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Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs.We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred.Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-κB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR.Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-κB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-κB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation.These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium.PCB 153 causes an increase in inflammatory cytokines in intestinal epithelial cells.PCB 153 increases intestinal permeability.PCB 153 activates the transcription factor NF-κB to cause these effects.PCB 153 is genotoxic to intestinal epithelial cells.PCB 153 activates NF- κB through the ATM/NEMO pathway.