to hypoxia and amino acid metabolism. Overall, our results highlight specific biological processes that potentially underlie negative effects of PFAS on neuronal health.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Transcriptomics effects of per- and polyfluorinated alkyl substances in differentiated neuronal cells

Running,

Cristobal,

Karageorgiou

et al. 2024

Preprint

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“…It is well-known that highly fluorinated chemicals can persist in the environment, ,, and in some cases can elicit toxic effects, , which has led to the phasing out and replacement of several PFAS . If released chemicals are found to be persistent and harmful, it may be too late to regulate the novel replacements, and thus, the careful choice and study of potential replacement compounds before they go to market is vital for creating sustainable products that can be used for generations.…”

Section: Resultsmentioning

confidence: 99%

Avoiding Regrettable Replacements: Can the Introduction of Novel Functional Groups Move PFAS from Recalcitrant to Reactive?

Folkerson,

Schneider,

Abbatt

et al. 2023

Environ. Sci. Technol.

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“…Fourth, short-chain PFAS have been found to have a high affinity for binding to serum albumin [156, 157], which could lead to a high distribution and concentration in highly vascularized tissues, including antral follicles. Last but not least, short-chain PFAS have been shown to exhibit similar or even more toxic effects than long-chain PFAS in non-reproductive tissues through similar or distinct toxic mechanisms [75, 158, 159]. These facts highlight the need of further in-depth studies to fully understand their female reproductive impact.…”

Section: Discussionmentioning

confidence: 99%

Ovarian disrupting effects and mechanisms of long- and short-chain per- and polyfluoroalkyl substances in mice

Pattarawat,

Zhan,

Fan

et al. 2024

Preprint

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BackgroundThe extensive use of per- and polyfluoroalkyl substances (PFAS) has led to environmental contamination and bioaccumulation. Previous research linked PFAS exposure to female reproductive disorders, but the mechanism remains elusive. Further, most studies focused on legacy long-chain PFOA and PFOS, yet the reproductive impacts of other long-chain PFAS and short-chain alternatives are rarely explored.ObjectivesWe investigated the effects and mechanisms of long- and short-chain PFAS on the ovary and associated ovarian functions.MethodsA 3Din vitroovarian follicle culture system and anin vivomouse model, together with approaches of reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, RNA-sequencing, pharmacological treatment,in situzymography, histology,in situhybridization, analytical chemistry, and benchmark dose modeling (BMD), were used to test environmentally relevant exposure levels of six long- and short-chain PFAS on follicle maturation, hormone secretion, and ovulation.ResultsIn vitroexposure revealed that long-but not short-chain PFAS interfered with gonadotropin-dependent follicle maturation, ovulation, and hormone secretion. Mechanistically, long-chain perfluorononanoic acid (PFNA) acted as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist in granulosa cells to disrupt follicle-stimulating hormone (FSH)-dependent follicle maturation, luteinizing hormone (LH)-stimulated ovulation, and associated gene regulatory pathways.In vivomouse exposure confirmed the ovarian accumulation of PFNA and the mechanism of PPARγ-mediated ovarian toxicities of PFNA observedin vitro. The BMD analysis ofin vitroandin vivoresults suggested human relevant exposure levels of long-chain PFAS in our study pose an extra risk of ovarian defects, with follicular rupture as the most sensitive endpoint.DiscussionUsingin vitrofollicle culture andin vivomouse models, we discovered that long-chain PFAS interfere with gonadotropin-dependent follicle maturation, hormone secretion, and ovulation, posing a non-negligible risk to women’s reproductive health including anovulation, irregular menstrual cycles, and sub- or infertility.

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Comparative cytotoxicity of seven per- and polyfluoroalkyl substances (PFAS) in six human cell lines

Cited by 22 publications

References 90 publications

Transcriptomics effects of per- and polyfluorinated alkyl substances in differentiated neuronal cells

Transcriptomics effects of per- and polyfluorinated alkyl substances in differentiated neuronal cells

Avoiding Regrettable Replacements: Can the Introduction of Novel Functional Groups Move PFAS from Recalcitrant to Reactive?

Ovarian disrupting effects and mechanisms of long- and short-chain per- and polyfluoroalkyl substances in mice

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