White, L.A., C.D. Capperino and B.L. Allen-Hoffmann. (2000). TCDD Induces Expression of Matrix Remodeling Proteases. The Toxicologist 54(1). Abstract #1299.

TCDD - 01746-01-6

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a number of pathological conditions including chloracne, a hyperkeratinization of the skin, as well as an increased incidence of liver and skin cancer. It is generally accepted that the pathological effects of TCDD are mediated through its binding to the aryl hydrocarbon receptor (AhR), TCDD binding to AhR results in translocation into the nucleus, where it dimerizes with ARNT and becomes an active transcription factor binding to specific sequences knwon as xenobiotic response elements (XRE). How this pathway results in the pathological effects of TCDD in target tissues is unclear. Using human skin as a model, we have focused on the effect of TCDD on a family of matrix proteases, the matrix metalloproteinases (MMP). These enzymes are responsible for the majority of extracellular matrix degradation, and their expression is required for processes involving tissue remodeling such as wound healing and development. We identified two potential XRE elements in the promoter of the human MMP-1 (collagenase) gene, suggesting a role for the AhR/ARNT pathway in regulation of this gene. Northern analysis demonstrates that expression of MMP-1, as well as other MMPs, is increased in TCDD-treated keratinocytes, but not in TCDD-treated dermal fibroblasts. Mobility shift analysis shows binding to both the putative XRE elements in the MMP-1 promoter. Our findings have identified a new class of target genes that may be involved in mediating the pathological response of human skin to TCDD exposure.