Cell sensitivity to transplacental carcinogenesis by N-ethyl-N-nitrosoureais greatest in early post-implantation development

In a clear demonstration of the changing sensitivity of the developing mamm al to transplacental carcinogenesis, Ivankovic and Druckrey [S. Ivankovic, ii. Druckrey, Transplacentare Erzeugung maligner Tumoren des Nervensystem: I.;Athyl-nitroso-harnstoff (ANH) an ED IX-Ratten, Z. Krebsforsch. 71 (1968) 320-360] exposed pregnant ED IX rats to a pulse of N-ethyl-N-nitrosourea ( ENU), a reactive carcinogen with a half-life of 20 min. No tumors were seen with ENU exposure before gestation day 12, but the multiplicity of neuroge nic tumors increased steadily thereafter and was greatest with treatment on day 30, followed by a decline in sensitivity for the last three days of ge station. Similarly, a transplacental study of ENU in the Syrian hamster [B. A. Diwan, S. Rehm, J.M. Rice, Age- and dose-dependent transplacental carcin ogenesis by N-nitrosoethylurea in Syrian golden hamsters, J. Cancer Res. Cl in. Oncol. 122 (1996) 643-652] found that the numbers of tumors induced wer e greatest after exposure of late fetal stages. While these observations su ggested that embryonic cells are refractory to carcinogenesis, an alternati ve explanation could be that a significant tumor yield was not observed bec ause too few target cells were present in the embryo. I have resolved this issue by combining these published data with others on the numbers of neuro ectodermal cells in the developing ED IX rat brain [R. Miiller, M.F. Rajews ky, Elimination of O-6-ethylguanine from the DNA of brain, liver, and other rat tissues exposed to ethylnitrosourea at different stages of prenatal de velopment? Cancer Res. 43 (1983) 2897-2904] and total cell counts of succes sive developmental stages of the Syrian hamster fetus [P.J. Donovan, G.T. S mith, Cell sensitivity to transplacental mutagenesis by N-ethyl-N-nitrosour ea is greatest during early gestation in the Syrian hamster, Mutation Res., 1999, this issue], allowing the risk per cell at different stages of gesta tion to be calculated. Sensitivity to carcinogenesis was found to be greate st early in gestation and to decrease as gestation proceeds. For the rat mo del, tumor frequency per cell changed from 1.3 X 10(-6) at day 12 exposure to 2.6 x 10(-6) at day 23 exposure, a 50-fold decrease. For the hamster mod el, the tumor-initiation rate decreased 1250-fold from 1.2 X 10(-5) at day 7 exposure to 9.6 X 10(-9) at day 13 exposure. Thus, two independent experi ments with different rodent species demonstrate that sensitivity of individ ual cells to damage leading to transplacental carcinogenesis is greatest in the early fetus and lessens markedly as gestation proceeds, in parallel wi th changing sensitivity to mutation (Donovan et al,, Mutat. Res., this issu e). (C) 1999 Elsevier Science B.V,All rights reserved.