Carcinogenesis: a late effect of irreversible toxic damage during development

Intrauterine and early postnatal life are periods of exceptionally high susceptibility to certain kinds of chemical carcinogens. The most potent known transplacental carcinogens are direct acting alkylating agents. Most nonreactive compounds, which require enzymes for metabolic conversion into chemically reactive “proximate carcinogens,” are less effective because the required enzymes are present at low levels in the fetus, and many proximate carcinogens are too reactive to reach the fetus when formed in maternal tissues. Despite this, many carcinogens which require metabolic activation are very active transplancentally, as the intrinsic susceptibility of rapidly dividing fetal cells compensates effectively for comparatively low tissue levels of reactive metabolites. Transplacental carcinogens of all kinds are most effective late in gestation, generally after organogenesis has begun and after the period of greatest susceptibility to teratogens. Only a small number of known carcinogens have been tested for transplacental carcinogenic activity. The great majority of tumors induced transplacentally in the well-studied rodent and lagomorph species (mouse, rat, Syrian hamster, and rabbit) have morphologic features of adult, rather than embryonal, tissues. A given agent tends to induce in a given species largely the same types of tumor when given transplacentally as when administered directly to postweaning animals, unless its carcinogenic effect in the latter is ascribable to some peculiarity of distribution, metabolism, or physiology. In a second species, the spectrum of tumors induced either before of after birth may be quite different. For bioassay of suspected carcinogens, the significance of perinatal carcinogenesis lies in the facts that the fetal and preweaning rodent is an extremely sensitive indicator of carcinogenic activity, and that the facile adaptibility of fetal cells to tissue culture and their rapid expression in vitro of properties of neoplastic transformation make possible a rapid in vivo/in vitro screening system for chemical carcinogens.