Mouse a-fetoprotein shows reproducible changes in concentration of its electrophoretic variants with time of development. Mixtures of the a-fetoprotein containing Fpl-3, Fpl-5, and Fp5 were purified from day 12.5 amniotic fluid, day 15.5 amniotic fluid, and day 18.5 plasma, respectively. The molecular weights of these purified protein mixtures, determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, were similar (about 70 000). Antibody produced against Fpl-3 immunologically reacted with Fpl-5 and Fp5. Analyses of amino acids and carbohydrates indicated that they were similar in these a-fetoprotein mixtures except in the number of sialic acid residues. Neuraminidase treatment of the a-fetoproteins caused a disappearance of the faster moving electrophoretic variants with a corresponding increase in the concentration of the less acidic components. Purification of each electrophoretic component (Fpl, Fp2, Fp3, Fp4, and Fp5) from day 14.5-15.5 amniotic fluid was carried out in long M any glycoproteins show microheterogeneity due to variations in the type and amount of carbohydrate covalently attached to their polypeptide chains. In several cases electrophoretic variants of these glycoproteins, which appear homogeneous by many other criteria, have resulted from variations of the terminal sialic acid residues of the glycoprotein. Sialic acid is responsible, at least in part, for the microheterogeneity of transferrin (Chen and Sutton, 1967;Gustine and Zimmerman, 1973), fetuin (Oshira and Eylar, 1968), mouse myeloma immunoglobulin (Melchers et al., 1966), and afetoprotein of human (Ruoslahti and Sepalla, 1971; Alpert et al., 1972) and mouse (Gustine and Zimmerman, 1973).During gestation, marked changes in plasma proteins in various species have been noted. For example, the concentration of a-fetoprotein at first increases during development and then decreases during the later fetal period (Bergstrand and Czar, 1957;Weller and Schectman, 1962). Some of these plasma proteins also show electrophoretic variations during development (Pantelouris and Hale, 1962; Parker and Bearn, 1962;Wise et al., 1963). While exploring the developmental changes in fetal plasma proteins of mice, we observed three electrophoretically separable transferrins (Tr 1-3) and five tu-fetoproteins (Fpl-5)' a t day 14.5 of development. By day
A comparison was made of the teratogenic effects of triamcinolone (induction of cleft palate) and its ability to inhibit RNA synthesis in the C3H and A/J strains of mice. The “critical period” for induction of cleft palate in C3H mice was at day 11.5 of gestation, 3 days before palate shelf elevation. The extent of inhibition of RNA synthesis decreased when the drug was administered at later times of development and was correlated with a lower concentration of drug in fetuses. However when a higher dose (15 mg/kg) was administered at a later time (day 13.5), although the fetal drug concentration and inhibition of RNA synthesis were approximately equal to that produced by 10 mg/kg triamcinolone administered at day 11.5 (which produces 80% cleft palate), the frequency of cleft palate was much lower (33%). Thus the critical period for teratogenesis is not related to maximal absorption of drug. In A/J mice the critical period was at day 12.5. When one‐fifth as much triamcinolone (2 mg/kg) was administered to A/J mice the inhibition of RNA synthesis in palate and total fetus was similar to that seen after 10 mg/kg in the C3H strain. The concentration of drug in fetuses of each strain was approximately proportional to the dose administered. Thus A/J may be more sensitive to the effect of triamcinolone on RNA synthesis than C3H. The mechanism of action of the glucocorticoid with respect to the “critical period,” inhibition of RNA synthesis, and strain differences is discussed.
The distribution and metabolism of labeled triamcinolone acetonide was compared in A/J, C3H, and CBA inbred mice. 3H-Triamcinolone acetonide ( 5 mg/kg) administered at day 11.5 of gestation caused 100% cleft palate in A/J, 40% in C3H, and 0% in CBA. A half to 3 h later CBA maternal tissue (skeletal muscle) contained 60% as much radioactivity as did A/J and C3H tissue. CBA mice metabolized the drug faster than A/Js and C3Hs, although levels of unmetabolized drug and metabolites in livers of the three strains were not significantly different. As a consequence of the increased maternal metabolism of the drug in CBAs the level of unmetabolized drug in CBA embryos was 60% of that in A/J and C3H embryos. It is concluded that the cleft palate resistance of CBA embryos derives from the increased maternal metabolism of administered teratogen. However, the greater resistance of C3H than A/J is probably not due to increased metabolism, nor to altered distribution of drug.
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