Obesity predisposes to cardiovascular disease, which is the primary cause of death in the obese population. During the current period of support, 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. We have previously demonstrated that Angll-induced AAAs are associated with marked inflammation in vascular and surrounding peri-aortic adipose tissue, and that obesity increases the susceptibilty to Angll-induced AAAs. The working hypothesis of this proposal is that adiposity and proinflammatory adipokine expression in response to coplanar PCBs promotes Angll-induced AAAs. Moreover, we hypothesize that dietary manipulation of fat content will modulate the adverse effects of coplanar PCBs on Angll-induced AAAs.
In aim 1, we will identify 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, we 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.
In aim 2 we will define the role of the adipocyte AhR in the effects of PCB77 on proinflammatory adipokine expression, body weight, and Angll-induced AAAs.
In aim 3 we will determine 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. Results from these studies will directly relate to all projects of this superfund, through elaboration of mechanisms whereby 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 definition of contribution of PCBs to obesity and to obesity-associated cardiovascular disease.
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