P-298 PCB 153 Causes Genotoxic Activation of NF-κB Leading to Inflammation in Intestinal Epithelial Cells

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Abstract

Background:

Xenobiotics are increasingly becoming a concern as a cause for intestinal inflammation and have been hypothesized as a reason for the recent increase in inflammatory bowel disease. Polychlorinated biphenyls (PCBs) are ubiquitous and persistent organic pollutants that adversely affect human health. Although industrial production of PCBs has been discontinued, they remain a pressing environmental problem due to their slow biodegradation and high lipophilicity. These properties enable PCBs to bio-accumulate in food chains leading to high tissue levels in organism important for human consumption. Once in the body, PCBs accumulates in various organs leading to inflammation and activation of the transcription factor NF-кB. NF-кB is a driver of inflammation and has been linked to a multitude of diseases including inflammatory bowel disease. Despite dietary exposure being one of the main routes of exposure to PCBs, the human gastrointestinal tract has been widely ignored when studying the pro-inflammatory effects of PCBs. We investigated the effects of PCB 153, the most common PCB congener found in the environment, on intestinal epithelial cells to elucidate the mechanism of its inflammatory effects.

Methods:

Human intestinal epithelial cells (SW480) were exposed to PCB 153. We measured NF-кB activation using a reporter assay and downstream consequences were assessed. Mice were also exposed via oral gavage to PCB 153 for 2 days and intestinal epithelial cells (IECs) were collected and evaluated for PCB 153 induced toxicity and inflammation.

Results:

Exposure of SW480 cells to PCB 153 led to an increase in inflammatory cytokines transcription and an increase in NF-кB activity. This activity was triggered by genotoxic effects of PCB 153 and the subsequent activation of the ATM/NEMO pathway. IECs isolated from mice exposed to PCB 153 also showed signs of genotoxic damage, NF-кB activation, and an increase in inflammatory cytokine transcription.

Conclusions:

These results suggest PCB 153 is genotoxic to IECs and that this induces downstream inflammation in the intestinal epithelium.

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