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Updated: May 22, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Bisphenol Analog-Induced Cytotoxicity: Unraveling Endoplasmic Reticulum (ER) Stress and Apoptotic Pathways
Rafia Afroze Rifa1, Ramon Lavado1
1Department of Environmental Science, Baylor University, Waco, Texas, USA.
Abstract:
Bisphenol A (BPA) is increasingly replaced by structural analogs, yet their safety remains insufficiently characterized. This study investigated whether BPA and selected analogs, bisphenol AF (BPAF), bisphenol AP (BPAP), bisphenol P (BPP), and bisphenol E (BPE), induce cytotoxicity through activation of endoplasmic reticulum (ER) stress and apoptosis-related signaling in a cell-type-specific manner. Human intestinal (Caco-2), hepatic (HepaRG), and microglial (HMC-3) cells were exposed to environmentally relevant concentrations (0.001-10 μM) of bisphenols for 24 h. Key endoplasmic reticulum (ER) stress markers (PERK, eIF2α, ATF4) and the apoptosis-associated protein cytochrome C were quantified using ELISA-based approaches. Bisphenol exposure elicited distinct, compound- and cell-type-dependent activation of the PERK-eIF2α-ATF4 pathway. HepaRG cells showed the most robust and dose-responsive ER stress activation, accompanied by consistent increases in cytochrome C and strong correlations between ER stress markers and apoptosis-related responses. Caco-2 cells exhibited moderate ER stress activation with limited propagation toward cytochrome C modulation, whereas HMC-3 cells displayed pronounced ER stress signaling without significant cytochrome C association. Regression analyses confirmed cell-specific coupling between ER stress and apoptosis-related responses. These findings demonstrate that BPA analogs are not biologically inert substitutes and highlight the importance of mechanistic, multicell-based approaches for bisphenol risk assessment and safer chemical design.
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