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Characterization of Histochemically Detectable Altered Hepatocyte Foci and Their Relationship to Hepatic Tumorigenesis in Rats Treated Once with Diethylnitrosamine or Benzo(a)pyrene within One Day after Birth¹

Division of Biological and Medical Research, Argonne National Laboratory, Argonne, Illinois 60439 [C. P., E. F. S., B. A. C., V. A. L., J. A. B.], and Department of Radiology, The University of Chicago, Chicago, Illinois 60637 [S. D. V.]

A new experimental system was used to examine the stages of chemically induced hepatic neoplasia in the rat. The treatment protocol involved the i.p. injection of a single dose of carcinogen [diethylnitrosamine or benzo(a)pyrene] into male and female rats within 1 day after birth, followed by dietary exposure to promoter (0.05% dietary phenobarbital) beginning at weaning. Rats were killed at intervals, and their livers were examined for tumors and for histochemically detectable foci of altered hepatocytes using six histochemical markers. Through serial frozen-sectioning techniques and computer-assisted image analysis, foci containing between one and six markers were identified, and their average diameters were calculated. The same complement of histochemical tests was applied to the primary hepatic tumors observed in this study.

The principal findings were the following. (a) Both the diethylnitrosamine and benzo(a)pyrene treatments were tumorigenic and produced foci with similar phenotypic properties (numbers and identities of histochemical markers). (b) Foci relative growth rates and growth capacities (ranges of possible growth rates) were directly related to foci phenotypic complexity levels (numbers of markers per focus). (c) Individual foci were phenotypically stable; i.e., they neither gained nor lost markers. (d) A substantial fraction of the tumors observed in this study had fewer markers than the most complex foci.

On the basis of these observations, we suggest that foci emerge as the result of a specific set of cellular changes solely inducible by carcinogenic stimuli, but the foci do not evolve through progressively more deviated forms into tumors. Instead, we postulate that tumorigenesis involves a separate transformation event that may occur in a susceptible fraction of foci subsequent to their induction or, alternatively, may occur at the time of exposure to carcinogen, in parallel with the carcinogenmediated events leading to focus formation.

¹ Supported by the United States Department of Energy under Contract W-31-109-ENG-38.

² To whom requests for reprints should be addressed.

Received 9/15/83. Accepted 5/ 9/84.

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