Differentiating true androgen receptor inhibition from cytotoxicity-mediated reduction of reporter-gene transactivation in-vitro

Marin-Kuan, Maricel; Fussell, Karma C.; Riederer, Nicolas; Latado, Hélia; Serrant, Patrick; Mollergues, Julie; Coulet, Myriam; Schilter, Benoı̂t

doi:10.1016/j.tiv.2017.03.014

Cited by 17 publications

(14 citation statements)

References 25 publications

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“…In order to exclude any non-specific cytotoxicity-related effects of LC-PCBs from our analyses (Marin-Kuan et al, 2017), cytotoxicity was checked in all cell lines using the neutral red (NR) uptake or MTT assays. For additional information on methods, see Supplemental Experimental Procedures, where the results of cytotoxicity assays are also summarized in Supplementary Table 4.…”

Section: Methodsmentioning

confidence: 99%

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Pěnčíková

Svržková

Strapáčová

et al. 2018

Environmental Pollution

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The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.

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Section: Methodsmentioning

confidence: 99%

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Pěnčíková

Svržková

Strapáčová

et al. 2018

Environmental Pollution

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“…This illustrates the need for further investigations in the development of techniques to determine induced cell-effects of tested samples in the cryo-assay. Some efforts have already been done in this direction where the discrimination of cytotoxicity and antagonistic effects was investigated (Schmitz et al, 2010;Marin-Kuan et al, 2017).…”

Section: Interlaboratory Cryo-assay Resultsmentioning

confidence: 99%

Development and validation of a ready to use cryo-EROD assay for the standardized screening of dioxins and dioxin-like compounds in foodstuffs

Levy

Schramm

Henkelmann

et al. 2018

Food and Chemical Toxicology

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“…To discriminate between activity induction and potential cytotoxic effect, two approaches were applied: (LAB C) used an in-well multiplex method RealTime-Glo™ MT Cell Viability Assay (Promega, Dübendorf, Switzerland) [ 29 ] and (LAB D) used a cell line designed for that purpose (Cytotox CALUX) using the tributyltin acetate substance as reference [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Interlaboratory Study to Evaluate a Testing Protocol for the Safety of Food Packaging Coatings

Marin-Kuan

Pagnotti

Patin

et al. 2023

Toxics

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According to European regulations, migration from food packaging must be safe. However, currently, there is no consensus on how to evaluate its safety, especially for non-intentionally added substances (NIAS). The intensive and laborious approach, involving identification and then quantification of all migrating substances followed by a toxicological evaluation, is not practical or feasible. In alignment with the International Life Sciences Institute (ILSI) and the European Union (EU) guidelines on packaging materials, efforts are focused on combining data from analytics, bioassays and in silico toxicology approaches for the risk assessment of packaging materials. Advancement of non-targeted screening approaches using both analytical methods and in vitro bioassays is key. A protocol was developed for the chemical and biological screening of migrants from coated metal packaging materials. This protocol includes guidance on sample preparation, migrant simulation, chemical analysis using liquid chromatography (LC-MS) and validated bioassays covering endocrine activity, genotoxicity and metabolism-related targets. An inter-laboratory study was set-up to evaluate the consistency in biological activity and analytical results generated between three independent laboratories applying the developed protocol and guidance. Coated packaging metal panels were used in this case study. In general, the inter-laboratory chemical analysis and bioassay results displayed acceptable consistency between laboratories, but technical differences led to different data interpretations (e.g., cytotoxicity, cell passages, chemical analysis). The study observations with the greatest impact on the quality of the data and ultimately resulting in discrepancies in the results are given and suggestions for improvement of the protocol are made (e.g., sample preparation, chemical analysis approaches). Finally, there was agreement on the need for an aligned protocol to be utilized by qualified laboratories for chemical and biological analyses, following best practices and guidance for packaging safety assessment of intentionally added substances (IAS) and NIAS to avoid inconsistency in data and the final interpretation.

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Differentiating true androgen receptor inhibition from cytotoxicity-mediated reduction of reporter-gene transactivation in-vitro

Cited by 17 publications

References 25 publications

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Development and validation of a ready to use cryo-EROD assay for the standardized screening of dioxins and dioxin-like compounds in foodstuffs

Interlaboratory Study to Evaluate a Testing Protocol for the Safety of Food Packaging Coatings

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