In utero analysis of sister chromatid exchange: alterations in suscptibility to mutagenic damage as a function of fetal cell type and gestational age.

Abstract

Frequencies of baseline and cyclophosphamide-induced sister chromatid exchanges (SCE) were measured in mouse maternal and fetal cells between days 11 and 19 of gestation. Baseline levels of SCE did not vary as a function of gestational age in either the mother or fetus. Cyclophosphamide-induced SCE frequencies remained constant in maternal cells but declined dramatically in the fetus throughout the latter half of development. Because cyclophosphamide is a metabolically activated mutagen, a direct-acting drug, mitomycin C, was given on days 11 and 15 to determine if the decline in induced SCE levels seen with gestational results from alterations in activating enzymes. A similar decline in mitomycin C-induced SCE levels was noted in fetal tissues as a function of gestational age. Dose-response curves to cyclophosphamide performed on day 13 of gestation showed increases in SCE as a function of cyclophosphamide concentration in both the mother and the fetus. When mutagen-induced SCE levels were compared in different fetal organs, the direct-acting drugs (mitomycin C and daunomycin) were found to induce similar levels in all tissues. Cyclophosphamide, which is metabolically activated, induced higher SCE levels in fetal liver than in lung or gut. Whereas cyclophosphamide induced similar SCE levels in fetal and maternal cells on day 13 of gestation, daunomycin produced fetal SCE levels that were approximately 50% of maternal levels. Simultaneous measurement of the distribution of [14C]cyclophosphamide and [3H]daunomycin in maternal and fetal cells revealed that the lower SCE induction by daunomycin was probably due to decreased ability to cross the placental barrier.