The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes chloracne in humans by mechanisms that are as yet poorly understood. Because TCDD is known to affect keratinocyte differentiation in vitro, we have studied TCDD-dependent morphologic changes and the expression of murine keratin 1 (MK1; differentiation associated) and keratin 17 (MK17; presumably hyperproliferation associated) in HRS/J hr/hr hairless mouse skin. TCDD (0.2 microg in acetone) applied topically to the dorsal skin caused epidermal acanthosis and hyperkeratosis of the dermal cysts as well as an involution of the utricles and the sebaceous glands. By means of in situ hybridization with digoxigenin-labeled riboprobes of sections from untreated and vehicle (control)-treated skin, we localized MK1 mRNA to the epidermal spinous cell compartment. MK17 transcripts were detected only in the derivatives of the hair follicle-utricle epithelium and dermal cysts. No spatial overlap was observed between MK1 and MK17 expression. After TCDD application, MK17 was newly expressed in the upper spinous cell layers of the interfollicular epidermis, although it was suppressed in the involuting utricles. In contrast, MK1 expression in the interfollicular epidermis was not affected by TCDD. Furthermore, MK1 expression was induced in the epithelium of the utricle remnants and in some dermal cysts. These data suggest that increased keratinization of the part of the follicular epithelium corresponding to the dermal cyst epithelium of hairless mice most probably explains the pathogenesis of TCDD-induced chloracne. The results demonstrate, furthermore, that TCDD can differentially affect keratinocyte differentiation in vivo as well as in vitro.