Superfund Research Program

The Aryl Hydrocarbon Receptor/Transcription Factor as a Regulator of Hydrocarbon Bioactivity

Project Leader: David H. Sherr
Grant Number: P42ES007381
Funding Period: 1995 - 2005

Project-Specific Links

Final Progress Reports

Year:   2004  1999 

Scientific evidence is accumulating that common environmental pollutants that are carcinogenic, including many that we breathe daily, may also suppress the human immune system. This combination of traits suggests that in addition to inducing cancers, they suppress the primary biologic system responsible for defending against newly formed tumors.

In previous studies, Dr. Sherr and his research team demonstrated that aromatic hydrocarbons produced by the combustion of fossil fuel are among those substances that can both induce cancer and suppress the immune system. They demonstrated that hydrocarbons induce a suicide program in immature B lymphocytes (i.e. the antibody-producing cells) within the bone marrow, where B lymphocytes develop. The implications of these studies is that exposure to aromatic hydrocarbons may compromise the ability to generate robust, effective antibody responses against pathogenic bacteria or viruses. Notably, the induction of a B cell suicide program appears to be a mechanism of immunotoxicity common to several environmental chemicals.

For example, in the past year, project investigators have shown that phthalates, a class of chemicals mainly used as plasticizers in many common consumer products, similarly induce a genetically encoded death program in immature lymphocytes. The molecular mechanism through which this occurs involves a protein receptor within the B cells (the peroxisome proliferator activated receptor, or PPAR.). In addition to phthalates, which are environmentally ubiquitous, other molecular agonists that can bind to PPAR include prostaglandins, which are signaling molecules produced in the body, and anti-diabetic drugs currently in wide clinical use. Once bound by these agonists, PPAR initiates a cascade of biochemical interactions resulting in the cell’s demise.

Over the last year, project investigators have made considerable progress in defining the components of that biochemical cascade. The death signal appears to be initiated by biochemical modifications involving kinases, enzymes that add phosphate groups onto signaling molecules, often other kinases. The addition of these phosphate groups activates the target protein/kinase and thereby propagates a death signal. Death kinases are activated at extremely low concentrations of PPAR agonists, and their activation results in the recruitment of a group of proteins (caspases) that deliver the final death stimulus.

The researchers' current studies are focused on defining the order of death kinase and caspase activation. By mapping out the death pathways of such chemically disparate environmental pollutants as aromatic hydrocarbons and phthalates, they will be able to compare them and determine if they are similar or distinct. Indeed, the researchers are also investigating the possibility that these two classes of pollutants can interact to yield a more intense death signal than could either alone.

Project investigators' results indicate that the bone marrow microenvironment in which antibody-forming B lymphocytes develop is exquisitely sensitive to environmental chemicals. Their experiments also raise the likely possibility that other lineages of blood cells that develop in the marrow environment, such as neutrophils and red cells, are also at risk from exposures to phthalates or aromatic hydrocarbons.