While numerous investigations involving animals and techniques of molecular biology have defined some parameters relating to dioxin intoxication, the mechanism of this toxicity and the target organ remain unknown. Current efforts to alleviate the possible public health consequence of dioxin exposure involve detection of these compounds by costly high resolution chemical analysis. However, such techniques, while both precise and definitive, are expensive and may not be able to handle the vast number of samples needed to be tested in an environmental monitoring program. We have recently demonstrated that 2,3,7,8-TCDD is extremely potent in inducing a reversible in vitro change in post confluent cell proliferation and morphology of a cell line, designated XBF, derived frm a keratinizing cell line (XB) cloned from a mouse teratoma. Concentrations of 2,3,7,8-TCDD as low as 10-11 M will induce the """"""""flat-cell effect"""""""". Preliminary experiments indicate that the flat-cell effect will be useful as a novel tool for the study of the mechanism of toxicity associated with exposure to dioxinlike compounds. Other work performed in this laboratory indicates that this effect is specific for the more toxic polychlorinated dioxins and dibenzofurans, and that this system has potential for use as a relatively simple and inexpensive assay for the detection of this activity in various environmental samples including air, soil, sediment, fish, soot, surfaces, and water. We propose to investigate the mechanism of dioxinlike activity by studying various aspects of the flat-cell effect using 2,3,7,8-TCDD, the most potent member of this group, as a prototype. These studies will focus on the specificity of the XBF line, the function of the feeder cells and cell-cell interactions, the relation of this effect to differentiation and the possible association of this effect with gene products of the Ah locus. We also propose to determine the feasibility of using the induction of the flat-cell effect as a semiquantitative screening assay for dioxinlike compounds in environmental samples by validation studies using pure compounds, actual samples, and sample constructs as well as mixtures of chemicals to determine the extent of chemical interactions. Such an assay would allow priority ranking of positive samples for subsequent high resolution chemical analysis and the elimination of negative samples from further testing. This would allow more rational use of the more precise but limited analytical techniques.
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