Critical comparison of histological and morphometric changes in SENCAR mouse epidermis in response to n-dodecane, 12-O-tetradecanoylphorbol-13-acetate and mezerein

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Abstract
n-Dodecane, a previously little-studied tumor-promoting agent and mezerein, a diterpenoid natural product, have both been reported to have activity primarily in Stage II of two stage tumor promotion in SENCAR mouse skin. Histological changes in this tissue were therefore investigated in response to these agents in order to determine whether changes could be identified which were common to Stage II promotion by both compounds, and specific in this respect compared to those induced by the complete promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA). All three agents were applied at doses which have previously been found active in multistage tumorigenesis studies in this strain. A single dose of 50 mg dodecane induced no increase in the number of interfollicular cell layers or epidermal thickness, nor any observable inflammation, 6–144 h after application. In contrast, marked increases were predictably observed with TPA and mezerein, maximal responses occurring after 48–72 h. n-Dodecane induced no increase in the number of keratin-ocytes with dense cytoplasm and increased affinity for basophilic dyes (dark cells), only TPA demonstrating this activity. The alkane likewise did not increase the number of pyknotic basal keratinocytes indicating that toxicity would not account for the low Stage I activity of this agent in the way proposed for mezerein which was the most active in this respect, inducting a significant increase 48 h after treatment. Like TPA and mezerein, n-dodecane induced a significant increase in large intra-mitochondrial densities. Forty-eight to seventy-two hours after application, dodecane induced a significant decrease in the numbers of dendritic epidermal cells, a response which was also observed for TPA and mezerein, although occurring somewhat more rapidly. All three agents appeared to induce these cells to retract their characteristic processes. After four applications of n-dodecane the number of epidermal cell layers and mitotic index were equal to or greater than those observed with TPA. These findings show that in SENCAR epidermis the previously uncharacterized tumor-promoting agent n-dodecane induced essentially no histologic changes in mouse skin in common with mezerein, a second agent with activity primarily in Stage II of two stage tumor promotion, which were not also shown by the complete promoter TPA. The only characteristic specific to Stage II promoting agents therefore remains an inability to induce increased numbers of dark cells. In most other respects dodecane induced responses similar to those observed for TPA, although a distinctly different temporal dependence was noted in several cases. It is also reported for the first time that promoting agents of widely different chemical structure induced qualitative and quantitative changes in epidermal non-keratinocytes, which are principally of bone marrow origin.

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