Superfund Research Program
Bioavailability of Chlorinated Compounds
Project Leader: Margaret O. James
Grant Number: P42ES007375
Funding Period: 1995-2006
The goals of this research project are to understand factors affecting the bioavailability of Superfund chemicals. The project investigators are studying the processes involved in transferring Superfund chemicals from the environment into the body, as well as what happens to the chemical form of the pollutant once it is absorbed by the animal. The team’s studies use the channel catfish as an animal model for examining the interactions of Superfund chemicals with transporter proteins in the intestine and liver, and biotransformation enzymes in these organs. This research is important because the amount of chemical present in the body, and its exact molecular structure, will determine whether or not there will be adverse health effects related to exposure to the chemical.
Advances were made in 2004 regarding the biotransformation of the chlorinated pesticide, methoxychlor, to potentially toxic metabolites in a fish species likely to be exposed to this chemical at Superfund sites, the channel catfish. Methoxychlor was introduced as a pesticide in place of DDT, but subsequent studies have shown it is an endocrine disruptor, and it has recently been banned from the US. However, it is still present in the environment. The researchers showed that methoxychlor was metabolized by cytochrome P450 enzymes in the liver and intestine to mono-desmethylmethoxychlor (OH-MXC) and di-desmethylmethoxychlor (HPTE). Both of the metabolites produced by cytochrome P450 have been shown by other investigators to be endocrine disruptors through interactions with estrogen receptors. Treatment of the catfish with a polycyclic aromatic hydrocarbon to increase the amount of cytochrome P4501A1 in the liver and intestine resulted in more rapid formation of both OH-MXC and HPTE. In 2004, the team determined that the OH-MXC was further metabolized by glucuronidation (combination with a sugar molecule) to a non-toxic metabolite in liver and intestine, but that this process was relatively inefficient in the catfish. They found that methoxychlor treated catfish retained residues of OH-MXC and HPTE, but not parent methoxychlor in their livers. Preliminary studies suggested that more HPTE than OH-MXC was present, though we have not completed quantitation. These results are important in understanding the toxicity of methoxychlor. Finding that treatment with a polycyclic aromatic hydrocarbon increases methoxychlor metabolism suggests that exposure of fish to mixtures of these two chemicals with result in greater toxicity, because of the more rapid formation of the toxic metabolites. Furthermore, finding that residues of the toxic metabolites HPTE and OH-MXC are retained by the catfish suggests that the fish may be impacted by these toxic metabolites after the parent methoxychlor has been cleared from the animal.