Superfund priority organic chemicals may enter the human food chain by many routes. In areas where these chemicals leach into bodies of water, the chemicals may be taken up by resident fish and shellfish, which may in turn be eaten by humans. Contamination of crops and livestock by superfund chemicals is also possible. Since the adverse health effects of superfund chemicals are dose-dependent, the amount of the ingested material that is systemically absorbed is usually the most important parameter in determining risk. This project seeks to understand some of the factors that influence the bioavailability of superfund chemicals, including intestinal biotransformation and chronic exposure of the animal to other superfund chemicals, such as chlorinated planar polycyclic compounds, that are Ah receptor agonists. As well as inducing CYP1A1, Ah receptor agonists have numerous other biochemical and physiological effects. The investigators propose to test the hypotheses that two Ah receptor agonists found in Superfund sites, namely 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and 3,3',4,4'-tetrachlorobiphenyl (TCB) cause alterations in the physiological and structural make-up of intestinal cells that affect the intestinal bioavailability and biotransformation of lipophilic chemicals. The questions raised by these hypotheses will be investigated using in vivo, in situ and in vitro, including molecular biological, techniques with the catfish as the primary animal model. The first specific aim is to examine the intestinal biotransformation and bioavailability of radiolabeled TCB and 2,2',4,4',5,5'-hexachlorobiphenyl as well as the chlorinated solvent trichloroethene in control and TCDD- or TCB-induced catfish. The second specific aim relates to mechanisms of absorption. Although it is widely thought that lipophilic xenobiotics are absorbed solely by passive diffusion, there is evidence from previous studies that other vectorial carrier-mediated processes mediate absorption. We propose to investigate the expression of selected proteins, P-glycoprotein and glutathione S- transferases, that may be affected by Ah receptor agonists and involved in the transport of lipophilic xenobiotics in intestine of control and induced fish. These studies will provide insight into the processes affecting the dietary bioavailability of important superfund chemicals.
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