Endoplasmic Reticulum Stress Is Involved in Chronic Chlorpyrifos-Induced Jejunal Barrier Injury in Weaned Mice

Area of Science:

• Toxicology
• Gastroenterology
• Cell Biology

Background:

• Organophosphate insecticides like chlorpyrifos (CPF) are linked to intestinal toxicity.
• The precise mechanisms behind CPF-induced intestinal epithelial barrier damage are not fully understood.

Purpose of the Study:

• To investigate the role of endoplasmic reticulum stress (ERS) in chlorpyrifos (CPF)-induced tight junction (TJ) alterations and intestinal epithelial injury.
• To explore the therapeutic potential of modulating ERS in CPF toxicity.

Main Methods:

• An 8-week mouse model exposed to varying CPF concentrations via drinking water.
• A MODE-K cell model combined with pharmacological ERS modulators (4-PBA and tunicamycin).
• Quantitative single-cell immunofluorescence to assess TJ proteins and apoptosis markers over time.

Main Results:

• CPF exposure led to jejunal villus atrophy, reduced TJ protein expression (ZO-1, Occludin, Claudin-1), and impaired TJ integrity.
• CPF increased the protein levels of unfolded protein response (UPR) sensors (PERK, IRE1, ATF6) and promoted apoptosis.
• Pharmacological inhibition of ERS (4-PBA) partially restored TJ proteins and reduced apoptosis, while ERS induction (tunicamycin) worsened these effects.

Conclusions:

• Endoplasmic reticulum stress (ERS) is a significant contributor to chlorpyrifos (CPF)-induced intestinal epithelial barrier injury.
• CPF exposure triggers a cascade involving ERS, TJ disruption, and apoptosis in the intestinal epithelium.
• Targeting ERS pathways may offer a strategy to mitigate CPF-induced intestinal damage.