Developmental effects of PFOS, PFOA and GenX in a 3D human induced pluripotent stem cell differentiation model

Davidsen, Nichlas; Rosenmai, Anna Kjerstine; Lauschke, Karin; Svingen, Terje; Vinggaard, Anne Marie

doi:10.1016/j.chemosphere.2021.130624

Cited by 21 publications

(15 citation statements)

References 41 publications

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“…Eight days of treatment with PFOA or PFOS disrupted the expression of ISL1 , and this disruption persisted after 16 days, indicating their potential to disrupt early embryonic development in multiple directions. Interestingly, PFOS increased the expression of ISL1 in an hiPSC-induced EB model, while our conditions revealed that PFOA reduced the expression of ISL1 , indicating that PFOA and PFOS exert distinct effects on ISL1 expression, underscoring different mechanisms at play.…”

Section: Discussionmentioning

confidence: 56%

“…For example, previous research utilizing human induced pluripotent stem cells (hiPSCs) exposed to PFOS and PFOA at 50 μM for 6 days showed decreased EB size and eventual production of contracting cardiomyocytes. 40 When mouse EBs were exposed to PFOS at 200 μM for up to 6 days, no morphological changes were observed, although endoderm markers (Sox17 and Foxa2), and the ectoderm marker Nestin were significantly reduced. 41 While our ectoderm-related trends are similar, differences in endoderm and mesoderm outcomes may be attributed to species-specific variations as well as the considerably higher concentrations used in previous studies.…”

Section: Discussionmentioning

confidence: 94%

“…Comparing our model to previous studies, our model demonstrates increased sensitivity, as we observed differences in EB morphology at 10 μM concentrations. For example, previous research utilizing human induced pluripotent stem cells (hiPSCs) exposed to PFOS and PFOA at 50 μM for 6 days showed decreased EB size and eventual production of contracting cardiomyocytes . When mouse EBs were exposed to PFOS at 200 μM for up to 6 days, no morphological changes were observed, although endoderm markers ( Sox17 and Foxa2 ), and the ectoderm marker Nestin were significantly reduced .…”

Section: Discussionmentioning

confidence: 98%

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Assessment and Comparison of Early Developmental Toxicity of Six Per- and Polyfluoroalkyl Substances with Human Embryonic Stem Cell Models

Zhao,

Yin,

Yang

et al. 2024

Environ. Sci. Technol.

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Per-and polyfluoroalkyl substances (PFAS) are extensively utilized in varieties of products and tend to accumulate in the human body including umbilical cord blood and embryos/ fetuses. In this study, we conducted an assessment and comparison of the potential early developmental toxicity of perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid, perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate, and perfluorobutyric acid at noncytotoxic concentrations relevant to human exposure using models based on human embryonic stem cells in both three-dimensional embryoid body (EB) and monolayer differentiation configurations. All six compounds influenced the determination of cell fate by disrupting the expression of associated markers in both models and, in some instances, even led to alterations in the formation of cystic EBs. The expression of cilia-related gene IFT122 was significantly inhibited. Additionally, PFOS and PFOA inhibited ciliogenesis, while PFOA specifically reduced the cilia length. Transcriptome analysis revealed that PFOS altered 1054 genes and disrupted crucial signaling pathways such as WNT and TGF-β, which play integral roles in cilia transduction and are critical for early embryonic development. These results provide precise and comprehensive insights into the potential adverse health effects of these six PFAS compounds directly concerning early human embryonic development.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 98%

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Assessment and Comparison of Early Developmental Toxicity of Six Per- and Polyfluoroalkyl Substances with Human Embryonic Stem Cell Models

Zhao,

Yin,

Yang

et al. 2024

Environ. Sci. Technol.

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“…The DMSO concentration in the ENR medium was always 0.1% for both the chemical treatment and control groups. According to the available literature on PFOA/PFOS cytotoxicity, treatment concentrations of 100–400 μmol/L were selected in our study. − After 48 h of exposure, organoid samples were harvested for subsequent analysis.…”

Section: Methodsmentioning

confidence: 99%

PFOA/PFOS Facilitated Intestinal Fatty Acid Absorption by Activating the PPARα Pathway: Insights from Organoids Model

Zhang,

Tian,

Chen

et al. 2023

Environ. Health

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Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) continue to be extensively present in the natural environment and seriously threaten human health. The intestinal tract is the primary organ of PFOA/PFOS exposure due to the consumption of contaminated food and drinking water. However, it remains unclear how PFOA/PFOS affects intestinal function and overall health. The aim of this study was to investigate the influence of PFOA/PFOS on the absorption of fatty acids in the intestine and the underlying mechanisms using three-dimensional (3D) intestinal organoids. Our results showed that PFOS, but not PFOA, could significantly enhance the fatty acid uptake capacity without obvious damage to the organoids. Furthermore, PFOS markedly reduced the protein levels of ChgA in enteroendocrine cells, but with no observed impact on aldolase B + enterocytes. Mechanistically, exposure to PFOS induced the activation of the peroxisome proliferator-activated receptor (PPAR) α pathway in intestinal organoids, with enhanced expression of PPARα target genes associated with fatty acid metabolism, such as Fabp1 and Cd36 (fatty acid transporter genes), Acox1 and Pdk4 (fatty acid oxidation genes), and Plin2 and Plin3 (lipid droplet synthesis genes). These data suggest that PFOS have the potential to affect the absorption function of the intestinal epithelium through the PPARα pathway, and its effect is much stronger than that of PFOA. Our findings also highlight that organoids can be used as a valuable model for conducting toxicological research on environmental chemicals.

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“…Using the PluriBeat assay, we have previously detected developmental toxicity of the teratogen thalidomide, the fungicide epoxiconazole (Lauschke et al 2020 ), and of the three perfluoroalkyl substances (PFAS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and undecafluoro-2-methyl-3-oxahexanoic acid (GenX) (Davidsen et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Investigating the applicability domain of the hiPSC-based PluriLum assay: an embryotoxicity assessment of chemicals and drugs

Treschow,

Valente,

Lauschke

et al. 2024

Arch Toxicol

Self Cite

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To meet the growing demand for developmental toxicity assessment of chemicals, New Approach Methodologies (NAMs) are needed. Previously, we developed two 3D in vitro assays based on human-induced pluripotent stem cells (hiPSC) and cardiomyocyte differentiation: the PluriBeat assay, based on assessment of beating differentiated embryoid bodies, and the PluriLum assay, a reporter gene assay based on the expression of the early cardiac marker NKX2.5; both promising assays for predicting embryotoxic effects of chemicals and drugs. In this work, we aimed to further describe the predictive power of the PluriLum assay and compare its sensitivity with PluriBeat and similar human stem cell-based assays developed by others. For this purpose, we assessed the toxicity of a panel of ten chemicals from different chemical classes, consisting of the known developmental toxicants 5-fluorouracil, all-trans retinoic acid and valproic acid, as well as the negative control compounds ascorbic acid and folic acid. In addition, the fungicides epoxiconazole and prochloraz, and three perfluoroalkyl substances (PFAS), PFOS, PFOA and GenX were tested. Generally, the PluriLum assay displayed higher sensitivity when compared to the PluriBeat assay. For several compounds the luminescence readout of the PluriLum assay showed effects not detected by the PluriBeat assay, including two PFAS compounds and the two fungicides. Overall, we find that the PluriLum assay has the potential to provide a fast and objective detection of developmental toxicants and has a level of sensitivity that is comparable to or higher than other in vitro assays also based on human stem cells and cardiomyocyte differentiation for assessment of developmental toxicity.

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Developmental effects of PFOS, PFOA and GenX in a 3D human induced pluripotent stem cell differentiation model

Cited by 21 publications

References 41 publications

Assessment and Comparison of Early Developmental Toxicity of Six Per- and Polyfluoroalkyl Substances with Human Embryonic Stem Cell Models

Assessment and Comparison of Early Developmental Toxicity of Six Per- and Polyfluoroalkyl Substances with Human Embryonic Stem Cell Models

PFOA/PFOS Facilitated Intestinal Fatty Acid Absorption by Activating the PPARα Pathway: Insights from Organoids Model

Investigating the applicability domain of the hiPSC-based PluriLum assay: an embryotoxicity assessment of chemicals and drugs

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