Abstract
Maternal undernutrition (MUN) during pregnancy may lead to fetal intrauterine growth restriction (IUGR), which itself predisposes to adult risk of obesity, hypertension, and diabetes. IUGR may stem from insufficient maternal nutrient supply or reduced placental nutrient transfer. In addition, a critical role for maternal stress-induced glucocorticoids (GCs) has been suggested to contribute to both IUGR and the ensuing risk of adult metabolic syndrome. While GC-induced fetal organ defects have been examined, there have been few studies on placental responses to MUN-induced maternal stress. Therefore, we hypothesize that 50% MUN associates with increased maternal GC levels and decreased placental HSD11B. This in turn leads to decreased placental and fetal growth, hence the need to investigate nutrient transporters. We measured maternal serum levels of corticosterone, and the placental basal and labyrinth zone expression of glucocorticoid receptor (NR3C1), 11-hydroxysteroid dehydrogenase B 1 (HSD11B-1) predominantly activates cortisone to cortisol and 11-dehydrocorticosterone (11-DHC) to corticosterone, although can sometimes drive the opposing (inactivating reaction), and HSD11B-2 (only inactivates and converts corticosterone to 11-DHC in rodents) in control and MUN rats at embryonic day 20 (E20). Moreover, we evaluated the expression of nutrient transporters for glucose (SLC2A1, SLC2A3) and amino acids (SLC38A1, 2, and 4). Our results show that MUN dams displayed significantly increased plasma corticosterone levels compared to control dams. Further, a reduction in fetal and placental weights was observed in both the mid-horn and proximal-horn positions. Notably, the placental labyrinth zone, the site of feto-maternal exchange, showed decreased expression of HSD11B1-2 in both horns, and increased HSD11B-1 in proximal-horn placentas, but no change in NR3C1. The reduced placental GCs catabolic capacity was accompanied by downregulation of SLC2A3, SLC38A1, and SLC38A2 expression, and by increased SLC38A4 expression, in labyrinth zones from the mid- and proximal-horns. In marked contrast to the labyrinth zone, the basal zone, which is the site of hormone production, did not show significant changes in any of these enzymes or transporters. These results suggest that dysregulation of the labyrinth zone GC "barrier", and more importantly decreased nutrient supply resulting from downregulation of some of the amino acid system A transporters, may contribute to suboptimal fetal growth under MUN.
Highlights
Glucocorticoids (GCs) are critical for fetal organ growth and maturation [1,2], though GCs exposure must occur in a temporally specific pattern
At embryonic age 10 (E10) based upon day of expelled plug, dams were randomly allocated to a control diet (N = 6) in which they were continued on the ad libitum diet (AdLib) diet or a 50% food-restricted (MUN) diet (N = 6) that was determined by quantifying normal intake of the rats that were fed AdLib at the equivalent stage of gestation
Maternal corticosterone levels Maternal plasma corticosterone levels were significantly higher in Maternal undernutrition (MUN) dams at embryonic day 20 (E20) compared to AdLib dams (Figure 1A; P < 0.01, Student t-test), consistent with a maternal stress response
Summary
Glucocorticoids (GCs) are critical for fetal organ growth and maturation [1,2], though GCs exposure must occur in a temporally specific pattern. The placenta protects the fetus against maternal cortisol or corticosterone by 11-hydroxysteroid dehydrogenase (HSD11B)-mediated enzymatic oxidation of these hormones to their biological inactive forms. HSD11B type 1 (HSD11B-1) isoform possesses both oxidase and reductase activities but functions mainly as a reductase, converting cortisone and 11-dehydrocorticosterone (11DHC) to cortisol, and corticosterone, respectively. The activity and expression of HSD11B-2 within the placenta correlates with birth weight [14,15] and HSD11B-2 gene expression is reduced in IUGR rats and human gestations [14,16], relative changes in HSD11B-1/2 activity/expression cannot fully characterize the amount of active/inactive GCs within the placenta as there is an influx of GCs from maternal [17] and fetal [18] compartments to the placenta during pregnancy
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