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Here, we used high-content imaging and Cell Painting to determine whether exposure to 0.1\u00a0\u00b5M BPS for 96\u00a0h induces distinct morphology-based responses in primary human arterial endothelial cells from healthy and T2D donors. Multiplex staining of DNA, RNA-rich regions, RER, Golgi\/membrane structures, and mitochondria was combined with automated segmentation, multidimensional feature extraction, sparse partial least-squares discriminant analysis, and inferential statistics. Metabolic status was the main determinant of the endothelial morphology-based profile, clearly separating healthy and T2D-derived cells. In addition, BPS induced a pronounced multidimensional phenotypic shift in healthy endothelial cells, involving nuclear, mitochondrial, RNA-associated, and membrane\/perinuclear descriptors. In contrast, T2D-derived cells retained a dominant disease-associated profile, with a less evident whole-cell response to BPS. However, selected RER-associated descriptors remained BPS-responsive, indicating that BPS can still modulate stress-related subcellular organization under diabetic conditions. These findings show that BPS perturbs endothelial morphology under exposure-relevant low-dose conditions but that baseline metabolic status strongly shapes the magnitude and compartmental distribution of this response. The study identifies the diabetic endothelial phenotype as a key modifier of BPS-induced cellular remodeling and supports Cell Painting as a sensitive strategy to resolve context-dependent endothelial responses to environmental pollutants.<\/jats:p>","DOI":"10.1007\/s00418-026-02535-0","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T18:38:05Z","timestamp":1788979085000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential impact of bisphenol S on human arterial endothelial cells from healthy and type-2 diabetic donors: a high-content imaging study"],"prefix":"10.1007","volume":"164","author":[{"given":"Andrea","family":"di Credico","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Gaggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Bibb\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Marchisio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"di Baldassarre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Ghinassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"2535_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2025.121612","volume":"277","author":"MR Assenza","year":"2025","unstructured":"Assenza MR, Gaggi G, Di Credico A et al (2025) The effect of endocrine disruptors on the cardiovascular system: does sex matter? Environ Res 277:121612. https:\/\/doi.org\/10.1016\/j.envres.2025.121612","journal-title":"Environ Res"},{"key":"2535_CR2","doi-asserted-by":"publisher","first-page":"18670","DOI":"10.3390\/ijms140918670","volume":"14","author":"M Bexiga","year":"2013","unstructured":"Bexiga M, Simpson J (2013) Human diseases associated with form and function of the Golgi complex. Int J Mol Sci 14:18670\u201318681. https:\/\/doi.org\/10.3390\/ijms140918670","journal-title":"Int J Mol Sci"},{"key":"2535_CR3","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1038\/nprot.2016.105","volume":"11","author":"M-A Bray","year":"2016","unstructured":"Bray M-A, Singh S, Han H et al (2016) Cell painting, a high-content image-based assay for morphological profiling using multiplexed fluorescent dyes. 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