From epidemiologic studies, there is substan-tial evidence that cardiovascular diseases arelinked to environmental pollution and thatexposure to polycyclic and/or polyhalogenatedaromatic hydrocarbons can lead to humancardiovascular toxicity. For example, onestudy found a significant increase in mortal-ity from cardiovascular diseases amongSwedish capacitor manufacturing workersexposed to polychlorinated biphenyls (PCBs)for at least 5 years (Gustavsson and Hogstedt1997), and in another study most excessdeaths were due to cardiovascular disease inpower workers exposed to phenoxy herbi-cides and PCBs in waste transformer oil (Hayand Tarrel 1997). The increased prevalenceof atherosclerosis may be associated with theability of PCBs to modulate plasma and tis-sue lipids, events that can result in compro-mised lipid metabolism and lipid-dependentcellular signaling pathways. In a study withrhesus monkeys, Bell et al. (1994) found acausal relationship between plasma lipidchanges and PCB intake after oral exposureof Aroclor 1254. Moreover, a report byTokunaga et al. (1999) confirms many otherstudies with chronic Yusho patients (acciden-tal ingestion of rice-bran oil contaminatedwith PCBs), which showed in this popula-tion that elevated serum levels of triglyceridesand total cholesterol were significantly associ-ated with the blood PCB levels. Serum lipidsalso have been shown to be affected by PCBs,which apparently can modify the regulatorymechanisms of synthesis and degradation ofcholesterol (Jenke 1985). A major route ofexposure to PCBs in humans is via oralingestion of contaminated food products(Safe 1994). Therefore, circulating environ-mental contaminants derived from diets,such as PCBs, are in intimate contact withthe vascular endothelium.In addition to serum and vascular lipidchanges, a number of studies have reported anincrease in liver and hepatic microsomal lipids(total lipids, phospholipids, neutral lipids, andcholesterol) after PCB administration(Garthoff et al. 1977; Ishidate et al. 1978).Asais-Braesco et al. (1990) reported that asingle injection of PCB-77 resulted in amarked change in the fatty acid compositionof rat hepatic microsomal fractions. Also,Matsusue et al. (1999) found that coplanarPCBs have a significant effect on the reducedsynthesis of physiologically essential long-chain unsaturated fatty acids, such as arachi-donic acid in rat liver, by suppressing delta-5and delta-6 desaturase activities and thusallowing the omega-6 parent fatty acid,linoleic acid, to accumulate.Little is known about the interaction ofdietary fats and PCBs in the pathology ofatherosclerosis. We have reported a significantdisruption in endothelial barrier functionwhen cells were exposed to linoleic acid(Hennig et al. 2001a). In addition toendothelial barrier dysfunction, anotherfunctional change in atherosclerosis is theactivation of the endothelium that manifestsas an increase in the expression of specificcytokines and adhesion molecules. Thesecytokines and adhesion molecules are pro-posed to mediate the inflammatory aspects ofatherosclerosis by regulating the vascularentry of leukocytes. We reported previouslythat coplanar PCBs and linoleic acid inducethe expression of cytokines and adhesionmolecules in cultured endothelial cells(Hennig et al. 2002; Toborek et al. 2002). Inaddition, both linoleic acid and PCB-77—and more markedly when applied in combina-tion—can generate reactive oxidative speciesthat can trigger oxidative-stress–sensitiveproinflammatory signaling pathways (Henniget al. 2002a). These studies suggest thatenvironmental contaminants such as PCBsare atherogenic in part by their ability to alterendothelial cell lipid profile and metabolismand by inducing oxidative stress and pro-inflammatory genes.Exposure to physiologic concentrations ofspecific fatty acids, such as linoleic acid, cantrigger inflammatory pathways leading to theup-regulation of inflammatory cytokines [e.g.,interleukin-6 (IL-6), IL-8] and adhesion mol-ecules [e.g., vascular cell adhesion molecule-1(VCAM-1), E-selectin]. These genes initiatethe chemoattraction and adhering of mono-cytes, events occurring early in the pathogene-sis of atherosclerosis. The differential effect ofvarious fatty acids is most likely due to differ-ent susceptibility to oxidation and thusgeneration of oxidative stress as well as theirEnvironmental Health Perspectives•VOLUME 113 | NUMBER 1 | January 200583Address correspondence to B. Hennig, Molecular andCell Nutrition Laboratory, College of Agriculture,University of Kentucky, 591 Wethington HealthSciences Building, 900 South Limestone, Lexington,KY 40536-0200 USA. Telephone: (859) 323-4933ext. 81387. Fax: (859) 257-1811. E-mail: [email protected] study was supported in part by grants from theNational Institute of Environmental Health Sciences/National Institutes of Health (ES 07380), the U.S.Department of Agriculture (2001-35200-10675), andthe Kentucky Agricultural Experimental Station.The authors declare they have no competingfinancial interests.Received 24 May 2004; accepted 23 September2004.Research|ArticleDietary Fat Interacts with PCBs to Induce Changes in Lipid Metabolism in Mice Deficient in Low-Density Lipoprotein Receptor Bernhard Hennig,1,2Gudrun Reiterer,2Michal Toborek,3Sergey V. Matveev,4Alan Daugherty,5Eric Smart,4and Larry W. Robertson61Molecular and Cell Nutrition Laboratory, College of Agriculture, 2Graduate Center for Nutritional Sciences, 3Department of Surgery,4Department 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, USAThere 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 vasculardiseases. To test the hypothesis that the interaction of PCBs with dietary fat is dependent on thetype of fat, low-density lipoprotein receptor–deficient (LDL-R–/–) mice were fed diets enrichedwith either olive oil or corn oil for 4 weeks. Half of the animals from each group were injectedwith PCB-77. Vascular cell adhesion molecule-1 (VCAM-1) expression in aortic arches was non-detectable in the olive-oil–fed mice but was highly expressed in the presence of PCB-77. PCBtreatment increased liver neutral lipids and decreased serum fatty acid levels only in