Publication Date

2017-12-11

Availability

Open access

Embargo Period

2017-12-11

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2017-08-21

First Committee Member

Maria T. Abreu

Second Committee Member

Michal J. Toborek

Third Committee Member

Emmanuel Thomas

Fourth Committee Member

Rebecca Adkins

Fifth Committee Member

Noula Shembade

Abstract

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. Although production of PCBs has stopped, 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 levels of PCBs in the tissues of foodstuffs, especially fish. 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 set out to investigate the effects of PCB 153, the most environmentally prevalent PCB, on the gut, looking specifically for proinflammatory effects and a breakdown of the intestinal barrier. We further wanted to address the mechanism by which PCB 153 affected intestinal permeability or inflammation. 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-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time qPCR. Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB 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 via NF-kB in the intestinal epithelium.

Keywords

Polychlorinated Biphenyl; intestinal inflammation; PCB; intestinal epithelial cells; ATM; NEMO

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