Mark Peter J, Augustus Sheldon, Lewis Jessica L, Hewitt Damien P, Waddell Brendan J
School of Anatomy and Human Biology, The University of Western Australia, Western Australia, Australia.
Biol Reprod. 2009 Jun;80(6):1209-15. doi: 10.1095/biolreprod.108.073650. Epub 2009 Feb 4.
Glucocorticoid excess in utero inhibits fetal growth and programs adverse outcomes in adult offspring. Access of maternal glucocorticoid to the glucocorticoid receptor (NR3C1) in the placenta and fetus is regulated by metabolism via the 11beta-hydroxysteroid dehydrogenase (HSD11B) enzymes, as well as multidrug resistance P-glycoprotein (ABCB1)-mediated efflux of glucocorticoids from the syncytiotrophoblast. This study determined expression of genes encoding the two HSD11B isoforms (Hsd11b1 and Hsd11b2), the two ABCB1 isoforms (Abcb1a and Abcb1b), and Nr3c1 in the junctional and labyrinth zones of rat placentas at Days 16 and 22 of normal gestation (Day 23 is term). To assess possible regulation of the Hsd11b and Abcb1 isoforms by glucocorticoids and progesterone, their placental expression was also measured at Day 22 after partial progesterone withdrawal from Day 16 (maternal ovariectomy plus full estrogen and partial progesterone replacement) or after treatment with dexamethasone acetate (1 microg/ml of drinking water from Day 13). Expression of Hsd11b1 mRNA increased in the labyrinth zone (the site of maternal-fetal exchange) from Day 16 to Day 22, whereas that of Hsd11b2 fell dramatically. Consistent with these changes, corticosterone levels increased 10-fold in the labyrinth zone over this period. Expression of both Abcb1a and Abcb1b was markedly higher in the labyrinth zone compared with the junctional zone on both days, consistent with the proposed barrier role of ABCB1 in the placenta. Nr3c1 mRNA expression was similar in the two placental zones at Day 16 but increased 3-fold in the labyrinth zone by Day 22. Partial progesterone withdrawal increased Hsd11b1 mRNA and protein expression in the labyrinth zone but decreased Nr3c1 mRNA expression. These data show that the dynamic expression patterns of the placental HSD11Bs in late gestation are associated with dramatic shifts in placental corticosterone. Moreover, the late gestational rise in labyrinthine Hsd11b1 seems to be driven by the normal prepartum fall in progesterone level.
子宫内糖皮质激素过量会抑制胎儿生长，并使成年后代出现不良后果。母体糖皮质激素通过11β-羟基类固醇脱氢酶（HSD11B）进行代谢，以及多药耐药P-糖蛋白（ABCB1）介导糖皮质激素从合体滋养层流出，从而调节母体糖皮质激素与胎盘和胎儿中糖皮质激素受体（NR3C1）的结合。本研究测定了正常妊娠第16天和第22天（第23天为足月）大鼠胎盘交界区和迷路区中编码两种HSD11B同工型（Hsd11b1和Hsd11b2）、两种ABCB1同工型（Abcb1a和Abcb1b）以及Nr3c1的基因表达。为了评估糖皮质激素和孕酮对Hsd11b和Abcb1同工型的可能调节作用，在第16天部分孕酮撤药（母体卵巢切除术加全量雌激素和部分孕酮替代）或醋酸地塞米松治疗（从第13天起饮用含1微克/毫升的饮用水）后第22天，也测定了它们在胎盘中的表达。从第16天到第22天，迷路区（母胎交换部位）的Hsd11b1 mRNA表达增加，而Hsd11b2的表达则急剧下降。与此变化一致，在此期间迷路区的皮质酮水平增加了10倍。在这两天中，迷路区的Abcb1a和Abcb1b表达均明显高于交界区，这与ABCB1在胎盘中的屏障作用一致。第16天，Nr3c1 mRNA在两个胎盘区的表达相似，但到第22天，迷路区增加了3倍。部分孕酮撤药增加了迷路区Hsd11b1 mRNA和蛋白表达，但降低了Nr3c1 mRNA表达。这些数据表明，妊娠晚期胎盘HSD11B的动态表达模式与胎盘皮质酮的显著变化有关。此外，迷路区Hsd11b1在妊娠晚期的升高似乎是由产前孕酮水平的正常下降所驱动。
