Changes in the placental glucocorticoid barrier during rat pregnancy: impact on placental corticosterone levels and regulation by progesterone

Abstract

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.

FIG. 1.

Relative levels of Hsd11b1 (A) and Hsd11b2 (B) mRNA expression and placental corticosterone levels (C) relative to maternal plasma levels in the junctional (JZ) and labyrinth (LZ) zones of the rat placenta at Days 16 and 22 of normal gestation. Values are mean ± SEM (n = 5–8 per group). *P < 0.01 compared with corresponding value on Day 16 (two-way ANOVA and least significant difference test).

FIG. 2.

Relative levels of Abcb1a (A), Abcb1b (B), and Nr3c1 (C) mRNA expression in the junctional (JZ) and labyrinth (LZ) zones of the rat placenta at Days 16 and 22 of normal gestation. Values are mean ± SEM (n = 5–8 per group). *P < 0.01 compared with corresponding junctional zone (two-way ANOVA and least significant difference test).

FIG. 3.

Relative levels of Hsd11b1 mRNA and HSD11B1 protein in the junctional (JZ) and labyrinth (LZ) zones of the rat placenta following progesterone manipulation. Animals were ovariectomized on Day 16, and estradiol was replaced to parallel its normal increase over the final week of pregnancy. Progesterone levels were either fully restored (P₄-Rest) or replaced at a reduced level (P₄-Red). Control animals (Sham) were sham operated and injected with vehicle. Values are mean ± SEM (n = 7–13 per group). *P < 0.05 compared with corresponding Sham or P₄-Rest value (two-way ANOVA and least significant difference test).

FIG. 4.

Relative levels of Abcb1a (A), Abcb1b (B), and Nr3c1 (C) mRNA in the junctional (JZ) and labyrinth (LZ) zones of the rat placenta following progesterone manipulation. Animals were ovariectomized on Day 16, and estradiol was replaced to parallel its normal increase over the final week of pregnancy. Progesterone levels were either fully restored (P₄-Rest) or replaced at a reduced level (P₄-Red). Control animals (Sham) were sham operated and injected with vehicle. Values are mean ± SEM (n = 5 per group). *P < 0.05 compared with corresponding Sham or P₄-Rest value (two-way ANOVA and least significant difference test).

FIG. 5.

Relative levels of Abcb1a (A) and Abcb1b (B) mRNA in the junctional (JZ) and labyrinth (LZ) zones of the rat placenta at Day 22 in control animals (Con) and following maternal dexamethasone administration from Day 13 (Dex). Values are mean ± SEM (n = 5–8 per group). *P < 0.05 compared with corresponding Con value (two-way ANOVA and least significant difference test).