Tumour promotion by TCDD in skin of HRS/J hairless mice

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) serves as the prototype for a group of environmental toxicants, the halogenated aromatic hydrocarbons 1–3 , which evoke a characteristic pattern of acute toxic and biochemical responses, and which produce these effects by stereospecific and reversible binding to a soluble protein receptor 2,4,5 . The chronic administration of TCDD6 –9 (and several other halogenated aromatic hydrocarbons) 10–13 to rats and mice has produced an increased incidence of hepatocellular carcinomas as well as tumours in other tissues. However, because TCDD is not a mutagen 14,15 and does not bind appreciably to DNA in vivo 16 , it has been suggested that this compound is not a complete carcinogen, but rather acts as a tumour promoter, enhancing neoplastic expression in already initiated cells 17,18 . TCDD has been shown to be a potent tumour promoter in a two-stage model of carcinogenesis in rat liver 19 , but has proven ineffective in the classical model in mouse skin (using CD-1 and Swiss-Webster mice) 20,21 . We have recently shown that TCDD produces epidermal hyperplasia and hyper-keratosis, and squamous metaplasia of the sebaceous glands in mice bearing the recessive trait, hairless ( hr ), but causes no changes in the skin of mice which are wild type or heterozygous at this locus 22 . Here we examine the capacity of TCDD to promote tumour formation in the skin of HRS/J hairless ( hr/hr ) mice and their congeneic, haired ( hr /+) littermates. Following the application of an initiating dose of a carcinogen, repeated skin application of TCDD produced papillomas in hr/hr mice but not hr /+ mice. In HRS/J hairless mice, tumour promotion by TCDD elicits the same incidence and multiplicity of skin papillomas as does the classical tumour .promoter, 12- O -tetradecanoylphorbol-13-acetate (TPA), but at l/100th the dose.