Difference in teratogenic potency of ethylenethiourea in rats and mice: relative contribution of embryonic and maternal factors.
Ethylenethiourea (ETU) is a potent teratogen in the rat but not in the mouse or any other species tested. Embryotoxic and teratogenic effects are produced in mice only after exposure to 10-40 times the teratogenic dose of ETU in rats. This study was undertaken to determine whether the difference in sensitivity between rats and mice is due to differences within the embryo, to maternal metabolic differences, or both. Comparably staged rat and mouse embryos (gestation day 10.5 and 8.5, respectively) with intact extra-embryonic membranes were maintained under identical conditions in whole embryo culture and exposed to static concentrations of ETU for 48 hours. The teratogenic effects of ETU were qualitatively similar in both species, characterized by excessive fluid accumulations in embryonic structures. The most common abnormalities were distended neural tube, especially in the hindbrain, and clear blisters on the caudal region. At least two times as much ETU was required to produce a similar incidence of abnormalities in mice as in rats. Thus, there is some intrinsic difference in the quantitative response of rat and mouse embryos to ETU, but it is insufficient to account for the in vivo discrepancy. The role of maternal metabolism in modifying the teratogenicity of ETU was assessed by adding hepatic S-9 fractions from Aroclor 1254-induced rats and mice to whole embryo culture. Rat S-9 had no effect on ETU teratogenicity. Mouse S-9 virtually eliminated the formation of abnormalities typical of ETU in both rat and mouse embryos. Decreased exocoelomic fluid osmolality, a physiological effect produced by ETU, also was not observed in embryos exposed to ETU and mouse S-9. ETU-typical defects were observed in embryos exposed to ETU and mouse S-9 which had been treated with carbon monoxide to inactivate its monooxygenase system, indicating that the mouse S-9 was metabolizing ETU. A surprising result was that adding mouse S-9 to embryo cultures containing ETU resulted in the formation of abnormalities (principally open neural tube) that were not observed in in vitro rat or mouse embryos exposed to ETU alone, or in mouse embryos in vivo. We believe that the most likely cause of these abnormalities is a putative ETU metabolite, which is rapidly excreted by the dam in vivo, but accumulates to teratogenic concentrations in vitro.
Daston
G P
GP
Human and Environmental Safety Division, Procter & Gamble Company, Cincinnati, Ohio 45239-8707.
Yonker
J E
JE
Powers
J F
JF
Heitmeyer
S A
SA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005031:Ethylenethiourea / Q000378:metabolism / Q000633:toxicity*; D007093:Imidazoles / Q000633:toxicity*; D048289:Imidazolidines; D008099:Liver / Q000378:metabolism; D008110:Liver Extracts / Q000494:pharmacology*; D051379:Mice / Q000196:embryology*; D009924:Organ Culture Techniques; D051381:Rats / Q000196:embryology*; D011919:Rats, Inbred Strains
D007093:Imidazoles; D048289:Imidazolidines; D008110:Liver Extracts; D005031:Ethylenethiourea; C004916:ethylene urea; C029899:imidazole