In vitro transcriptomic analyses reveal pathway perturbations, estrogenic activities, and potencies of data-poor BPA alternative chemicals
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA869442 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21043200.fastq.gz | Fastqsanger.gz | |||
| SRR21043300.fastq.gz | Fastqsanger.gz | |||
| SRR21043400.fastq.gz | Fastqsanger.gz | |||
| SRR21043500.fastq.gz | Fastqsanger.gz | |||
| SRR21043600.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 768 |
Similar Datasets
Project description:Since initial regulatory action in 2010 in Canada, bisphenol A (BPA) has been progressively replaced by structurally related alternative chemicals. Unfortunately, many of these chemicals are data-poor, limiting toxicological risk assessment. We used high-throughput transcriptomics to evaluate potential hazards and compare potencies of BPA and 15 BPA alternative chemicals in cultured breast cancer cells. MCF-7 cells were exposed to BPA and 15 alternative chemicals (0.0005 – 100 µM) for 48 hrs. TempO-Seq sequencing (BioSpyder Inc.) was used to examine general toxicological effects and estrogen receptor alpha (ERα)-associated transcriptional changes. Benchmark concentration (BMC) analysis was conducted to identify two global transcriptomic points of departure (tPODs): (a) the lowest pathway median gene BMC and (b) the 25th lowest rank-ordered gene BMC. ERα activation was evaluated using a published transcriptomic biomarker and an ERα-specific tPOD was derived. Genes fitting BMC models were subjected to upstream regulator and canonical pathway analysis in Ingenuity Pathway Analysis. Biomarker analysis identified BPA and eight alternative chemicals as ERα active. Global and ERα tPODs produced highly similar potency rankings with BPAF as the most potent chemical tested, followed by BPA, BPC, 4,4’-BPF, BPAP, BPS, BADGE, 2,4’-BPF, Pergafast201®, D-8, 2,4’-BPS, TGSA, and BPS-MAE. Further, BPA and transcriptionally active alternative chemicals enriched similar gene sets associated with increased cell division and cancer-related processes. These data provide support for future read-across applications of transcriptomic profiling for risk assessment of data-poor chemicals and suggest that several BPA alternative chemicals may cause hazards at similar concentrations to BPA.
2022-08-18 | GSE211183 | GEO
Project description:Since initial regulatory action in 2010 in Canada, bisphenol A (BPA) has been progressively replaced by structurally related alternative chemicals. Unfortunately, many of these chemicals are data-poor, limiting toxicological risk assessment. We used high-throughput transcriptomics to evaluate potential hazards and compare potencies of BPA and 15 BPA alternative chemicals in cultured breast cancer cells. MCF-7 cells were exposed to BPA and 15 alternative chemicals (0.0005-100 µM) for 48 h. TempO-Seq (BioSpyder Inc) was used to examine global transcriptomic changes and estrogen receptor alpha (ERα)-associated transcriptional changes. Benchmark concentration (BMC) analysis was conducted to identify 2 global transcriptomic points of departure: (1) the lowest pathway median gene BMC and (2) the 25th lowest rank-ordered gene BMC. ERα activation was evaluated using a published transcriptomic biomarker and an ERα-specific transcriptomic point of departure was derived. Genes fitting BMC models were subjected to upstream regulator and canonical pathway analysis in Ingenuity Pathway Analysis. Biomarker analysis identified BPA and 8 alternative chemicals as ERα active. Global and ERα transcriptomic points of departure produced highly similar potency rankings with bisphenol AF as the most potent chemical tested, followed by BPA and bisphenol C. Further, BPA and transcriptionally active alternative chemicals enriched similar gene sets associated with increased cell division and cancer-related processes. These data provide support for future read-across applications of transcriptomic profiling for risk assessment of data-poor chemicals and suggest that several BPA alternative chemicals may cause hazards at similar concentrations to BPA.
| S-EPMC9936204 | biostudies-literature
Project description:Some everyday consumer products contain endocrine disruptors like bisphenol A (BPA) and its replacements. To date, most in vitro chemical screening to evaluate these compounds has been accomplished using immortalized cell lines, which differ significantly from human tissues. Our goal was to test BPA and select alternatives previously screened in breast cancer cells for toxicological potency and mechanism of action in human mammary epithelial cells (HMECs). HMECs from three human donors were exposed to BPA and four alternative chemicals (in concentration response format from 0.001 – 50 µM) for 48 h and global transcriptomic changes were quantified. Transcriptomic biomarker analysis was employed to explore chemically induced estrogen receptor alpha (ERα) activation and alterations in stress response pathways. Benchmark concentration (BMC) analysis was applied to gene expression data to derive transcriptomic points of departure (tPODs) to compare chemicals for potency. Pathway and upstream regulator analysis was applied among the genes fitting BMCs. All chemicals had tPODs within an order of magnitude of each other. Bisphenol AF (BPAF) was the most potent, followed by tetramethyl bisphenol F (TMBPF), bisphenol C (BPC), 4,4’-bisphenol S (BPS), and BPA. None of the chemicals activated the ERα active biomarker. Some stress response biomarkers were activated at high exposure concentrations. Genes fitting BMCs clustered chemicals into two groups, with one group (BPAF and TMBPF) primarily inhibiting expression patterns and the other (BPC, BPS, and BPA) mostly activating. These data suggest that the BPA alternatives tested have similar toxicological potencies in HMECs and oppositely enrich cancer related gene sets.
2026-01-06 | GSE304327 | GEO
Project description:Many environmental toxicants can activate the estrogen receptor α (ERα), contributing to disruption of normal endocrine function. Although these activities are known from in silico, in vitro and in vivo models, transferring the active concentrations between the different models is often challenging. We hypothesized that cellular uptake and the resulting active free intracellular concentration could bridge the gap in efficacy between assays of different complexity. Here, we tested this hypothesis by comparing cell-free (hER) and cellular (ERα-CALUX cells) estrogen assays. First, we used predictive modeling to select representative estrogenic chemicals from the ToxCast collection. Three classes of compounds were identified: Bisphenols, parabens and phthalates. We then confirmed that the potency of many of the estrogenic chemicals differed between the two systems. Next, we determined cellular uptake and intracellular binding using computational and experimental methods. Finally, we used cellular uptake and intracellular binding to improve the correlation between ERα activities in cell-free systems (hER) and cellular systems (ERα-CALUX cells) to allow translation of active concentrations between the two models. Both the computationally derived and measured cellular TK parameters varied widely between the different classes and chemicals within these classes. The free intracellular concentration was up to 1000 times lower than the nominal extracellular concentration. Correcting the active concentrations in the cell-free and cell-based assays for the computationally predicted or experimentally derived free (unbound) concentration resulted in significantly improved correlations between the two assays. The potencies in the two systems corrected by the experimentally derived cell uptake and binding showed a better correlation (Pearson coefficient, r = 0.887) than the computationally derived one (r = 0.811), and both were significantly improved compared to the uncorrected values (r=0.623). Our results indicate that the free intracellular concentration plays a crucial role for the biological activity of the tested estrogenic compounds and that its determination should be considered for a correct prediction of the potency of estrogenic toxicants. Furthermore, the computational predictions of cellular uptake and binding for these chemicals approach the accuracy of the experimentally determined data and could provide a reliable alternative for rapid screening for potential estrogenicity.
2025-07-31 | PXD059544 | Pride
Project description:Transcriptomic analysis of BPA alternative chemicals in primary human mammary epithelial cells
| PRJNA1300393 | ENA
Project description:The identification of endocrine disruptive properties of chemicals certain to enter the aquatic environment relies on toxicity tests with fish, assessing adverse effects on reproduction and sexual development. The demand for quick, reliable endocrine disruption (ED) assays favored the use of fish embryos as alternative test organisms. We investigated the application of a transcriptomics-based assay for estrogenic and anti-androgenic chemicals with zebrafish embryos. Two reference compounds, 17a-ethinylestradiol and flutamide, were tested to evaluate the effects on development and the transcriptome after 48h-exposures. Comparison of the transcriptome response with other estrogenic and anti-androgenic compounds (genistein, bisphenol A, methylparaben, linuron, prochloraz, propanil) showed commonalities and differences in regulated pathways, enabling us to classify the estrogenic and anti-androgenic potencies. This demonstrates that different mechanism of ED can be assessed already in fish embryos. Newly fertilized embryos (<2hpf) were exposed for 48 hours to 0.65mg/l (EC10) and 0.8mg/l (EC20) 17-alpha ethinylestradiol (EE2), 1.2mg/l (EC10) and 1.4mg/l (EC20) flutamide, 8 mg/l (EC10)and 8.5mg/l (EC20) bisphenol A(BPA), 0.8 mg/l (EC10) and 1.1mg/l (EC20) propanil, 19.8mg/l (EC10) and 24.4mg/l (EC20) methylparaben, 1.2 mg/l (EC10) and 1.3mg/l (EC20) linuron as well as to 1.7mg/l (EC10) and 2 mg/l (EC20) prochloraz. Water controls were included in all studies and acetone solvent controls were applied when indicated (AC). For each study, four replicates (a,b,c,d) were performed per condition, each consisting of 24 pooled embryos.
2014-03-06 | E-GEOD-44263 | biostudies-arrayexpress
Project description:Bisphenol A (BPA), a widely used chemical in the production of plastics and epoxy resins, has garnered significant attention due to its association with adverse health effects, particularly its endocrine-disrupting properties. Regulatory measures aimed at reducing human exposure to BPA have led to a proliferation of alternative chemicals used in various consumer products. While these alternatives serve to reduce BPA exposure, concerns have arisen regarding their safety and potential toxicity as regrettable substitutes. Previous efforts have demonstrated that in vitro high-throughput transcriptomics (HTTr) studies can be used to assess the endocrine-disrupting potential of BPA alternatives, and this strategy produces transcriptomic points-of-departure (tPoDs) that are protective of human health when compared to the PODs from traditional rodent studies. In this study, we leveraged in vitro HTTr advancements to assess the toxicity of eleven data-poor legacy chemicals sharing structural similarities to BPA. Human breast cancer MCF-7 cells were exposed to BPA and 11 alternatives at concentrations ranging from (0.1 - 25 µM) to assess toxicity. Analysis of global transcriptomic changes and a previously characterized estrogen receptor alpha (ERα) biomarker signature revealed that 9/11 chemicals were bioactive. One of the chemicals (2,4’-Bisphenol A) activated the ERα biomarker at the same concentration as BPA (i.e., 4,4’-BPA) but was deemed to be more potent as it induced global transcriptomic changes at lower concentrations. These results are addressing data gaps in ongoing screening assessments to identify BPA alternatives with hazard potential and are helping to identify potential candidates to serve as safer alternatives.
2024-08-26 | GSE271332 | GEO
Project description:The identification of endocrine disruptive properties of chemicals certain to enter the aquatic environment relies on toxicity tests with fish, assessing adverse effects on reproduction and sexual development. The demand for quick, reliable endocrine disruption (ED) assays favored the use of fish embryos as alternative test organisms. We investigated the application of a transcriptomics-based assay for estrogenic and anti-androgenic chemicals with zebrafish embryos. Two reference compounds, 17a-ethinylestradiol and flutamide, were tested to evaluate the effects on development and the transcriptome after 48h-exposures. Comparison of the transcriptome response with other estrogenic and anti-androgenic compounds (genistein, bisphenol A, methylparaben, linuron, prochloraz, propanil) showed commonalities and differences in regulated pathways, enabling us to classify the estrogenic and anti-androgenic potencies. This demonstrates that different mechanism of ED can be assessed already in fish embryos.
2014-03-06 | GSE44263 | GEO
Project description:To examine whether the BPA-induced morphological alterations of the fetal mouse mammary glands are a) associated with changes in mRNA expression reflecting estrogenic actions and/or b) dependent on the estrogen receptor α (ERα), we compared the transcriptomal effects of BPA and the steroidal estrogen ethinylestradiol (EE2) on fetal mammary tissues of wild type and ERα knock-out mice.
2013-03-01 | GSE44387 | GEO
Project description:Humans are regularly exposed to mixtures of BPA alternative chemicals through their diets, consumer products and other sources. Like BPA, many alternatives perturb nuclear hormone receptors and are considered endocrine disrupting chemicals. We used high-throughput transcriptomics (HTTr) to evaluate the potency and potential modes of action of seven mixtures of BPA alternatives, along with their 12 individual components, in MCF-7 breast cancer cells. Our primary aim was to explore whether alternatives present in mixtures act additively. MCF-7 cells were exposed to chemicals (0.001 – 50 µM) for 48 h in serum-free conditions and TempO-Seq (BioSypder Inc.) was used to determine global and estrogen receptor alpha (ERα)-specific transcriptomic changes. Transcriptomic points of departure were derived using benchmark concentration (BMC) modelling. We first identified the concentration at which global transcriptional activity was robustly altered. Then, a novel ERα transcriptomic biomarker was used to identify ERα agonists and model a predicted ERα activation point of departure. Mixtures modelling was employed to predict potency of BPA alternatives and test for additive effects in vitro. Ingenuity Pathway Analysis (IPA; Qiagen) was used to identify upstream regulators and canonical pathways from genes fitting BMCs. All seven mixtures had additive effects across all transcriptomic points of departure modelled. BPAF was the most potent individual chemical tested overall, followed by BPA and BPC. The ERα transcriptomic biomarker classified all mixtures as ERα activators along with several individual BPA alternatives. Pathway analysis revealed that all mixtures and most individual components perturbed similar upstream regulators and pathways, suggesting common modes of action. These data support the use of HTTr as part of new approach methodologies to assess the toxicological potency of mixtures in vitro.
2025-06-30 | GSE276869 | GEO