Toward elucidation of dioxin-mediated chloracne and Ah receptor functions.

Target cells and molecular targets responsible for dioxin-mediated chloracne, the hallmark of dioxin toxicity, are reviewed. The dioxin TCDD accumulates in sebum, and thereby persistently activates the Ah receptor (AhR), expressed in bipotential stem/progenitor cells of the sebaceous gland. AhR operates in cooperation with other transcription factors including c-Myc, Blimp1 and ß-Catenin/TCF: c-Myc stimulates exit of stem cells from quiescence to proliferating sebocyte progenitors; Blimp1 is a major c-Myc repressor, and ß-Catenin/TCF represses sebaceous gland differentiation and stimulates differentiation to interfollicular epidermis. TCDD has been demonstrated to induce Blimp1 expression in the sebocyte stem/progenitor cell line SZ95, leading to sebocyte apoptosis and proliferation of interfollicular epidermis cells. These findings explain observations in TCDD-poisoned individuals, and identify target cells and molecular targets of dioxin-mediated chloracne. They clearly demonstrate that the AhR operates in a cell context-dependent manner, and provide hints to homeostatic functions of AhR in stem/progenitor cells.