Histochem Cell Biol. 2026 Sep 9;164(1):84. doi: 10.1007/s00418-026-02535-0.
ABSTRACT
Endothelial dysfunction is a central mechanism linking type 2 diabetes (T2D) to cardiovascular complications, and environmental endocrine-disrupting chemicals may further perturb vascular homeostasis. Bisphenol S (BPS), widely used as a bisphenol A substitute, is increasingly detected in human and environmental samples, but its impact on endothelial morphology in the context of pre-existing metabolic disease remains poorly defined. Here, we used high-content imaging and Cell Painting to determine whether exposure to 0.1 µM BPS for 96 h 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.
PMID:42717042 | DOI:10.1007/s00418-026-02535-0