Two-stage skin carcinogenesis by systemic initiation of pregnant mice with 7,12-dimethylbenz(a)anthracene during gestation days 6?20 and postnatal promotion of the F1-generation with the phorbol ester 12-tetradecanoylphorbol-13-acetate

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Abstract
The DMBA-TPA-mediated two-stage skin carcinogenesis experiment was modified in that pregnant mice were systemically treated once during pregnancy with the carcinogen. Intragastric application times were fetal days 6, 8, and 10–20. A control group of pregnant mice received repeated doses (from days 8–20) of sesame oil, which was used as a solvent for DMBA. At the age of 12 weeks, the offspring of the control group were divided into two groups, one of which was left completely untreated, the other received TPA applications over 26 weeks. The 12-week old F 1-progeny of each transplacentally initiated group was also divided into subgroups, which either received no further treatment (subgroups A) or were promoted with TPA (subgroups B). Neither the F 1-animals of the two control groups nor that of the transplacentally initiated but postnatally not promoted subgroups 6A–20A developed skin tumors. The same holds true for the TPA-promoted offsprings of mother animals which had received DMBA at days 6 and 8 of gestation. Skin tumor development after TPA promotion was first observed in animals of subgroup 10B. Thereafter, tumor rates and tumor yields increased and latency periods decreased progressively in the B-subgroups with the postponenment of initiation to later fetal periods. Day 19 of prenatal development proved to be the most sensitive period to transplacental initiation, whereas initiation at day 20 led to a significant decrease in tumor rate and yield. The capability to initiate skin tumors and the extent of initiation can be correlated to both the organogenesis of the epidermis and its proliferative rate in utero.