Carcinogenesis is a multistep process which can be divided experimentally into at least two distinct stages termed initiation and promotion. Tumor promotion has been demonstrated in a variety of tissues and in terms of human cancer there is evidence for multiple stages, some of which appear to be related to a tumor promotion-like stage. Several organochlorine pesticides have been implicated as hepatic tumor promoters. The mechanisms of hepatic tumor promotion are not known, nor is it known if hepatic tumor promoters, such as the organochlorine pesticides, promote tumors in organs other than liver. From a mechanistic, regulatory and health standpoint it is important to determine if tumor promoters are active in more than one organ as is only through the elucidation of common critical events and/or mechanisms that we will be able to identify and safely regulate this group of chemicals. The objectives of this grant proposal are 1), to determine whether organochlorine pesticides that are hepatic tumor promoters mimic and share in common certain biochemical and morphological effects induced by known skin tumor promoters such as 12-0-tetradecanoylphorbol-13-acetate (TPA) on mouse skin and to determine whether they are complete, first or second stage tumor promoters utilizing the mouse skin initiation-promotion models. 2), To investigate and compare the effect of these organochlorine pesticides and TPA in isolated epidermal cells and hepatocytes on various signal-transduction pathways some of which are considered to be involved in skin tumor promotion in an attempt to identify a common mechanism of tumor promotion in more than one organ, and 3), To examine specific TPA or organochlorine pesticide-induced protein phosphorylation utilizing 2-dimensional gel electrophoresis to identify common proteins which are phosphorylated and involved in tumor promotion. These specific 2-D fingerprints will also be examined for their utility to identify tumor promoters in our environment. The above parameters will be investigated in one or more of the following: mouse epidermis in vivo: isolated epidermal cells from CD-1 mice; isolated human epidermal foreskin cells; and isolated mouse hepatocytes.
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