Sequence-dependent toxicity and small bowel mucosal injury in neonatal mice treated with low doses of 5-azacytidine and X-irradiation at the late organogenesis stage.

A combined treatment of pregnant mice on day 12 of gestation with both azacytidine and X-irradiation in low doses induces sequence-dependent histological effects. These effects, in turn, induce different symptomatic signs if evaluated either prenatally or neonatally. In the azacytidine treatment/X-irradiation sequence the malformations of the fetal forebrain are predominant. Consequently, these dams show a high incidence in the stillbirth rate. Conversely, the X-irradiation/azacytidine treatment schedule leads only to a mild brain hypoplasia, and does not cause an increased stillbirth rate. In these offspring, however, a severe impairment of small bowel epithelial proliferation capacity was found. This is linked to an outstanding neonatal mortality within 48 h after birth. The pathogenesis of these sequence-dependent effects can be attributed to a selective vulnerability of cells in different stages of the generation cycle. This comprises a high degree of cytolethality affecting the S/G2-stage cells in azacytidine/X-irradiation treatment and the G1/S-stage cells in the reverse combinations (Schmahl 1979). The present observations show the validity of a teratological assay in providing a detailed analysis of the cell kinetic responses after combined noxious influences.