PXD059544

PXD059544 is an original dataset announced via ProteomeXchange.

Title	The intracellular free concentration of EDCs enables successful translation between cell-free and cell-based estrogenic activity assays
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.
HostingRepository	PRIDE
AnnounceDate	2025-07-31
AnnouncementXML	Submission_2025-07-31_00:33:12.045.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alina Meyer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-08 03:57:29	ID requested
⏵ 1	2025-07-31 00:33:12	announced

Munic Kos V, Arvidsson S, Islam B, Nikiforova V, Mickols E, Meyer A, Svensson R, Boztepe UG, Banti E, Lundquist P, Khalidi H, Gardner I, Spjuth O, Cotgreave I, Artursson P, The intracellular free concentration of endocrine disrupting chemicals enables translation between cell-free and cell-based estrogenic activity assays. Environ Toxicol Pharmacol, 117():104750(2025) [pubmed]

10.1016/j.etap.2025.104750;

submitter keyword: in vitro,Endocrine-Disrupting Chemicals, estrogenic chemicals, intracellular free concentration

Per Artursson
contact affiliation	Professor at Department of Pharmacy, Drug Delivery, Uppsala University
contact email	Per.Artursson@farmaci.uu.se
lab head
Alina Meyer
contact affiliation	Department of Pharmacy, Uppsala University
contact email	alina.meyer@farmaci.uu.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD059544
     1. Label: PRIDE project
     2. Name: The intracellular free concentration of EDCs enables successful translation between cell-free and cell-based estrogenic activity assays