Aryl Hydrocarbon Receptor-Mediated Disruption of Intestinal Epithelial Barrier Integrity by Dioxin Isomers

The intestinal epithelium constitutes a critical barrier that protects the host from luminal toxins. Persistent organic pollutants (POPs), including dioxins and dioxin-like polychlorinated biphenyls, are ubiquitous aryl hydrocarbon receptor (AhR) ligands. However, their effects on intestinal barrier integrity remain poorly understood. We examined representative POPs in vitro (using human Caco-2 monolayers) and in vivo (using a mouse jejunal loop model). Measurements of transepithelial electrical resistance, fluorescein isothiocyanate-dextran permeability, and cytotoxicity revealed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impaired barrier function at non-cytotoxic concentrations. This effect was accompanied by increased ethoxyresorufin-O-deethylase activity and subsequently reversed by the AhR antagonist CH223191, indicating AhR dependence. Mechanistically, TCDD suppressed claudin-1, claudin-4, and zonula occludens-1 expression while upregulating the transcription factor Slug, consistent with junctional remodeling. In vivo, TCDD enhanced systemic dextran leakage and reduced claudin-4 expression in jejunal epithelia. These findings identify intestinal barrier disruption as a sensitive toxicological endpoint of POP exposure and provide mechanistic insight into the link between environmental pollutants and gastrointestinal dysfunction.