Possible mechanism of congenital malformations induced by exposure of mouse preimplantation embryos to mitomycin C.
ICR mice were treated intraperitoneally with mitomycin C at 5 mg/kg on day 3 of gestation. On day 18 of gestation, fetuses of treated dams were inspected for external, skeletal and visceral malformations. At 6 or 12 hr after mitomycin C treatment, the blastocysts were obtained from the uteri of treated dams and the degenerated cells within inner cell mass (ICM) and trophectoderm (TE) tissues were examined microscopically. On day 5, 8, 11, or 18 of gestation, the uteri of treated dams were obtained and those including embryos/fetuses and placentae were examined histologically. Finally, on each of gestational days 5-14, the blood of the treated dams was collected and the hematological parameters determined. Pre- and postimplantation losses in the dams treated with mitomycin C were significantly increased; increased frequency of abdominal wall defects and lumbar ribs in term fetuses, decreased fetal weight, and increased placental weight were noted as well. No significant increase in visceral malformations was found in term fetuses treated with mitomycin C. Frequency of degenerated cells within ICM and TE of blastocysts from dams treated with mitomycin C was significantly increased as compared with the controls. In dams treated with mitomycin C, decidua developed insufficiently and the trophoblast giant cell layer was not separated from the uterine lumen by maternal components; hemorrhage from the denuded trophoblast giant cell layer into the uterine lumen was noted. The number of erythrocytes, as well as hemoglobin concentration, hematocrit, and the percentage of reticulocytes in blood of dams treated with mitomycin C were significantly lower from days 6-12 of gestation, as compared with controls. The results of the present study showed that an increase in number of degenerated cells within blastocysts results in preimplantation loss and both maternal and embryonic hypoxia during major organogenesis results in postimplantation loss and congenital fetal malformations.
Nagao
T
T
Department of Developmental Toxicology, Hatano Research Institute, Food and Drug Safety Center, Kanagawa 257-8523, Japan. nagaot@kb3.so-net.ne.jp
Saitoh
Y
Y
Yoshimura
S
S
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000818:Animals; D001755:Blastocyst / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D003656:Decidua / Q000187:drug effects / Q000473:pathology; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D051379:Mice; D008813:Mice, Inbred ICR; D016685:Mitomycin / Q000633:toxicity*; D010920:Placenta / Q000187:drug effects / Q000473:pathology*; D011247:Pregnancy; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013723:Teratogens; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D013723:Teratogens; D016685:Mitomycin