Abstract
So-called coplanar polychlorinated biphenyls (PCBs), as well as other environmental contaminants that are aryl hydrocarbon receptor (AhR) agonists, may compromise the normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. To test this hypothesis, porcine endothelial cells were exposed to PCB 153 and to three coplanar PCBs (PCB 77, PCB 126, or PCB 169). In contrast to PCB 153, which is not a ligand for the Ah receptor (AhR), all coplanar PCBs disrupted endothelial barrier function. All coplanar PCBs increased expression of the CYP1A1 gene, oxidative stress (DCF fluorescence), and the DNA-binding activity of nuclear factor κB (NF-κB). PCB-induced oxidative stress was concentration-dependent, with PCB 126 exhibiting a maximal response at the lowest concentration (0.5 μM) tested. The increase in NF-κB-dependent transcriptional activity was confirmed in endothelial cells by a luciferase reporter gene assay. In contrast to PCB 153, coplanar PCBs that are AhR ligands increased endothelial production of interleukin-6. At 3.4 μM, expression of the adhesion molecule VCAM-1 was most sensitive to PCB 77 and 169. We also provide in vivo evidence, suggesting that binding to the AhR is critical for the proinflammatory properties of PCBs. Twenty hours after a single administration of PCB 77, VCAM-1 expression was increased only in wild-type mice, while mice lacking the AhR gene showed no increased staining for VCAM-1. These data provide evidence that coplanar PCBs, agonists for the AhR, and inducers of cytochrome P450 1A1, produce oxidative stress and an inflammatory response in vascular endothelial cells. An intact AhR may be necessary for the observed PCB-induced responses. These findings suggest that activation of the AhR can be an underlying mechanism of atherosclerosis mediated by certain environmental contaminants.
| Original language | English |
|---|---|
| Pages (from-to) | 174-183 |
| Number of pages | 10 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 181 |
| Issue number | 3 |
| DOIs | |
| State | Published - Jul 22 2002 |
| Externally published | Yes |
Fingerprint
Keywords
- Aryl hydrocarbon receptor
- Atherosclerosis
- Disease
- Endothelial cells
- Environmental contaminants
- Oxidative stress
- Polychlorinated biphenyls
ASJC Scopus subject areas
- Pharmacology
- Toxicology
Cite this
Proinflammatory properties of coplanar PCBs : In vitro and in vivo evidence. / Hennig, Bernhard; Meerarani, Purushothaman; Slim, Rabih; Toborek, Michal J; Daugherty, Alan; Silverstone, Allen E.; Robertson, Larry W.
In: Toxicology and Applied Pharmacology, Vol. 181, No. 3, 22.07.2002, p. 174-183.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Proinflammatory properties of coplanar PCBs
T2 - In vitro and in vivo evidence
AU - Hennig, Bernhard
AU - Meerarani, Purushothaman
AU - Slim, Rabih
AU - Toborek, Michal J
AU - Daugherty, Alan
AU - Silverstone, Allen E.
AU - Robertson, Larry W.
PY - 2002/7/22
Y1 - 2002/7/22
N2 - So-called coplanar polychlorinated biphenyls (PCBs), as well as other environmental contaminants that are aryl hydrocarbon receptor (AhR) agonists, may compromise the normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. To test this hypothesis, porcine endothelial cells were exposed to PCB 153 and to three coplanar PCBs (PCB 77, PCB 126, or PCB 169). In contrast to PCB 153, which is not a ligand for the Ah receptor (AhR), all coplanar PCBs disrupted endothelial barrier function. All coplanar PCBs increased expression of the CYP1A1 gene, oxidative stress (DCF fluorescence), and the DNA-binding activity of nuclear factor κB (NF-κB). PCB-induced oxidative stress was concentration-dependent, with PCB 126 exhibiting a maximal response at the lowest concentration (0.5 μM) tested. The increase in NF-κB-dependent transcriptional activity was confirmed in endothelial cells by a luciferase reporter gene assay. In contrast to PCB 153, coplanar PCBs that are AhR ligands increased endothelial production of interleukin-6. At 3.4 μM, expression of the adhesion molecule VCAM-1 was most sensitive to PCB 77 and 169. We also provide in vivo evidence, suggesting that binding to the AhR is critical for the proinflammatory properties of PCBs. Twenty hours after a single administration of PCB 77, VCAM-1 expression was increased only in wild-type mice, while mice lacking the AhR gene showed no increased staining for VCAM-1. These data provide evidence that coplanar PCBs, agonists for the AhR, and inducers of cytochrome P450 1A1, produce oxidative stress and an inflammatory response in vascular endothelial cells. An intact AhR may be necessary for the observed PCB-induced responses. These findings suggest that activation of the AhR can be an underlying mechanism of atherosclerosis mediated by certain environmental contaminants.
AB - So-called coplanar polychlorinated biphenyls (PCBs), as well as other environmental contaminants that are aryl hydrocarbon receptor (AhR) agonists, may compromise the normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. To test this hypothesis, porcine endothelial cells were exposed to PCB 153 and to three coplanar PCBs (PCB 77, PCB 126, or PCB 169). In contrast to PCB 153, which is not a ligand for the Ah receptor (AhR), all coplanar PCBs disrupted endothelial barrier function. All coplanar PCBs increased expression of the CYP1A1 gene, oxidative stress (DCF fluorescence), and the DNA-binding activity of nuclear factor κB (NF-κB). PCB-induced oxidative stress was concentration-dependent, with PCB 126 exhibiting a maximal response at the lowest concentration (0.5 μM) tested. The increase in NF-κB-dependent transcriptional activity was confirmed in endothelial cells by a luciferase reporter gene assay. In contrast to PCB 153, coplanar PCBs that are AhR ligands increased endothelial production of interleukin-6. At 3.4 μM, expression of the adhesion molecule VCAM-1 was most sensitive to PCB 77 and 169. We also provide in vivo evidence, suggesting that binding to the AhR is critical for the proinflammatory properties of PCBs. Twenty hours after a single administration of PCB 77, VCAM-1 expression was increased only in wild-type mice, while mice lacking the AhR gene showed no increased staining for VCAM-1. These data provide evidence that coplanar PCBs, agonists for the AhR, and inducers of cytochrome P450 1A1, produce oxidative stress and an inflammatory response in vascular endothelial cells. An intact AhR may be necessary for the observed PCB-induced responses. These findings suggest that activation of the AhR can be an underlying mechanism of atherosclerosis mediated by certain environmental contaminants.
KW - Aryl hydrocarbon receptor
KW - Atherosclerosis
KW - Disease
KW - Endothelial cells
KW - Environmental contaminants
KW - Oxidative stress
KW - Polychlorinated biphenyls
UR - http://www.scopus.com/inward/record.url?scp=0036311088&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036311088&partnerID=8YFLogxK
U2 - 10.1006/taap.2002.9408
DO - 10.1006/taap.2002.9408
M3 - Article
C2 - 12079426
AN - SCOPUS:0036311088
VL - 181
SP - 174
EP - 183
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 3
ER -