Effects of developmental stage and tissue type on embryo/fetal DNA distributions and 5-fluorouracil-induced cell-cycle perturbations.
Cell-cycle analysis of nuclei obtained from the circulating erythroblasts (gestational day [GD] 11-16), livers (GD 14-19), and whole embryos (GD 10-13) or remaining (extrahepatic) tissues (GD 14-16) of rat embryos/fetuses revealed age- and tissue-dependent variations in the relative percentages of cells in the G0/G1, S, and G2/M phases of the cell cycle. With development, the rate of cell proliferation declined resulting in decreases in the relative percentage of S-phase cells and increases in the G0/G1 percentage, while the percentage of G2/M-phase cells remained relatively constant. Comparing tissue cell-cycle profiles during development, erythroblasts exhibited the most rapid age-dependent decline in S-phase percentage (from 75% at GD 11 to 8% by GD 14), embryos/extrahepatic tissues exhibited a more gradual reduction (from 55% at GD 10 to 14% by GD 15), while the hepatic isolates exhibited a relatively constant S-phase percentage of approximately 40% from GD 14 to GD 18 before decreasing to 23% at GD 19. These age-dependent variations suggest that cell-cycle distribution may be useful in staging embryogenesis and in detecting abnormal development. To determine how these developmental and organ-specific cell-cycle variations affect toxic response, we sampled GD 11-13 embryos 6 hr after maternal administration of a teratogenic dose of 5-fluorouracil (5-FU), a thymidylate synthetase inhibitor that induces S-phase accumulation. The results indicate that, on a relative basis, the amount of induced S-phase accumulation in erythroblasts and whole embryos 6 hr postdosing increased with development.(ABSTRACT TRUNCATED AT 250 WORDS)
Elstein
K H
KH
ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina 27709.
Zucker
R M
RM
Andrews
J E
JE
Ebron-McCoy
M
M
Shuey
D L
DL
Rogers
J M
JM
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects; D004247:DNA / Q000032:analysis*; D004622:Embryo, Mammalian / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D004900:Erythroblasts / Q000737:chemistry; D005333:Fetus / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology* / Q000633:toxicity; D005865:Gestational Age; D008099:Liver / Q000196:embryology; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley
D004247:DNA; D005472:Fluorouracil