Dioxin-like Organohalogen Carcinogenesis

Dioxin-like organohalogens include polychlorinated dibenzodioxins, dibenzofurans and 11 planar bifenyls (PCB). In addition, brominated flame retardants (PCDE) may share many of their characteristics. They are persistent environmental pollutants which acc umulate in food chains. Human exposure occurs from food, predominantly from oily fish or derived products. They are concidered carcinogenic, inhibit the immune system, and induce developmental disorders in reproductive and neural organs. Their toxicity an d risk assessments are important to Norway, as a main producer of oily fish. These issues, including their carcinogenic properties, have recently gained high interest in scientific and public discussions. These substances bind to and activate an intracell ular receptor, the Aryl hydrocarbon (Ah) receptor, which subsequently translocate to the nucleus and initiate transcription of a specific set of genes. It is currently not understood how or if this effect is related to the development of cancer. In this p roject we will investigate if Ah receptor activation cross-talk with two cell regulatory pathways; the growth regulatory signalling from EGF receptor to ERK1/2, and the regulation of the cell cycle and cell death regulation by Mdm2-p53. Such effects may explain the growth inhibition observed in non-preneoplastic cells, and the increased cell survival observed during carcinogenesis. Included in the project is a research stay at Institute of Environmental Medicine at Karolinska Institutet, Stockholm.