University of Kentucky: Details
Superfund Research Program
The Impact of Obesity on PCB Toxicity
Project Leader: Lisa A. Cassis
Grant Number: P42ES7380
Funding Period: 2005-2019
Obesity predisposes to cardiovascular disease, which is the primary cause of death in the obese population. During the 2005-2008 funding period, results demonstrate that coplanar PCB ligands of the arylhydrocarbon receptor (AhR), which accumulate markedly in adipose tissue, increase adipocyte differentiation and proinflammatory gene expression. Administration of PCB77 to apolipoprotein E (apoE)-/- mice resulted in an increase in body weight, adipose mass, and macrophage imrnunostaining in adipose tissue (Importantly, mice administered PCB77 exhibited a marked increase in their susceptibility to angiotensin II (Angll)-induced abdominal aortic aneurysm (AAA) formation). Scientists previously demonstrated that Angll-induced AAAs are associated with marked inflammation in vascular and surrounding peri-aortic adipose tissue, and that obesity increases susceptibilty to Angll-induced AAAs.
The working hypothesis of this research is that adiposity and proinflammatory adipokine expression, in response to coplanar PCBs, promote Angll-induced AAAs. Scientists hypothesize that dietary manipulation of fat content will modulate the adverse effects of coplanar PCBs on Angll-induced AAAs.
The first objective identifies the mechanisms for coplanar PCB-induced regulation of proinflammatory gene expression in adipocytes, focusing on oxidative stress and NFkappaB as signaling intermediates. Given that adipocytes store fatty acids, scientists will examine the interplay between polyunsaturated fatty acids (PUFA) of the n-6 versus n-3 family in their ability to promote or abrogate the effects of coplanar PCBs.
The second objective defines the role of the adipocyte AhR in the effects of PCB77 on proinflammatory adipokine expression, body weight, and Angll-induced AAAs.
The third objective determines the effect of diets enriched with linoleic acid (n-6) or linolenic acid (n-3) on PCB77-induced regulation of body weight, ectopic lipid deposition, and the formation and progression of Angll-induced AAAs.
The results of these studies will directly relate to all projects of Superfund through the elaboration of mechanisms where dietary intervention, through fatty acids, can mitigate or augment the toxicity of PCBs on the vascular system, on the ability to measure and detect PCBs in biological samples, and on the pathophysiologic effects of PCB remediation products on adipocyte and vascular function. The long-term health benefits of this research relate to the definition of contribution of PCBs to obesity and to obesity-associated cardiovascular disease.