The new generation PFAS C6O4 does not produce adverse effects on thyroid cells in vitro

Coperchini, Francesca; Croce, Laura; Pignatti, Patrizia; Ricci, Gianluca; Gangemi, David J.; Magri, Flavia; Imbriani, Marcello; Rotondi, Mario; Chiovato, Luca

doi:10.1007/s40618-020-01466-4

Cited by 17 publications

(11 citation statements)

References 35 publications

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“…Importantly, this effect is not due to non-specific endpoints such as cell viability or membrane biophysical properties in the range of concentrations from 0.1 to 100 ng/mL. The lack of a cytotoxic effect on thyroid cells is in agreement with a recent study on the same molecules from Coperchini et al (21). Conversely, the absence of significant impairment of membrane fluidity, evaluated by merocyanine 540 staining, represents a novel result, particularly compared with previous studies in which PFAS exposure was associated with an increased membrane fluidity in different cell models, such as dopaminergic neurons (27), sperm (38).…”

Section: Discussionsupporting

confidence: 89%

Comparative Evaluation of the Effects of Legacy and New Generation Perfluoralkyl Substances (PFAS) on Thyroid Cells In Vitro

et al. 2022

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BackgroundPer- and poly-fluorinated alkyl substances (PFAS) are environment-persitent emerging endocrine disrupting chemicals raising health concerns worldwide. Exposure to PFAS has been associated with the imbalance of thyroid hormones. However, available studies addressing the cell mechanism underlying thyroid disrupting feature of legacy PFAS, such as perfluoro-octanoic acid (PFOA), perfluoro-octane-sulfonic acid (PFOS), and the new generation substitutes, such as C6O4, are still lacking. In this study the potential disrupting effect of PFOA, PFOS, and C6O4 on a murine thyroid cell model was assessed.MethodsA rat FRTL-5 cell line was used as the normal thyroid follicular cell model. Cell iodide-uptake, induced by thyroid stimulating hormone (TSH), was used to assess the functional impact of PFAS exposure on cell function. Tetrazolium salt-based cell viability assay and merocyanine 540-based cell staining were used to address the possible involvement of cell toxicity and membrane biophysical properties on altered cell function. The possible direct interaction of PFAS with TSH-receptor (TSH-R) was investigated by computer-based molecular docking and analysis of molecular dynamics. Evaluation of intracellular cAMP levels and gene expression analysis were used to validate the direct impairment of TSH-R-mediated downstream events upon PFAS exposure.ResultsDifferent from PFOS or C6O4, exposure to PFOA at a concentration ≥ 10 ng/mL was associated with significant impairment of the iodide uptake upon TSH stimulation (respectively: basal 100.0 ± 19.0%, CTRL + TSH 188.9 ± 7.8%, PFOA 10 ng/mL + TSH 120.4 ± 20.9%, p= 0.030 vs CTRL + TSH; PFOA 100 ng/mL + TSH 115,6 ± 12,3% p= 0.017 vs CTRL + TSH). No impairment of cell viability or membrane stability was observed. Computational analysis showed a possible direct differential interaction of C6O4, PFOA, and PFOS on a same binding site of the extracellular domain of TSH-R. Finally, exposure to PFOA was associated with a significant reduction of downstream intracellular cAMP levels and both sodium-iodide transporter and thyroperoxidase gene expression upon TSH-R stimulation.ConclusionsOur data suggest that legacy and new generation PFAS can differentially influence TSH dependent signaling pathways through the direct interaction with TSH-R.

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Section: Discussionsupporting

confidence: 89%

Comparative Evaluation of the Effects of Legacy and New Generation Perfluoralkyl Substances (PFAS) on Thyroid Cells In Vitro

et al. 2022

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“…A dose-dependent decrease in cell viability was also observed in primary cultured hepatocytes of freshwater tilapia ( Oreochromis niloticus ) treated for 24 h with PFOS or PFOA (1 to 30 mg/L) [ 30 ]. As for other cell models, FRTL5 rat thyroid cell lines and normal human thyroid cells (NHTs) were treated for 24, 48, 72, and 144 h with increasing concentrations (0, 0.01, 0.1, 1, 10, and 100 ng/mL) of C6O4, PFOS, and PFOA, and cell viability was then evaluated [ 31 ]. Exposure to C6O4 did not affect FRTL5 and NHT cell viability.…”

Section: Discussionmentioning

confidence: 99%

“…Exposure to C6O4 did not affect FRTL5 and NHT cell viability. Conversely, PFOS reduced the cell viability of FRTL5 rat thyroid cells and NHTs, whereas PFOA reduced the cell viability of FRTL5 only [ 31 ]. Both cytotoxic and genotoxic effects of PFOA and PFOS on human HepG2 cells were investigated after 1 or 24 h of exposure [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

First Evidence of In Vitro Effects of C6O4—A Substitute of PFOA—On Haemocytes of the Clam Ruditapes philippinarum

Fabrello

Targhetta

Ciscato

et al. 2021

Toxics

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Alternative chemicals to per- and poly-fluoroalkyl substances have recently been introduced in various industrial processes. C6O4 (difluoro{[2,2,4,5-tetrafluoro-5-(trifluoromethoxy)-1,3-dioxolan-4-yl]oxy}acetic acid) is a new surfactant and emulsifier used as a replacement for perfluorooctanoic acid (PFOA). From an ecotoxicological point of view, in vitro assays are useful tools for assessing the negative effects and understanding the mechanisms of action of chemicals at the cellular level. Here, we present the results of an in vitro study in which the effects of C6O4 were evaluated—for the first time—on haemocytes of the clam Ruditapes philippinarum. Cells were exposed to three concentrations of C6O4 (0.05, 0.5, 5 μg/mL) and the effects on haemocyte viability, haemocyte morphology, differential haemocyte count, lysosomal membrane stability, superoxide anion production, acid phosphatase, and β-glucuronidase activities, as well as on the percentage of micronuclei and chromosomal aberrations were evaluated. The results demonstrated that C6O4 significantly affected haemocyte morphology, lysosomal membrane stability, hydrolytic enzyme activity, and superoxide anion production, and promoted chromosomal aberrations. To the best of our knowledge, this is the first study revealing the in vitro effects of C6O4, a substitute for PFOA, on haemocytes from a bivalve species.

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“…In consideration of the above reported data, GenX was marked as a Substance of Very High Concern (SVHC) by the ECHA in June 2019 (33). At difference with GenX, the exposure to another new generation PFAS named Perfluoro {acetic acid, 2-[(5-methoxy-1,3-dioxolan-4-yl)oxy]}, ammonium salt (C6O4) was recently demonstrated to not exert adverse effect on thyroid cells in vitro (34). Table 1 shows the most To summarize our current knowledge, long-, short-chain, and emerging PFAS are potentially dangerous for human health making further studies and monitoring mandatory.…”

Section: Short-chain and Emerging Replacement Pfasmentioning

confidence: 99%

Thyroid Disrupting Effects of Old and New Generation PFAS

et al. 2021

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Per- and polyfluoroalkyl substances (PFAS) represent a group of synthetic compounds widely used in industry plants due to their low grade of degradation, surfactant properties, thermic and flame resistance. These characteristics are useful for the industrial production, however they are also potentially dangerous for human health and for the environment. PFAS are persistent pollutants accumulating in waters and soil and recoverable in foods due to their release by food packaging. Humans are daily exposed to PFAS because these compounds are ubiquitous and, when assimilated, they are difficult to be eliminated, persisting for years both in humans and animals. Due to their persistence and potential danger to health, some old generation PFAS have been replaced by newly synthesized PFAS with the aim to use alternative compounds presumably safer for humans and the environment. Yet, the environmental pollution with PFAS remains a matter of concern worldwide and led to large-scale epidemiological studies both on plants’ workers and on exposed people in the general population. In this context, strong concern emerged concerning the potential adverse effects of PFAS on the thyroid gland. Thyroid hormones play a critical role in the regulation of metabolism, and thyroid function is related to cardiovascular disease, fertility, and fetal neurodevelopment. In vitro, ex vivo data, and epidemiological studies suggested that PFASs may disrupt the thyroid hormone system in humans, with possible negative repercussions on the outcome of pregnancy and fetal-child development. However, data on the thyroid disrupting effect of PFAS remain controversial, as well as their impact on human health in different ages of life. Aim of the present paper is to review recent data on the effects of old and new generation PFAS on thyroid homeostasis. To this purpose we collected information from in vitro studies, animal models, and in vivo data on exposed workers, general population, and pregnant women.

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The new generation PFAS C6O4 does not produce adverse effects on thyroid cells in vitro

Cited by 17 publications

References 35 publications

Comparative Evaluation of the Effects of Legacy and New Generation Perfluoralkyl Substances (PFAS) on Thyroid Cells In Vitro

Comparative Evaluation of the Effects of Legacy and New Generation Perfluoralkyl Substances (PFAS) on Thyroid Cells In Vitro

First Evidence of In Vitro Effects of C6O4—A Substitute of PFOA—On Haemocytes of the Clam Ruditapes philippinarum

Thyroid Disrupting Effects of Old and New Generation PFAS

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