In vitro and in vivo effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on keratinocyte terminal differentiation

Human exposure to the environmental toxin, 2,3,7,8-Tetrachlodibenzo-p-dioxin (TCDD), produces a severe skin pathology known as chloracne. Although several laboratories have previously reported on the aryl hydrocarbon receptor (AhR)-mediated cellular responses of normal human or rodent keratinocytes to TCDD in vitro, little evidence has been available to link these observations to the specific pathology observed in skin. The goal of this thesis project has been to develop a biologically relevant model to explore the impact of TCDD on human epidermal morphogenesis and homeostasis and the role of AhR in mediating these effects. Studies presented here show that TCDD induces accelerated human keratinocyte terminal differentiation in vitro, in an organotypic culturing system, and in vivo, in developing murine skin. Furthermore, analysis of AhR null fetal mouse skin has identified expression of the intermediate filament associated protein, filaggrin, as being AhR responsive. These data suggest that AhR has an endogenous function as a modulator of late-stage keratinocyte terminal differentiation and that TCDD may exert its effects on skin through disruption of this function.