In vitro developmental toxicity of five direct-acting alkylating agents in rodent embryos: structure-activity patterns.
Five direct-acting alkylating agents were examined qualitatively and quantitatively for their ability to produce developmental toxicity in rodent postimplantation embryos. These agents were structurally related and were capable of donating either a methyl (methylnitrosourea, MNU; methylnitronitrosoguanidine, MNNG; methyl methanesulfonate, MMS) or ethyl (ethylnitrosourea, ENU; ethyl methanesulfonate, EMS) group to nucleophiles. These agents' reactivities were known to differ. In day 10 rat embryos in vitro a single, 2-hour exposure was shown to be sufficient to elicit dose-dependent increases in embryo lethality and malformations. Qualitatively, the patterns of embryo malformations reported in treated embryos paralleled those observed in in vivo studies, especially in regard to adverse effects on central nervous system and craniofacial systems. Quantitatively, the order of potency of these agents in vitro was: MNNG greater than MNU greater than ENU greater than MMS greater than EMS. In vivo studies reported a different order of potency. In vitro, methylating agents were consistently more potent than ethylating agents. Other chemical properties such as nucleophilic reactivity or half-life under physiological conditions could not explain observed potency relationships. Future investigation of other chemical properties of these agents such as specific alkylation and carbamylation reactivities may expand these initial structure-activity observations.
Faustman
E M
EM
Department of Environmental Health, University of Washington, Seattle 98195.
Kirby
Z
Z
Gage
D
D
Varnum
M
M
D000477:Alkylating Agents / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects*; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange; D008741:Methyl Methanesulfonate / Q000633:toxicity; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D008770:Methylnitrosourea / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D000477:Alkylating Agents; D008769:Methylnitronitrosoguanidine; D008770:Methylnitrosourea; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D005038:Ethylnitrosourea