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ToxSci Advance Access published online on January 26, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi093
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Toxicological Sciences © Society of Toxicology 2005; all rights reserved.
Received September 9, 2004
Accepted January 19, 2005

Environmental Toxicology

Effects of 2,2',4,4'-Tetrachlorobiphenyl on Granulocytic HL-60 cell Function and Expression of Cyclooxygenase-2

Steven A. Bezdecny 1, Robert A. Roth 1, and Patricia E. Ganey 1*

1 Department of Pharmacology and Toxicology, Center for Integrative Toxicology and National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824

* To whom correspondence should be addressed.
Patricia E. Ganey, E-mail: ganey{at}msu.edu


  Abstract

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants that affect a number of cellular systems, including neutrophils. It has been demonstrated that non-coplanar PCBs (i.e., ortho- substituted PCBs) alter function of primary rat neutrophils. The objectives of these experiments were to determine if responses in a human, neutrophil-like cell line exposed to PCBs were similar to those reported for rat neutrophils and to explore further PCB-mediated alterations in neutrophil function. The human promyelocytic leukemia cell line (HL-60) was differentiated with DMSO to a neutrophil-like phenotype. Treatment of differentiated HL-60 cells with 2,2',4,4'-tetrachlorobiphenyl, a non-coplanar, ortho-substituted PCB congener, caused an increase in f-Met-Leu-Phe-induced degranulation, as measured by release of myeloperoxidase (MPO). Treatment with the coplanar, non-ortho-substituted congener 3,3',4,4'-tetrachlorobiphenyl had no effect on MPO release. 2,2',4,4'-Tetrachlorobiphenyl caused a time- and dose-dependent release of [3H]-arachidonic acid (3H-AA). A significant increase in 3H-AA release was observed after 60 minutes of exposure, and concentrations of 10 µM or larger increased 3H-AA release. In contrast, 3,3',4,4'-tetrachlorobiphenyl had no effect on 3H-AA release. The effect of PCBs on mRNA levels for cyclooxygenase-2 (COX-2) was examined using semiquantitative RT-PCR. COX-2 mRNA was significantly elevated in response to 2,2',4,4'-tetrachlorobiphenyl in a concentration-dependent manner. COX-2 expression was maximal by 30 minutes of exposure to 2,2',4,4'-tetrachlorobiphenyl. COX-2 protein and activity were also increased after exposure to 2,2',4,4'-tetrachlorobiphenyl ; COX-1 protein and activity were unaffected. 3,3',4,4'-Tetrachlorobiphenyl did not increase COX-2 mRNA levels. These results demonstrate that a non-coplanar PCB alters the functional status of granulocytic HL-60 cells, causing enhanced degranulation and upregulation of COX-2, whereas a coplanar PCB lacks this activity. These data suggest that non-coplanar PCBs alter HL-60 cell function and COX-2 expression via an Ah-receptor-independent mechanism.


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