Superfund Research Program

Polychlorinated Biphenyls, Nutrition and Diabetes

Project Leader: Lisa A. Cassis
Grant Number: P42ES007380
Funding Period: 2005-2019

Project-Specific Links

Final Progress Reports

Year:   2019  2013  2007 

Obesity is at epidemic proportions in the US, with 64.5% of the adult population considered overweight. In humans and rodents, PCBs concentrate markedly in adipose tissue due to their high lipophilicity. Results during the previous period of support demonstrated that PCB77, an AhR ligand, increased adipocyte differentiation and expression of proinflammatory adipokines. These effects, coupled with the increased number of adipocytes from PCB exposure, would be anticipated to promote inflammation in adipose tissue. Low grade inflammation in obesity has been suggested to link obesity to various diseases, including atherosclerosis.  Previous research in Dr. Lisa Cassiss' University of Kentucky laboratory demonstrated that obesity promotes abdominal aortic aneurysms (AAAs), a vascular disease with a major proinflammatory component. It is currently unknown whether in vivo exposure to PCB77 regulates these dynamic vascular diseases.

During the current period of support, Cassis defined the in vivo effects of PCB77 on obesity and associated vascular diseases, including atherosclerosis and AAAs. Importantly, previous results suggest that inflammation in peri-aortic adipose tissue contributes to these vascular pathologies. Thus, Cassis hypothesized that PCB77, an AhR ligand, would promote inflammation in peri-aortic adipose tissue and worsen these vascular diseases. Male apolipoprotein E (apoE) deficient mice were infused by osmotic minipump with saline or angiotensin II (AngII, 1,000 ng/kg/min) for 28 days. One week prior to AngII infusion, mice were administered PCB77 by intraperitoneal injection. Mice received a second dose of PCB77 one week after the onset of AngII infusion. Interestingly, saline- and AngII-infused mice treated with PCB77 exhibited an increase in adipose tissue mass and weight gain. AAA incidence was increased by PCB77, and AAA severity increased markedly, with ruptured AAAs in several mice. The extent of atherosclerosis was also increased in AngII-infused mice injected with PCB77. Finally, Cassis' research team observed an unexpected phenotype of ectopic lipid deposition in PCB-injected mice.

In separate studies, this project team examined the effects of PCB77 in a different mouse model of atherosclerosis, and designed the protocol to specifically define whether PCB77 increases developing atherosclerotic lesions. Male LDL receptor -/- mice (LDLr-/) were fed a diet enriched in fat (42% kcal as fat) and cholesterol (0.05%) for three months. During months two and three, mice were separated into groups for administration of vehicle (safflower oil) or PCB77 (49 mg/kg, i.p., the same dosing regimen as used in apoE-/- mice, four injections over a two month period). Results demonstrate that administration of PCB77 increased the extent of atherosclerosis, even though PCB77-injected mice exhibited reductions in serum cholesterol concentrations and proatherogenic lipoproteins.

The significance of this research is that exposure of obese individuals to PCBs may promote further obesity, and contribute to obesity-associated inflammatory diseases (atherosclerosis, AAA).  Tthese findings are significant since they demonstrate, for the first time, that in vivo exposure to relatively low doses of PCB77 can increase inflammatory-based diseases of the metabolic syndrome, including obesity, atherosclerosis, and AAA formation.