Ultrastructural and Biochemical Changes Induced in Mouse Epidermis by a Hyperplastic Agent, Ethylphenylpropiolate¹ Free

A single application of ethylphenylpropiolate (EPP) to mouse skin induces an ordered sequence of morphological and metabolic changes which lead to cell proliferation and epidermal hyperplasia. EPP induces a marked stimulation of the incorporation of labeled precursors into the DNA and RNA of the skin and, to a lesser extent, into protein. The mitotic index, the number of nucleated cell layers, and the thickness of the interfollicular epidermis are increased. The most outstanding ultrastructural changes observed were the dispersion of the chromatin, enlargment of the nucleoli, expansion of the cytoplasm, and a marked increase in the number of polysomes. These ultrastructural changes reach a maximum 24 hr after treatment and then revert rapidly toward normal. They are considerably less 48 hr after treatment, and 96 to 120 hr after treatment the fine structural characteristics of the epidermis are again normal.

Focal areas of necrosis are observed in the epidermis treated with EPP. “Dark cells” seen in these areas morphologically resemble the “dark cells” observed in epidermal wounds induced by other means and the “dark cells” induced in intact mouse epidermis by 12-O-tetradecanoylphorbol-13-acetate (TPA).

EPP causes marked hyperplasia in mouse skin but has little promoting power. Since wounding has some promoting action in mouse skin, it is possible that the weak promoting action of EPP is due to the focal necroses it induces.

The ultrastructural alterations induced in mouse epidermis by EPP differ markedly from those induced by the powerful tumor promoter TPA. EPP fails to induce the opening of the intercellular spaces between the epidermal cells and the reversal of epidermal cell differentiation which are among the most striking effects induced by TPA. It produces only slight alterations in the rough endoplasmic reticulum. Golgi complex, and mitochondria instead of the prominent changes induced by TPA, and fine structural changes induced by EPP are shorter lasting than those induced by TPA.

It remains to be determined whether the differences between the reactions induced by EPP and TPA would be found if other hyperplastic and promoting agents were compared, and, if so, what their relevance is to promotion.