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 

Studies and Results:

Dr. Cassis and her research team demonstrated that administration of coplanar polychlorinated biphenyls (PCBs) to lean mice promotes glucose and insulin intolerance associated with increased expression of TNF-alpha in adipose tissue. This effect was abolished by an aryl hydrocarbon receptor (AhR) antagonist. Studies in 3T3-L1 adipocytes demonstrated that coplanar PCBs promote oxidative stress and TNF-alpha expression in an AhR-dependent manner. The research team also performed studies examining effects of coplanar PCBs on glucose homeostasis in obese mice. When mice were fed a high fat (HF) diet, PCB-induced impairment of glucose homeostasis was lost, potentially related to sequestration of lipophilic PCBs in adipose tissue. Even more interesting, when obese mice exposed to PCBs were made to lose weight, liberated PCBs began to impair glucose homeostasis, eliminating benefits from weight loss. These findings were published in Environmental Health Perspectives (121:105-10, 2013), and were accompanied by an invited editorial.

Over the last year, the team of researchers completed studies using resveratrol (RSV) as a nutritional polyphenol to mitigate effects of PCBs on glucose homeostasis in vitro and in vivo. Using 3T3-L1 adipocytes, the researchers demonstrated that RSV abolished PCB77-induced oxidative stress, impairment of insulin signaling, and abolishment of glucose uptake. They also demonstrated that administration of RSV in the diet of lean mice abolished PCB77-induced impairment of glucose and insulin tolerance. These findings were recently published in the Journal of Nutritional Biochemistry (24:2168-74, 2013).

The research team is in the midst of examining the phenotype of mice lacking AhR in adipocytes. Results demonstrate that adipocyte deficiency of AhR results in a body weight phenotype in the absence of PCB administration. When fed a HF diet, mice lacking AhR in adipocytes exhibit more pronounced obesity, associated with increased subcutaneous adipose tissue deposition. Moreover, in preliminary studies, the team found that adipocyte deficiency of AhR appears to mitigate acute and chronic effects of PCB77 in lean and obese mice. They plan to continue these studies over the next year.

Significance:

This team of scientists' research is clinically significant for the following reasons: (1) PCB exposure levels are linked to diabetes in humans, and their results demonstrate potential mechanisms for this link, (2) Obesity and type 2 diabetes influence a large percentage of the US population and thus an environmental link is significant, (3) A large percentage of the obese population is trying to lose weight. Their data suggest that a greater body burden of PCBs in obese people may blunt the beneficial effects of weight loss to improve their type 2 diabetes, (4) Resveratrol may be a nutritional intervention that would be beneficial in minimizing the harmful effects of PCBs on parameters of insulin sensitivity, (5) Their findings may uncover a previously unrecognized role of the AhR in adipocytes in body weight regulation. Finally, their data have implications within the context of cumulative risk assessment: obesity affects body burden kinetics of PCBs and associated risks and disease outcomes; and healthful nutrition intervention can reduce disease risks associated with exposure to PCBs.