Pollutant-Particle Systems and Xenobiotic Bioactivation

Dr. Wayne Backes and Dr. James R. Reed

Superfund sites typically contain complex mixtures of pollutants including chlorinated hydrocarbons, metals, and other toxic organic and inorganic compounds. Remediation of these sites results in some exposure of the surrounding population to airborne soil dust contaminated with hazardous substances or particulate matter (PM) emitted from the treatment devices. LSU-SRP researchers have shown environmentally persistent free radicals (EPFRs) are present in at least some contaminated Superfund soils and formed in high concentration during incineration and thermal treatment of hazardous substances. These PM-associated EPFRs exist for days in the atmosphere and may continually form in contaminated soils. Once inhaled, they initiate and participate in catalytic chain cycles generating reactive oxygen species (ROS) and persist in biological media long enough to lead to pulmonary and cardiovascular damage. Since the discovery of EPFRs associated with Superfund sites is relatively recent, little is known about their mechanisms of toxicity. The toxic responses are thought to be mediated through the generation of ROS, with several studies implicating the P450 system in this process. The goal of this study is to examine the roles of the P450 and HO-1 systems in the response to EPFR exposure within an organism. The hypothesis being addressed is that EPFRs associated with ultrafine particles:

  1. Directly inhibit cytochrome P450-mediated activities
  2. Decrease the expression of several P450 enzymes and increase the expression of ROS-protective enzymes (such as HO-1)
  3. Alter P450-dependent ROS production

Dr. Wayne Backes' research group is determining if decreases in P450 expression is the result of a ROS-mediated alteration in NFκB expression, where NFκB activation leads to decreases in P450 and increases in HO-1 expression that serve to limit oxidative damage in exposed tissues. Taken together, these studies are expected to provide novel information regarding how the P450 and HO-1 systems respond to EPFR exposure and affect EPFR-mediated toxicity.