Stage-specific induction of sister-chromatid exchanges in utero

In order to correlate the induction of sister-chromatid exchanges (SCE) to biological endpoints, and elucidate aspects of this relationships, 7,12-dimethylbenz[a]anthracene (DMBA) and methyl methanesulfonate (MMS), chemicals with different biological actions at different stages in development, have been evaluated for their ability to induce SCE at different gestational ages in the Sprague-Dawley rat. Transplacental exposure to these agents was accomplished by a recently developed intraperitoneal infusion technique to replenish metabolically degraded 5-bromo-2'-deoxyuridine used for SCE visualization. Maternal bone marrow and whole fetal tissue, fetal liver and fetal brain were compared. Day-9 embryo was found to be very sensitive to the effects of both agents, with the ability to induce SCE declining in development in whole fetus and fetal organs. The embryotoxic effects of the agents seem to be ones best correlated with the capacity of the agents to induce SCE. Also, fetal liver is more sensitive than fetal brain to the effects of DMBA compared with MMS, suggesting fetal metabolic activation may have occurred. Measurement of the amount of radiolabelled DMBA reaching the fetal tissue used to estimate SCE indicates that the amount of chemical reaching the fetus does not account for the increased sensitivity, especially at Day 9. Some factor(s) in development, such as differentiation stage, rather than the fetal accessibility to chemical, seem to be important in the induction of SCE in utero.