Test driving ToxCast: endocrine profiling for 1858 chemicals included in phase II

Filer, Dayne L.; Patisaul, Heather B.; Schug, Thaddeus T.; Reif, David M.; Thayer, Kristina A.

doi:10.1016/j.coph.2014.09.021

Cited by 62 publications

(61 citation statements)

References 13 publications

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“…The previous iteration of the signature was expanded to include newly available ToxCast assay data on critical vascular developmental targets including assays that measure events along the estrogen receptor (ER) pathway such as binding, dimerization, and transcription that could be relevant to downstream VEGF production, as well as assays that measure inhibition of proliferation in human primary vascular (endothelial and smooth muscle) cells. The ToxCast Phase I/II libraries (1060 unique compounds) were ranked according to their cumulative activity across 124 signature assays and visualized using the Toxicological Prioritization Index (ToxPi) tool [8; 18; 19]. This approach functions to rank chemicals based on their putative ability to disrupt blood vessel development.…”

Section: Methodsmentioning

confidence: 99%

Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

Tal

Kilty

Smith

et al. 2017

Reproductive Toxicology

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Chemically-induced vascular toxicity during embryonic development may cause a wide range of adverse effects. To identify putative vascular disrupting chemicals (pVDCs), a predictive pVDC signature was constructed from 124 U.S. EPA ToxCast high-throughput screening (HTS) assays and used to rank 1060 chemicals for their potential to disrupt vascular development. Thirty-seven compounds were selected for targeted testing in transgenic Tg(kdrl:EGFP) and Tg(fli1:EGFP) zebrafish embryos to identify chemicals that impair developmental angiogenesis. We hypothesized that zebrafish angiogenesis toxicity data would correlate with human cell-based and cell-free in vitro HTS ToxCast data. Univariate statistical associations used to filter HTS data based on correlations with zebrafish angiogenic inhibition in vivo revealed 132 total significant associations, 33 of which were already captured in the pVDC signature, and 689 non-significant assay associations. Correlated assays were enriched in cytokine and extracellular matrix pathways. Taken together, the findings indicate the utility of zebrafish assays to evaluate an HTS-based predictive toxicity signature and also provide an experimental basis for expansion of the pVDC signature with novel HTS assays.

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Section: Methodsmentioning

confidence: 99%

Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

Tal

Kilty

Smith

et al. 2017

Reproductive Toxicology

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“…Such prioritization efforts are being used by the Endocrine Disruption Screening Program (EDSP), where Phase I and II ToxCast data are evaluated to reduce the number of chemicals moving on to more traditional animal-based tests for disruption of the estrogen, androgen, and thyroid endocrine pathways. A similar approach has also been recommended for other pathways, including those related to the glucocorticoid and PPAR signaling networks (Filer et al , 2014b; Reif et al , 2010). To date, ToxCast prioritized chemical sets have yet to be screened in biologically relevant assays for evaluating human adipogenesis.…”

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confidence: 99%

Editor’s Highlight: Screening ToxCast Prioritized Chemicals forPPARGFunction in a Human Adipose-Derived Stem Cell Model of Adipogenesis

et al. 2016

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The developmental origins of obesity hypothesis posits a multifaceted contribution of factors to the fetal origins of obesity and metabolic disease. Adipocyte hyperplasia in gestation and early childhood may result in predisposition for obesity later in life. Rodent in vitro and in vivo studies indicate that some chemicals may directly affect adipose progenitor cell differentiation, but the human relevance of these findings is unclear. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARG) is the master regulator of adipogenesis. Human adipose-derived stem cells (hASC) isolated from adipose tissue express endogenous isoforms of PPARG and represent a biologically relevant cell-type for evaluating activity of PPARG ligands. Here, a multi-endpoint approach based on a phenotypic adipogenesis assay was applied to screen a set of 60 chemical compounds identified in ToxCast Phase I as PPARG active (49) or inactive (11). Chemicals showing activity in the adipogenesis screen were further evaluated in a series of 4 orthogonal assays representing 7 different key events in PPARG-dependent adipogenesis, including gene transcription, protein expression, and adipokine secretion. An siRNA screen was also used to evaluate PPARG-dependence of the adipogenesis phenotype. A universal concentration-response design enabled inter-assay comparability and implementation of a weight-of-evidence approach for bioactivity classification. Collectively, a total of 14/49 (29%) prioritized chemicals were identified with moderate-to-strong activity for human adipogenesis. These results provide the first integrated screening approach of prioritized ToxCast chemicals in a human stem cell model of adipogenesis and provide insight into the capacity of PPARG-activating chemicals to modulate early life programming of adipose tissue.

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“…Overall, effects of BPA alternatives have been poorly investigated. Recent studies have revealed that less studied endocrine-related systems such as glucocorticoid, PPAR, monoamine, noradrenaline and serotonin pathways could be targets of endocrine disruption (Filer et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

Mesnage

Phedonos

Arno

et al. 2017

Preprint

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BackgroundPlasticizers with estrogenic activity, such as bisphenol A (BPA), have been reported to have potential adverse health effects in humans. Due to mounting evidence of these health effects and public pressure, BPA is being phased out by the plastics manufacturing industry and replaced by other bisphenol variants in “BPA-free” products.ObjectivesWe have compared estrogenic activity of BPA to 6 bisphenol analogues (bisphenol S, BPS; bisphenol F, BPF; bisphenol AP, BPAP; bisphenol AF, BPAF; bisphenol Z, BPZ; bisphenol B, BPB) in three human breast cancer cell lines.MethodsEstrogenicity was assessed by cell growth in an estrogen receptor (ER)-mediated cell proliferation assay, and by the induction of estrogen response element (ERE)-mediated transcription in a luciferase assay. Gene expression profiles were determined in MCF-7 human breast cancer cells by microarray analysis and confirmed by Illumina-based RNA sequencing.ResultsAll bisphenols showed estrogenic activity in promoting cell growth and inducing ERE-mediated transcription. BPAF was the most potent bisphenol, followed by BPB > BPZ ~ BPA > BPF ~ BPAP > BPS. The addition of ICI 182,780 antagonized the activation of ERs by bisphenols. Data mining of ToxCast high-throughput screening assays confirms our results but also shows divergence in the sensitivities of the assays. The comparison of transcriptome profile alterations resulting from BPA alternatives with an ERα gene expression biomarker further indicates that all BPA alternatives act as ERα agonists in MCF-7 cells. These results were confirmed by RNA sequencing.ConclusionIn conclusion, BPA alternatives are not necessarily less estrogenic in a human breast cancer cell model. Three bisphenols (BPAF, BPB, and BPZ) were more estrogenic than BPA. The relevance of human exposure to BPA alternatives in hormone-dependent breast cancer risk should be investigated.

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Test driving ToxCast: endocrine profiling for 1858 chemicals included in phase II

Cited by 62 publications

References 13 publications

Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

Screening for angiogenic inhibitors in zebrafish to evaluate a predictive model for developmental vascular toxicity

Editor’s Highlight: Screening ToxCast Prioritized Chemicals forPPARGFunction in a Human Adipose-Derived Stem Cell Model of Adipogenesis

Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells

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