Placental glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase-2 recruitment indicates impact of prenatal adversity upon postnatal development in mice

Abstract

Prenatal stress may increase concentrations of maternal glucocorticoids, which restrict fetal growth, with variable impact upon postnatal development. Among key regulators of stress hormone effects are the glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase-2 (11βHSD2), the enzyme that inactivates glucocorticoid. This study utilized mice selectively bred for social dominance (Dom) or submissiveness (Sub), respectively exhibiting resilience or sensitivity to stress, to test whether stress-induced alterations in placental GR and 11βHSD2 protein expression may mediate divergent effects of prenatal adversity upon postnatal development. Pregnant Dom and Sub dams underwent prenatal restraint stress (PRS) for 45 min on gestational days (GD) 15-17. PRS induced a similar spike in serum corticosterone concentrations of dams from each strain on GD15 (p < .001, n = 8), and impaired fetal growth (p < .01, n = 5 litters), although Dom placentae were larger than Sub placentae (p < .01). Among placentae from Dom dams, PRS elevated protein contents of both GR (p < .05, n = 5 litters) and 11βHSD2 (p < .01) on GD19. In contrast, GR contents were reduced among placentae from PRS-exposed Sub mice (p < .01), without changes in 11βHSD2 content. Correspondingly, Dom PRS pup growth recovered by PND14, yet Sub PRS pups remained underweight into adolescence (p < .0001, n = 40 pups). Thus, prenatal stress more strongly increased placental GR and 11βHSD2 levels among Dom mice than in Subs. Increased GR may improve placental function and up-regulate 11βHSD2 expression, protecting fetuses from effects of prenatal stress upon postnatal development. Placental recruitment of GR and 11βHSD2 are potential markers of stress-induced developmental disorders, in accordance with maternal resilience or sensitivity to stress.

Innate sensitivity to stress facilitates inflammation, alters metabolism and shortens lifespan in a mouse model of social hierarchy

“…We have previously shown that Sub mice are characterized by a high sensitivity to various stressogenic triggers, including acute [14], chronic mild (CMS) [10], social [15, 16] and prenatal [17, 18] stresses. At physiological and biochemical levels, this stress sensitivity is underlined by the hyper-activation of the HPA axis, resulting in elevated levels of stress- induced corticosterone and in the decreased expression of glucocorticoid receptor (GR), leading to an altered negative feedback regulation of the HPA axis activity [18].…”

Animal Models of Depression: What Can They Teach Us about the Human Disease?

“…Exhibits significant differences in comparison to the human situation as it presents an abnormal HPA function [169][170][171]. Demonstrates good predictive validity for antidepressants treatment [180][181][182].…”

Effects of Maternal Chewing on Prenatal Stress-Induced Cognitive Impairments in the Offspring via Multiple Molecular Pathways

“…A markedly abnormal increase in GC disrupts the negative feedback system of the HPA axis, leading to long-lasting and irreversible effects on brain development and behavior and stress-related cognitive disorders [22,[27][28][29]. During the fetal period, the placenta forms a barrier to maternal GC depending on the activity of GR and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyzes the metabolism of GC into inactive metabolites [30][31][32]. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), on the other hand, converts inactive GC to its active forms [33,34].…”