Neoplastic transformation of immortalized human keratinocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most powerful carcinogen ever tested in animals. Recent epidemiological studies have suggested its carcinogenic potential in humans. In the present study, nontumorigenic human epidermal keratinocytes immortalized by adenovirus 12-simian virus 40 (Ad12-SV40) were transformed by exposures of TCDD equal to or greater than 0.1 nM for 2 wk. These transformed cells showed morphological alterations and induced carcinomas when transplanted into nude mice, whereas no such transformation phenotypes were observed with exposures of less than 0.1 nM for 2 wk. Primary human epithelial keratinocytes exposed to various concentrations of TCDD failed to show any evidence of transformation. Induction of aryl hydrocarbon hydroxylase activity was dose dependent, as was transformation. Thus, the carcinogenicity of TCDD in this human cell system appears to be an Ah receptor-mediated process. The present study represents the first evidence of neoplastic conversion of human cells exposed to this environmentally important chemical.