Superfund Research Program
Developmental Toxicity of non-Dioxin-like PCBs and Chemical Mixtures
During 2009, Dr. Stegemans team continued to address the regulation of cytochrome P450 (CYP) genes (coding for enzymes that metabolize environmental chemicals) in zebrafish, their primary developmental model, and killifish, which have developed resistance to the toxicity of PCBs. In zebrafish, the researchers examined selected CYP genes for regulation by a receptor, PXR, which could be the major xenobiotic sensor. Ten CYP2AA genes occur in tandem on chromosome 23. Some are developmentally expressed, and there is a PXR binding site in the cluster just upstream of CYP2AA1. Chemicals thought to bind the PXR differentially affected expression of CYP2AA genes in embryos and adults. The researchers completed analysis of gene structure of all 89 zebrafish CYP genes and constructed models of several CYP proteins, including all five CYP1s.
In New Bedford Harbor killifish, resistance adaptation following multi-generational exposure to PCBs includes lack of CYP1A induction. To address the resistance mechanism, the researchers examined (in collaboration with the Mechanism and Impacts of Dioxin Resistance in Fish project) activation of the AHR to a DNA binding form, in tissues of resistant and susceptible fish. The two populations differed markedly, with resistant fish directly from the field having an activated receptor, which decreased upon treatment with an AHR agonist. An opposite and predicted pattern was seen with susceptible fish. The researchers also examined whether PCB adaptation extends to CYPs other than CYP1s. Expression of PXR and also CYP3A65, and response to PCB congeners differed in fish from the two populations.
The studies in both species are expanding the view of how drug- and pollutant-metabolizing enzymes may be involved in effects in embryos and the nature of adaptation to chemicals.