TY - JOUR
T1 - Polychlorinated biphenyls disrupt intestinal integrity via NADPH oxidase-induced alterations of tight junction protein expression
AU - Choi, Yean Jung
AU - Seelbach, Melissa J.
AU - Pu, Hong
AU - Eum, Sung Yong
AU - Chen, Lei
AU - Zhang, Bei
AU - Hennig, Bernhard
AU - Toborek, Michal
PY - 2010/7
Y1 - 2010/7
N2 - BACKGROUND: Polychlorinated biphenyls (PCBs) are widely distributed environmental toxicants that contribute to numerous disease states. The main route of exposure to PCBs is through the gastrointestinal tract; however, little is known about the effects of PCBs on intestinal epithelial barrier functions. OBJECTIVE: The aim of the present study was to address the hypothesis that highly chlorinated PCBs can disrupt gut integrity at the level of tight junction (TJ) proteins. METHODS: Caco-2 human colon adenocarcinoma cells were exposed to one of the following PCB congeners: PCB153, PCB118, PCB104, and PCB126. We then assessed NAD(P)H oxidase (NOX) activity and expression and the barrier function of Caco-2 cells. In addition, the integrity of intestinal barrier function and expression of TJ proteins were evaluated in C57BL/6 mice exposed to individual PCBs by oral gavage. RESULTS: Exposure of Caco-2 cells to individual PCB congeners resulted in activation of NOX and increased permeability of fluorescein isothiocyanate (FITC)-labeled dextran (4 kDa). Treatment with PCB congeners also disrupted expression of TJ proteins zonula occludens-1 (ZO-1) and occludin in Caco-2 cells. Importantly, inhibition of NOX by apocynin significantly protected against PCB-mediated increase in epithelial permeability and alterations of ZO-1 protein expression. Exposure to PCBs also resulted in alterations of gut permeability via decreased expression of TJ proteins in an intact physiological animal model. CONCLUSIONS: These results suggest that oral exposure to highly chlorinated PCBs disrupts intestinal epithelial integrity and may directly contribute to the systemic effects of these toxicants.
AB - BACKGROUND: Polychlorinated biphenyls (PCBs) are widely distributed environmental toxicants that contribute to numerous disease states. The main route of exposure to PCBs is through the gastrointestinal tract; however, little is known about the effects of PCBs on intestinal epithelial barrier functions. OBJECTIVE: The aim of the present study was to address the hypothesis that highly chlorinated PCBs can disrupt gut integrity at the level of tight junction (TJ) proteins. METHODS: Caco-2 human colon adenocarcinoma cells were exposed to one of the following PCB congeners: PCB153, PCB118, PCB104, and PCB126. We then assessed NAD(P)H oxidase (NOX) activity and expression and the barrier function of Caco-2 cells. In addition, the integrity of intestinal barrier function and expression of TJ proteins were evaluated in C57BL/6 mice exposed to individual PCBs by oral gavage. RESULTS: Exposure of Caco-2 cells to individual PCB congeners resulted in activation of NOX and increased permeability of fluorescein isothiocyanate (FITC)-labeled dextran (4 kDa). Treatment with PCB congeners also disrupted expression of TJ proteins zonula occludens-1 (ZO-1) and occludin in Caco-2 cells. Importantly, inhibition of NOX by apocynin significantly protected against PCB-mediated increase in epithelial permeability and alterations of ZO-1 protein expression. Exposure to PCBs also resulted in alterations of gut permeability via decreased expression of TJ proteins in an intact physiological animal model. CONCLUSIONS: These results suggest that oral exposure to highly chlorinated PCBs disrupts intestinal epithelial integrity and may directly contribute to the systemic effects of these toxicants.
KW - Caco-2 cells
KW - Intestine
KW - Oxidative stress
KW - Polychlorinated biphenyls
KW - Tight junctions
UR - http://www.scopus.com/inward/record.url?scp=77954850393&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954850393&partnerID=8YFLogxK
U2 - 10.1289/ehp.0901751
DO - 10.1289/ehp.0901751
M3 - Article
C2 - 20299304
AN - SCOPUS:77954850393
SN - 0091-6765
VL - 118
SP - 976
EP - 981
JO - Environmental Health Perspectives
JF - Environmental Health Perspectives
IS - 7
ER -