Research Article Dietary Fat Interacts with PCBs to Induce Changes in Lipid Metabolism in Mice Deficient in Low Density Lipoprotein Receptor Bernhard Hennig 1 2 Gudrun Reiterer 2 Michal Toborek 3 Sergey V Matveev 4 Alan Daugherty 5 Eric Smart 4 and Larry W Robertson6 1Molecular and Cell Nutrition Laboratory College of Agriculture 2Graduate Center for Nutritional Sciences 3Department of Surgery of Pediatrics and 5Department of Cardiovascular Medicine University of Kentucky Lexington Kentucky USA 6Department of Occupational and Environmental Health College of Public Health University of Iowa Iowa City Iowa USA 4Department There is evidence that dietary fat can modify the cytotoxicity of polychlorinated biphenyls PCBs and that coplanar PCBs can induce inflammatory processes critical in the pathology of vascular diseases To test the hypothesis that the interaction of PCBs with dietary fat is dependent on the type of fat low density lipoprotein receptor deficient LDL R mice were fed diets enriched with either olive oil or corn oil for 4 weeks Half of the animals from each group were injected with PCB 77 Vascular cell adhesion molecule 1 VCAM 1 expression in aortic arches was nondetectable in the olive oil fed mice but was highly expressed in the presence of PCB 77 PCB treatment increased liver neutral lipids and decreased serum fatty acid levels only in mice fed the corn oil enriched diet PCB treatment increased mRNA expression of genes involved in inflammation apoptosis and oxidative stress in all mice Upon PCB treatment mice in both olive and corn oil diet groups showed induction of genes involved in fatty acid degradation but with upregulation of different key enzymes Genes involved in fatty acid synthesis were reduced only upon PCB treatment in corn oil fed mice whereas lipid transport export genes were altered in oliveoil fed mice These data suggest that dietary fat can modify changes in lipid metabolism induced by PCBs in serum and tissues These findings have implications for understanding the interactions of nutrients with environmental contaminants on the pathology of inflammatory diseases such as atherosclerosis Key words atherosclerosis dietary fat gene expression lipid metabolism PCB polychlorinated biphenyl vascular endothelial cells Environ Health Perspect 113 83 87 2005 doi 10 1289 ehp 7280 available via http dx doi org Online 23 September 2004 From epidemiologic studies there is substantial evidence that cardiovascular diseases are linked to environmental pollution and that exposure to polycyclic and or polyhalogenated aromatic hydrocarbons can lead to human cardiovascular toxicity For example one study found a signi cant increase in mortality from cardiovascular diseases among Swedish capacitor manufacturing workers exposed to polychlorinated biphenyls PCBs for at least 5 years Gustavsson and Hogstedt 1997 and in another study most excess deaths were due to cardiovascular disease in power workers exposed to phenoxy herbicides and PCBs in waste transformer oil Hay and Tarrel 1997 The increased prevalence of atherosclerosis may be associated with the ability of PCBs to modulate plasma and tissue lipids events that can result in compromised lipid metabolism and lipid dependent cellular signaling pathways In a study with rhesus monkeys Bell et al 1994 found a causal relationship between plasma lipid changes and PCB intake after oral exposure of Aroclor 1254 Moreover a report by Tokunaga et al 1999 con rms many other studies with chronic Yusho patients accidental ingestion of rice bran oil contaminated with PCBs which showed in this population that elevated serum levels of triglycerides and total cholesterol were signi cantly associated with the blood PCB levels Serum lipids Environmental Health Perspectives also have been shown to be affected by PCBs which apparently can modify the regulatory mechanisms of synthesis and degradation of cholesterol Jenke 1985 A major route of exposure to PCBs in humans is via oral ingestion of contaminated food products Safe 1994 Therefore circulating environmental contaminants derived from diets such as PCBs are in intimate contact with the vascular endothelium In addition to serum and vascular lipid changes a number of studies have reported an increase in liver and hepatic microsomal lipids total lipids phospholipids neutral lipids and cholesterol after PCB administration Garthoff et al 1977 Ishidate et al 1978 Asais Braesco et al 1990 reported that a single injection of PCB 77 resulted in a marked change in the fatty acid composition of rat hepatic microsomal fractions Also Matsusue et al 1999 found that coplanar PCBs have a signi cant effect on the reduced synthesis of physiologically essential longchain unsaturated fatty acids such as arachidonic acid in rat liver by suppressing delta 5 and delta 6 desaturase activities and thus allowing the omega 6 parent fatty acid linoleic acid to accumulate Little is known about the interaction of dietary fats and PCBs in the pathology of atherosclerosis We have reported a signi cant disruption in endothelial barrier function VOLUME 113 NUMBER 1 January 2005 when cells were exposed to linoleic acid Hennig et al 2001a In addition to endothelial barrier dysfunction another functional change in atherosclerosis is the activation of the endothelium that manifests as an increase in the expression of specific cytokines and adhesion molecules These cytokines and adhesion molecules are proposed to mediate the in ammatory aspects of atherosclerosis by regulating the vascular entry of leukocytes We reported previously that coplanar PCBs and linoleic acid induce the expression of cytokines and adhesion molecules in cultured endothelial cells Hennig et al 2002 Toborek et al 2002 In addition both linoleic acid and PCB 77 and more markedly when applied in combination can generate reactive oxidative species that can trigger oxidative stress sensitive proin ammatory signaling pathways Hennig et al 2002a These studies suggest that environmental contaminants such as PCBs are atherogenic in part by their ability to alter endothelial cell lipid pro le and metabolism and by inducing oxidative stress and proin ammatory genes Exposure to physiologic concentrations of speci c fatty acids such as linoleic acid can trigger in ammatory pathways leading to the up regulation of in ammatory cytokines e g interleukin 6 IL 6 IL 8 and adhesion molecules e g vascular cell adhesion molecule 1 VCAM 1 E selectin These genes initiate