Superfund Research Program
Endocrine Disruptors in the Environment and their Influence
Project Leader: Christopher K. Glass
Grant Number: P42ES010337
Funding Period: 2000-2010
Final Progress Reports
The overall goals of Dr. Glass’ project are to investigate the roles of nuclear receptors as targets of environmental pollutants that have the potential to disrupt endocrine functions. Nuclear receptors are a class of proteins that act to turn genes on or off in a manner that is regulated by small molecules. Examples of this class of proteins include the estrogen receptor, which in response the binding of estrogen controls the actions of many genes, including genes that are required for sexual development and function. The function of the estrogen receptor can be altered by a variety of environmental pollutants, including plychlorinated biphenyls (PCBs), raising the possibility that exposure to these compounds could disrupt numerous estrogen receptor-dependent process. Additional examples include the peroxisome proliferator-activated receptors (PPARs) and the liver X receptors (LXRs). PPARγ is a nuclear receptor that has regulates fat cell development, glucose metabolism and inflammation. It has recently been shown that PPARγ and the related receptor PPARδ can be regulated by pthalates that are used in industry as plasticizers. This observation raises the possibility that high levels of exposure to pthalates, which are nearly ubiquitous in the environment, could alter PPARγ function, resulting in effects on inflammation and metabolism. Liver X receptors regulate gene expression in response to the binding of oxysterols.
Project investigators made the unexpected finding during the past year that liver X receptors (LXRs), protect macrophages from chemical and bacterial-induced apoptosis. In collaboration with Dr. Michael Karin’s laboratory, Dr. Glass’ team demonstrated that combined activation of LXR and RXR protected macrophages from apoptosis caused by infection with B. anthracis, E. coli or S. typhimuirum. Expression profiling studies demonstrated that LXR and RXR agonists induced the expression of anti-apoptotic regulators including AIM/CT2, Bcl-XL, and Birc1a. Conversely, LXR and RXR agonists inhibited expression of pro-apoptotic regulators/effectors including caspases 1, 4/11, 7 and 12, Fas ligand, and Dnasel13. The combination of LXR and RXR agonists was more effective than either agonist alone at inhibiting apoptosis in response to a variety of inducers of apoptosis and acted synergistically to induce expression of AIM/CT2. Inhibition of AIM/CT2 expression in response to LXR/RXR agonists partially reversed their anti-apoptotic effects. These findings reveal unexpected roles of LXRs and RXRs in the control of macrophage survival and raise the possibility that LXR/RXR agonists may be exploited to protect macrophages from bacterial pathogens and chemical inducers of apoptosis.