Loertscher, J.A., C.A. Sattler, and B.L. Allen-Hoffmann. (2000). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Accelerate Differentiation, But Not Apoptosis, of Human Keratinocytes in Organotypic Culture. The Toxicologist 54(1). Abstract #1298.

TCDD - 01746-01-6

Human exposure to the environmental toxin TCDD produces a severe skin pathology known as chloracne. Historically, the primary tool employed to explore the molecular basis of TCDD's effect upon skin has been monolayer culture of keratinocytes. Because monolayer culture cannot recapitulate the three dimensional architecture or epithelial-mesenchymal interactions found in skin, organotypic culture, which accounts for these factors, would be an ideal system in which to investigate the effect of TCDD on intact skin. In new experiments we have shown that TCDD causes accelerated differentiation in a three dimensional, organotypic skin model. Analysis at both the light and electron microscope levels reveals a fully diferentiated cornified layer in TCDD-treated organotypic cultures at earlier time points than observed in vehicle (DMSO)-treated controls. In situ 3' end labeling reveals no increase in nucleosomal fragmentation, a characteristic of apoptosis, in TCDD-treated organotypic cultures. Furthermore, basal cells in TCDD- and DMSO-treated organotypic cultures show no differences in proliferation as measured by quantification of BrdU positive nuclei. We hypothesize that TCDD exerts its effects upon intact skin through transcriptional modification of a mesenchymally-produced growth factor, which in turn could produce changes in the differentiation program of the epithelial layer. The described in vitro organotypic skin model will be used to test both the validity of this hypothesis and the cell type-specific role that the aryl hydrocarbon receptor (AhR) plays in TCDD toxicity in skin.