Harnish D C, Barua A B, Soprano K J, Soprano D R
Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140.
Differentiation. 1990 Nov;45(2):103-8. doi: 10.1111/j.1432-0436.1990.tb00463.x.
Retinoic acid is required for normal growth and development, however excessive doses are teratogenic. Recently several nuclear retinoic acid receptors (RAR) have been identified and postulated to mediate the response of retinoic acid at the gene level. We wished to determine if alpha-RAR mRNA or beta-RAR mRNA levels are modulated by teratogenic doses of retinoic acid in vivo. We have found that beta-RAR mRNA levels in 9-day-gestation mouse conceptuses are increased as early as 3 h after administration of a completely teratogenic dose of retinoic acid (100 mg/kg body weight; b.w.) and reach a maximum of approximately sixfold after 6 h of treatment. Maternal liver and maternal kidney demonstrated a similar pattern of increase in beta-RAR mRNA, however this was only approximately threefold. Retinoic acid dose-response experiments demonstrated a reduced increase of beta-RAR mRNA levels with 10 mg/kg b.w. (minimally teratogenic dose), and no increase with a more-physiological dose of 1 mg/kg b.w. in the conceptuses. beta-RAR mRNA levels were elevated in 18-day-gestation fetuses to a similar extent to that observed in the 9-day-gestation conceptuses. Therefore, the twofold difference in the extent to which beta-RAR mRNA levels increase does not occur because the fetuses are at a developmental stage that is sensitive to the teratogenic effects of retinoic acid. Finally, treatment with another teratogenic retinoid, etretinate, and a nonteratogenic retinoid, retinoyl beta-glucuronide, both resulted in increase in the level of beta-RAR mRNA in the conceptuses and the maternal tissues. Therefore, an increase in beta-RAR mRNA levels caused by treatment with retinoids does not necessarily commit a fetus to undergo an abnormal pattern of development characteristic of teratogenic retinoids.
维甲酸是正常生长发育所必需的，但过量使用则具有致畸性。最近，几种核维甲酸受体（RAR）已被鉴定出来，并推测它们在基因水平上介导维甲酸的反应。我们希望确定在体内，致畸剂量的维甲酸是否会调节α-RAR mRNA或β-RAR mRNA的水平。我们发现，在妊娠第9天的小鼠胚胎中，早在给予完全致畸剂量的维甲酸（100 mg/kg体重；b.w.）后3小时，β-RAR mRNA水平就开始升高，在治疗6小时后达到最大值，约为原来的6倍。母体肝脏和母体肾脏中β-RAR mRNA也呈现出类似的升高模式，但仅约为原来的3倍。维甲酸剂量反应实验表明，给予10 mg/kg b.w.（最低致畸剂量）时，β-RAR mRNA水平的升高幅度减小，而给予更接近生理剂量的1 mg/kg b.w.时，胚胎中的β-RAR mRNA水平没有升高。在妊娠第18天的胎儿中，β-RAR mRNA水平升高的程度与在妊娠第9天的胚胎中观察到的相似。因此，β-RAR mRNA水平升高程度的两倍差异并不是因为胎儿处于对维甲酸致畸作用敏感的发育阶段。最后，用另一种致畸性类维生素A（阿维A酯）和一种非致畸性类维生素A（维甲酸β-葡萄糖醛酸酯）进行治疗，均导致胚胎和母体组织中β-RAR mRNA水平升高。因此，类维生素A治疗引起的β-RAR mRNA水平升高并不一定会使胎儿出现致畸性类维生素A特有的异常发育模式。
