Superfund Research Program
PCBs: Metabolism, Genotoxicity and Gene Expression in vivo
Project Leader: Larry W. Robertson
Grant Number: P42ES013661
Funding Period: 2006-2020
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Using fundamental concepts and experimental approaches developed in part by PCBs: Metabolism, Genotoxicity, and Gene Expression in vivo researchers, these scientists have learned that the intracellular concentration of glutathione, the principal redox buffer of red blood cells, varies considerably from person to person. In a classic twin study, researchers found that a good fraction (~60%) of this variation is due to genetics, i.e., the intracellular concentration of glutathione in red blood cells is a heritable trait. This heritability also extends to red blood cells that have been stored as well as to other metabolites. This is an exciting discovery; it is another significant step to understand individual variability in the susceptibility to toxicants. A long term goal will be to understand how to use this discovery in personal toxicology to improve human health.
Most airborne PCBs are efficiently absorbed into the body after ingestion or inhalation exposure but then very quickly metabolically changed, making a determination of human exposure difficult. Researchers discovered that PCB 3 (4-chlorobiphenyl), which is a major component of airborne PCBs, is biotransformed to sulfate metabolites in vivo. These sulfates are excreted and were detectable in serum and urine of rats after intraperitoneal and inhalation exposure. The discovery of these metabolites is a major breakthrough in the search for a biomarker of exposure for this common contaminant.
Unlike bolus exposures via food or accidents, exposure by inhalation is usually continuous. Such a chronic exposure is difficult to mimic in the laboratory. Researchers achieved such a chronic, low dose exposure of rats with the help of PCB-coated polymeric implants. The slow, continuous exposure to PCB 126 (3,3',4,4',5-pentachlorobiphenyl) via polymeric implants for up to 45 days caused a significant increases in 8-oxo-dG in both liver and lung, implicating oxidative stress in PCB 126-carcinogenicity, and showing lung as a target organ. Moreover, co-exposure to PCB 126 and PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) changed the tissue distribution of PCB 153, decreasing the levels in fatty tissue and increasing the levels in the liver, suggesting that exposure to mixtures may produce larger toxic effects than observed with the individual compounds. These results clearly demonstrate the value of this novel method and the need for more research on mixture effects.
The ultimate goal of PCBs: Metabolism, Genotoxicity, and Gene Expression in vivo is to identify protection methods for exposed populations. Animal studies showed that dietary Se or Cu levels had only minor influence on PCB toxicity, but supplementation with N-acetyl cysteine (NAC) reduced the severity of PCB-induced fatty liver. However, NAC and Se reduced blood PON1 activity, a major antioxidant and anti-atherosclerosis enzyme. Thus, supplementation with specific amino acid precursors or minerals may be a pathway to achieve chemoprotection, but a cautious approach is advised.