MORPHOLOGICAL DIFFERENCES ELICITED BY 2 WEAK ACIDS, RETINOIC AND VALPROIC, IN RAT EMBRYOS GROWN-INVITRO

被引:25
作者
SEEGMILLER, RE
HARRIS, C
LUCHTEL, DL
JUCHAU, MR
机构
[1] UNIV WASHINGTON, DEPT PHARMACOL, SEATTLE, WA 98195 USA
[2] UNIV WASHINGTON, DEPT ENVIRONM HLTH, SEATTLE, WA 98195 USA
关键词
D O I
10.1002/tera.1420430206
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
We compared in rat whole-embryo culture the morphological changes elicited by valproic acid (VPA) with those elicited by trans-retinoic acid (RA). Rat embryos explanted on day 9.5 of gestation were treated on day 10 with RA or VPA at concentrations producing equivalent reductions in embryonic protein. The concentrations selected for morphological assessment by scanning and transmission electron microscopy, 2.3 and 800-mu-M, respectively, for RA and VPA, produced approximately a 50% incidence of abnormally open anterior neuropores in initial range-finding experiments in the culture system. Protein and DNA analyses were also performed on corresponding groups of embryos at three different doses. With concurrent control groups used as reference standards, the two treatment groups were compared for differences in external and internal morphology, protein and DNA contents, and growth indices. While certain variables responded similarly in the two treatment groups, e.g., the growth variables, protein and DNA contents, each drug produced selective morphological effects. Whereas treatment with RA produced underdeveloped branchial arches, symmetrically cleft cranial defects resulting in openings in rhombencephalic and prosencephalic regions, and exteriorized neural tissue in the caudal neuropore region, VPA produced irregular clefts with wavy margins along the entire length of the neural tube, and an open caudal neuropore without eversion of the neuroepithelium, while producing no detectable effect on the branchial arches. The similar effects of these two drugs on protein and DNA contents suggest comparable degrees of overall toxicity; however, the dissimilar effects on neural tube and branchial arches, coupled with the large difference in concentration of the drug required to produce the effects, add to the evidence that their mechanisms for elicitation of abnormal development are qualitatively different.
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页码:133 / 150
页数:18
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