A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells

Yadav, Ajay; Amber, Mazia; Zosen, Denis; Labba, Nils Anders; Erdem, Johanna Samulin; Haugen, Fred; Berntsen, Hanne Friis; Zienolddiny, Shanbeh; Paulsen, Ragnhild E.; Ropstad, Erik; Connolly, Lisa; Verhaegen, Steven

doi:10.1016/j.toxlet.2020.12.007

Cited by 9 publications

(6 citation statements)

References 42 publications

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“…The selection of this set of POPs was based on recent studies that warned about the endocrine disruptive potential of these chemicals and their mixtures (McComb et al, 2020;Shannon et al, 2019;Yadav et al, 2021). Moreover, their demonstrated presence in water, food, blood, and breast milk, arouses great interest in their analysis (Berntsen et al, 2017;Collet et al, 2020;Doan et al, 2020;Thomsen et al, 2010).…”

Section: In Vitro Bioassaymentioning

confidence: 99%

Assessing the chemical-induced estrogenicity using in silico and in vitro methods

Goya-Jorge

Amber

Gozalbes³

et al. 2021

Environmental Toxicology and Pharmacology

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Section: In Vitro Bioassaymentioning

confidence: 99%

Assessing the chemical-induced estrogenicity using in silico and in vitro methods

Goya-Jorge

Amber

Gozalbes³

et al. 2021

Environmental Toxicology and Pharmacology

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“…For example, PFOS promoted adipogenesis via peroxisome proliferator-activated receptors (PPARs) in mouse preadipocyte 3T3-L1 cells; PFDA and PFDoA might disrupt the function of the thyroid hormone system via aryl hydrocarbon receptor (AhR) in rat pituitary GH3 cell; PFOS stimulated insulin secretion via membrane G-protein coupled receptor (GPR) 40 in mouse islet β-TC-6 cells . Neurotoxicity is also of concern; for example, PFOS enhanced nerve growth factor-induced neurite outgrowth in rat pheochromocytoma PC12 cells . To relate the observed effects to baseline toxicity is a way to allow comparison between different test systems and end points and to identify effects that are of particular concern due to high TR nom or SR nom .…”

Section: Introductionmentioning

confidence: 99%

“…Four cell-based HTS were selected as experimental batteries, including three reporter gene assays targeting oxidative stress (AREc32 assay), nuclear receptors of PPARγ and AhR, as well as an image-based neurotoxicity assay that quantifies inhibition of neurite outgrowth of differentiated SH-SYSY cells, because these targets may be relevant to PFAS according to previous studies. − , 24 PFAS were then tested in a 384-well plate format. The cytotoxicity IC 10,nom and the effect concentrations EC 10,nom from these assays were compared with the IC 10,nom,baseline to derive TR nom and SR nom , which were used to determine if the effects of PFAS are specific.…”

Section: Introductionmentioning

confidence: 99%

“… 15 Neurotoxicity is also of concern; for example, PFOS enhanced nerve growth factor-induced neurite outgrowth in rat pheochromocytoma PC12 cells. 16 To relate the observed effects to baseline toxicity is a way to allow comparison between different test systems and end points and to identify effects that are of particular concern due to high TR nom or SR nom .…”

Section: Introductionmentioning

confidence: 99%

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Baseline Toxicity Model to Identify the Specific and Nonspecific Effects of Per- and Polyfluoroalkyl Substances in Cell-Based Bioassays

Qin,

Henneberger,

Glüge

et al. 2024

Environ. Sci. Technol.

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High-throughput screening is a strategy to identify potential adverse outcome pathways (AOP) for thousands of perand polyfluoroalkyl substances (PFAS) if the specific effects can be distinguished from nonspecific effects. We hypothesize that baseline toxicity may serve as a reference to determine the specificity of the cell responses. Baseline toxicity is the minimum (cyto)toxicity caused by the accumulation of chemicals in cell membranes, which disturbs their structure and function. A mass balance model linking the critical membrane concentration for baseline toxicity to nominal (i.e., dosed) concentrations of PFAS in cell-based bioassays yielded separate baseline toxicity prediction models for anionic and neutral PFAS, which were based on liposome-water distribution ratios as the sole model descriptors. The specificity of cell responses to 30 PFAS on six target effects (activation of peroxisome proliferator-activated receptor (PPAR) gamma, aryl hydrocarbon receptor, oxidative stress response, and neurotoxicity in own experiments, and literature data for activation of several PPARs and the estrogen receptor) were assessed by comparing effective concentrations to predicted baseline toxic concentrations. HFPO−DA, HFPO−DA-AS, and PFMOAA showed high specificity on PPARs, which provides information on key events in AOPs relevant to PFAS. However, PFAS were of low specificity in the other experimentally evaluated assays and others from the literature. Even if PFAS are not highly specific for certain defined targets but disturb many toxicity pathways with low potency, such effects are toxicologically relevant, especially for hydrophobic PFAS and because PFAS are highly persistent and cause chronic effects. This implicates a heightened need for the risk assessment of PFAS mixtures because nonspecific effects behave concentration-additive in mixtures.

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“…In addition, several sub-mixtures were designed, containing either chlorinated (Cl), brominated (Br), or perfluorinated compounds (PFAA) to be able to assign specific effects to one of these classes [17]. The total POP mixture was shown to antagonize the androgen receptor transactivation and nuclear translocation [18], inhibit the transactivation activity of the aryl hydrocarbon receptor [19], and to enhance the nervegrowth-factor-induced neurite outgrowth in PC12 cells at high concentration [18][19][20][21]. It also induces cytotoxicity and some of the sub-mixtures affect the number of cells, nuclear area and mitochondrial membrane potential in human A-498 kidney cells [21].…”

Section: Introductionmentioning

confidence: 99%

A realistic mixture of ubiquitous persistent organic pollutants affects bone and cartilage development in zebrafish by interaction with nuclear receptor signaling

Guerrero-Limón,

Zappia,

Muller

2024

PLoS ONE

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"Persistent organic pollutants (POPs)" have a plethora of deleterious effects on humans and the environment due to their bioaccumulative, persistent, and mimicking properties. Individually, each of these chemicals has been tested and its effects measured, however they are rather found as parts of complex mixtures of which we do not fully grasp the extent of their potential consequences. Here we studied the effects of realistic, environmentally relevant mixtures of 29 POPs on cartilage and bone development using zebrafish as a model species. We observed developmental issues in cartilage, in the form of diverse malformations such as micrognathia, reduced size of the Meckel’s and other structures. Also, mineralized bone formation was disrupted, hence impacting the overall development of the larvae at later life stages. Assessment of the transcriptome revealed disruption of nuclear receptor pathways, such as androgen, vitamin D, and retinoic acid, that may explain the mechanisms of action of the compounds within the tested mixtures. In addition, clustering of the compounds using their chemical signatures revealed structural similarities with the model chemicals vitamin D and retinoic acid that can explain the effects and/or enhancing the phenotypes we witnessed. Further mechanistic studies will be required to fully understand this kind of molecular interactions and their repercussions in organisms. Our results contribute to the already existing catalogue of deleterious effects caused by exposure to POPs and help to understand the potential consequences in at risk populations.

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A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells

Cited by 9 publications

References 42 publications

Assessing the chemical-induced estrogenicity using in silico and in vitro methods

Assessing the chemical-induced estrogenicity using in silico and in vitro methods

Baseline Toxicity Model to Identify the Specific and Nonspecific Effects of Per- and Polyfluoroalkyl Substances in Cell-Based Bioassays

A realistic mixture of ubiquitous persistent organic pollutants affects bone and cartilage development in zebrafish by interaction with nuclear receptor signaling

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