Related Experiment Video
Updated: May 22, 2026
09:18
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.
Journal of Applied Toxicology : JAT
|May 21, 2026
Summary
Bisphenol A (BPA) and its analogs can trigger cell damage via endoplasmic reticulum (ER) stress and apoptosis. This cellular response varies significantly by chemical and cell type, indicating potential risks with BPA substitutes.
Area of Science:
- Toxicology and Environmental Health
- Cellular and Molecular Biology
- Biochemistry
Background:
- Bisphenol A (BPA) is widely used, but its replacements' safety is unknown.
- Structural analogs of BPA are increasingly used, necessitating safety evaluations.
- Endoplasmic reticulum (ER) stress and apoptosis are critical cellular pathways.
Purpose of the Study:
- To investigate if BPA and its analogs (BPAF, BPAP, BPP, BPE) induce cytotoxicity.
- To determine if cytotoxicity is mediated by ER stress and apoptosis signaling.
- To assess cell-type-specific responses in intestinal, hepatic, and microglial cells.
Main Methods:
- Human cell lines (Caco-2, HepaRG, HMC-3) were exposed to bisphenols (0.001–10 μM).
- ER stress markers (PERK, eIF2α, ATF4) and cytochrome C were quantified via ELISA.
- Cell-type-specific responses and correlations between ER stress and apoptosis were analyzed.
Main Results:
- Bisphenol exposure activated the PERK-eIF2α-ATF4 pathway in a compound- and cell-dependent manner.
- HepaRG cells showed robust ER stress, cytochrome C increase, and strong ER stress-apoptosis links.
- Caco-2 cells had moderate ER stress with limited apoptosis signaling; HMC-3 cells showed ER stress without significant apoptosis.
Conclusions:
- BPA analogs are not inert and can induce cytotoxicity through ER stress and apoptosis.
- Cell-type specificity is crucial in understanding bisphenol toxicity mechanisms.
- Multicell-based mechanistic studies are essential for accurate bisphenol risk assessment and designing safer chemicals.
Related Concept Videos
01:17Role of ER in the Secretory Pathway
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
01:31Regulation of the Unfolded Protein Response
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
01:31The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
01:37The Unfolded Protein Response
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
01:22Cellular Injury V: Apoptosis and Autophagy
Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...