Sister-chromatid exchange and cell replication kinetics in fetal and maternal cells after treatment with chemical teratogens

Abstract

Effects of selected chemical teratogens on sister-chromatid exchange (SCE) frequencies and cell replication kinetics (CRK) in pregnant mice and their fetuses were investigated. Maternal and fetal cells were analyzed for SCE and classified as to whether they had gone through 1 (M1), 2 (M2), or 3 or more (M3+) cell cycles for quantifying cell replication kinetics and estimating average generation time (AGT). The teratogens tested in this system were mitomycin C (MMC), cyclophosphamide (CP), ethylnitrosourea (ENU), dimethylnitrosamine (DMN), lead acetate (LA), benzene (BEN), diethylstilbestrol (DES), diphenyldantoin (DPH), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and dimethyl sulfoxide (DMSO). MMC, CP, ENU, DMN, LA and BEN induced significant increases in SCE in both maternal and fetal cells compared with control values. DES and DPH induced increases in SCE in fetal cells only, whereas MNNG and DMSO did not induce any increase in SCE in either maternal or fetal cells. Chi-square analysis of the relative numbers of M1, M2 and M2+ cells revealed significant heterogeneity among test chemical doses in both maternal and fetal cells treated with all of the chemicals except DES. DES had an effect on fetal cells but not on maternal cells. A significant linear relationship between AGT and test chemical dose was noted for ENU and DMSO in maternal cells and DPH and MNNG in fetal cells. Although statistically significant, the effects of DPH, MNNG, and DMSO on AGT were small, with increases in AGT of only 1 h or less at the highest doses tested. ENU, however, resulted in more than a 2-h increase in the AGT of maternal cells. Average generation time was consistently lower in fetal cells as compared with maternal cells (overall mean AGT +/- S.D. from solvent controls was 8.6 +/- 0.3 h for fetal cells and 11.6 +/- 0.7 h for maternal cells). The results indicate that SCE induction and cell replication inhibition can occur independently, and that the assessment of SCE and CRK in maternal and fetal cells may be a promising approach to the identification of teratogenic agents.