Assessment of the teratogenic potential of acrolein and cyclophosphamide in a rat embryo culture system.
Rat conceptuses were explanted from the uterus on day 10.5 of gestation. The embryos within the yolk-sacs were then transferred to culture bottles containing pure male rat serum either with or without liver microsomes and NADPH. Acrolein (AC), present worldwide in the environment and one of the intermediate metabolites of cyclophosphamide (CPA), was added to these culture mediums. The conceptuses were grown for a period of 48 h after which the morphological features and their degree of differentiation were examined and the DNA and protein contents determined. The effects produced by AC were compared with those obtained by CPA treatment, using the same culture conditions. AC treated embryos and yolk-sacs showed slight but statistically significant inhibition of growth at concentrations of 100 microM and 150 microM. Higher dose levels (200 microM and 250 microM) resulted in a drastic inhibition of growth and differentiation. However, no gross structural defects were observed at the dose-levels used. In contrast, conceptuses cultivated in the presence of CPA (350 microM), liver microsomes and NADPH showed characteristic morphologic lesions. Our findings indicate that AC is lethal to embryos within a narrow dose-range, but has no teratogenic potential. Therefore, AC is not the metabolite which is responsible for the teratogenic effects observed after CPA treatment in vivo. The results also demonstrate that the postimplantation embryo culture system can discriminate between embryolethal and teratogenic effects and that whole embryos in culture can respond to teratogens in a manner similar to embryos exposed in vivo.
D000014:Abnormalities, Drug-Induced; D000171:Acrolein / Q000633:toxicity*; D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D003520:Cyclophosphamide / Q000378:metabolism / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D000447:Aldehydes; D000171:Acrolein; D003520:Cyclophosphamide