Bisphenol Analog‐Induced Cytotoxicity: Unraveling Endoplasmic Reticulum (ER) Stress and Apoptotic Pathways

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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BibTeX RIS

BibTeX

@article{rifa2026bisphenol,
  title = {{Bisphenol Analog‐Induced Cytotoxicity: Unraveling Endoplasmic Reticulum (ER) Stress and Apoptotic Pathways}},
  author = {Rafia Afroze Rifa and Ramon Lavado},
  journal = {Journal of Applied Toxicology},
  year = {2026},
  month = may,
  doi = {10.1002/jat.70248},
  url = {https://doi.org/10.1002/jat.70248},
  note = {CC BY-NC 4.0},
}

RIS

TY  - JOUR
TI  - Bisphenol Analog‐Induced Cytotoxicity: Unraveling Endoplasmic Reticulum (ER) Stress and Apoptotic Pathways
AU  - Rafia Afroze Rifa
AU  - Ramon Lavado
PY  - 2026
DA  - 2026/05/20
JO  - Journal of Applied Toxicology
DO  - 10.1002/jat.70248
UR  - https://doi.org/10.1002/jat.70248
AB  - 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.
SN  - 0260-437X
SN  - 1099-1263
ER  -

Abstract

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