Superfund Research Program
Mechanisms and Consequences of Neutrophil Activation by Polychlorinated Biphenyls
One of the most commonly found contaminants on Superfund sites, polychlorinated biphenyls (PCBs) are also widely dispersed in sediments, soils, lakes, and rivers throughout the world. Large quantities of these synthetic organochlorine compounds were introduced into the environment between the 1930's and the 1960's, a time when the compounds were extensively used in a wide range of industrial and consumer products, and when PCB wastes were routinely disposed in waterways, on the ground, and in municipal landfills.
During the first three decades of PCB use in this country, few concerns were raised about any negative impacts of these compounds. Awareness of the potential hazards of PCBs grew rapidly, however, after the 1968 poisoning of over 1,000 Japanese citizens by PCB-contaminated cooking oil. At that time, scientists were also beginning to realize that PCBs persisted in the environment and had a tendency to accumulate in living organisms. Today, we know that PCBs can cause immune dysfunction, cancer, reproductive toxicity, developmental toxicity, and a number of other adverse effects in laboratory animals. Some epidemiological studies suggest that PCBs can cause similar effects in humans; however, these studies do not provide definitive evidence of a cause-effect relationship. Defining the biological mechanisms underlying the toxic effects of PCBs has become important to understanding the suspected adverse health effects of PCBs in humans.
The task of understanding how polychlorinated biphenyls (PCBs) produce toxicity at the cellular level has been complicated, though, because this group of organochlorine compounds consists of 209 individual chemicals (congeners), each containing a unique chlorine substitution pattern on the ten possible locations around a biphenyl ring. Depending on the chlorine substitution pattern, some PCB congeners have a "coplanar" structure with the two phenyl rings lying in the same plane. Congeners with phenyl rings in different planes are considered "non-coplanar." In the past, research into the mechanisms of PCB toxicity focused on the coplanar congeners, which act similarly to dioxin in cells by binding to the Aryl hydrocarbon (Ah) receptor. It was assumed that non-coplanar PCBs, which have a low affinity for the Ah receptor, were biologically inactive. More recent research indicates that non-coplanar congeners can initiate important biological activities through different biochemical mechanisms.
Researchers in the Michigan State University Superfund Basic Research Program have discovered that non-coplanar PCBs can influence the activity of neutrophils (a type of white blood cell) through mechanisms unrelated to the Ah receptor. In studies with rat- and human-derived neutrophils, these researchers have found that non-coplanar PCBs can activate biochemical pathways that lead to the production of reactive oxygen species (ROS). Although the production of ROS is a normal function of neutrophils -- it is designed to destroy bacteria and viruses, and to break down tissue damaged by burns, chemicals, and physical injuries -- when inappropriately activated by PCBs this neutrophil function could initiate harmful effects on healthy tissues due to the destructive nature of ROS. Because neutrophils are among the first white blood cells sent to sites of infection or inflammation, these results also raise the possibility that exposure to PCBs may weaken the body's immune and inflammatory responses.
Recent studies have identified three pathways that are necessary for PCB-mediated activation of neutrophils. An enzyme known as phospholipase A2(PLA2) was necessary for the PCB-induced production of ROS in neutrophils. PLA2 frees a compound from the neutrophil membrane that is necessary for the production of superoxide anion, a specific type of ROS. Interruption of this pathway with inhibitors greatly reduced the production of superoxide anion. The activation of tyrosine kinases in neutrophils was also necessary for the PCB-induced generation of superoxide anion. Tyrosine kinases are enzymes that play an important role in intracellular signalling; they phosphorylate a number of other cellular messengers in neutrophils that lead to the production of ROS. The release of intracellular calcium also played a role in the activation of neutrophils by PCBs.
Importantly, these three pathways do not appear to involve the Ah receptor. Only non-coplanar PCB congeners with low affinity for the Ah receptor stimulated the production of ROS in neutrophils; coplanar PCB congeners with high affinity for the Ah receptor did not activate neutrophils in these studies.
According to the researchers, "each pathway appears to be necessary ... and interruption of any one dramatically reduces [superoxide anion] production in response to non-coplanar PCB congeners. This suggests either that convergence of all three pathways is necessary for activation of neutrophils, or that these pathways occur in series. Elucidation of the sequence of events and the interactions among these pathways will likely shed light on the ... mechanism of activation of neutrophils by PCBs."
Because PLA2 and tyrosine kinases are contained within many different kinds of cells in the body, and calcium release is an important physiologic function throughout the body, it is important to determine whether PCBs can activate these enzymes and biochemical events in other types of cells. It is possible that these pathways may be important in other forms of PCB-induced toxicity. These findings also have important implications for the risk assessment of PCBs because, at the present time, human health risk estimates for PCBs assume these chemicals act solely by biochemical mechanisms mediated through the Ah receptor.
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To learn more about this research, please refer to the following sources:
- Fischer L, Seegal R, Ganey PE, Pessah IN, Kodavanti PR. 1998. Symposium overview: toxicity of non-coplanar PCBs. Toxicol Sci 41(1):49-61. doi:10.1006/toxs.1997.2386 PMID:9520341
- Tithof PK, Peters-Golden M, Ganey PE. 1998. Distinct phospholipases A2 regulate the release of arachidonic acid for eicosanoid production and superoxide anion generation in neutrophils. J Immunol 160:953-960. PMID:9551934
- Tithof PK, Watts S, Ganey PE. 1997. Protein tyrosine kinase involvement in the production of superoxide anion by neutrophils exposed to Aroclor 1242, a mixture of polychlorinated biphenyls. Biochem Pharmacol 53:1833-1842. PMID:9256158
- Tithof PK, Peters-Golden M, Schiamburg L, Ganey PE. 1996. Aroclor 1242 activates neutrophils by a mechanism which involves phospholipase A2. Environ Health Perspect 104:52-58.
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