Fetal anomalies produced subsequent to treatment of zygotes with ethylene oxide or ethyl methanesulfonate are not likely due to the usual genetic causes.
Earlier studies in this laboratory revealed that ethylene oxide (EtO) or ethyl methanesulfonate (EMS) induced high frequencies of midgestation and late fetal deaths, and of malformations among some of the surviving fetuses, when female mice were exposed at the time of fertilization of their eggs or during the early pronuclear stage of the zygote. Effects of the two mutagens are virtually identical. Thus, in investigating the mechanisms responsible for the dramatic effects in the early pronuclear zygotes, the two compounds were used interchangeably in the experiments. First, a reciprocal zygote-transfer study was conducted in order to determine whether the effect is directly on the zygotes or indirectly through maternal toxicity. And second, cytogenetic analyses of pronuclear metaphases, early cleavage embryos, and midgestation fetuses were carried out. The zygote transplantation experiment rules out maternal toxicity as a factor in the fetal maldevelopment. Together with the strict stage specificity observed in the earlier studies, this result points to a genetic cause for the abnormalities. However, the cytogenetic studies failed to show structural or numerical chromosome aberrations. Since intragenic base changes and deletions may also be ruled out, it appears that the lesions in question induced in zygotes by the two mutagens are different from conventional ones and, therefore, could be a novel one in experimental mammalian mutagenesis. Alternatively, the mechanism could involve a non-mutational 'imprinting' process that caused changes in gene expression.
Katoh
M
M
Biology Division, Oak Ridge National Laboratory, TN 37831.
Cacheiro
N L
NL
Cornett
C V
CV
Cain
K T
KT
Rutledge
J C
JC
Generoso
W M
WM
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D002970:Cleavage Stage, Ovum / Q000187:drug effects; D003582:Cytogenetics; D004624:Embryo Transfer; D005020:Ethyl Methanesulfonate / Q000633:toxicity*; D005027:Ethylene Oxide / Q000633:toxicity*; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D051379:Mice; D011247:Pregnancy; D015053:Zygote / Q000187:drug effects*
D005020:Ethyl Methanesulfonate; D005027:Ethylene Oxide