The Effects of Glucocorticoids on Fetal and Placental Development

Korgun, Emin Türkay; Ozmen, Asli; Unek, Gozde; Mendilcioğlu, İnanç

doi:10.5772/50103

Cited by 10 publications

(7 citation statements)

References 187 publications

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“…We found that GCs excess induced an increase in GLUT1 protein levels, in accordance with data from placental endothelial cells (HPECs) [ 31 , 32 ] and pregnant rats under dexamethasone treatment [ 43 ]. GLUT1 is the only transporter present as a functional protein in the syncytium near term [ 44 ]; thus changes in its density and/or activity would deeply influence placental and fetal development.…”

Section: Discussionsupporting

confidence: 88%

Excess Hydrocortisone Hampers Placental Nutrient Uptake Disrupting Cellular Metabolism

Mateos

Jiménez

Álvarez-Gil

et al. 2018

BioMed Research International

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Low birth weight increases neonatal morbidity and mortality, and surviving infants have increased risk of metabolic and cardiovascular disturbances later in life, as well as other neurological, psychiatric, and immune complications. A gestational excess of glucocorticoids (GCs) is a well-known cause for fetal growth retardation, but the biological basis for this association remains elusive. Placental growth is closely related to fetal growth. The placenta is the main regulator of nutrient transport to the fetus, resulting from the difference between placental nutrient uptake and the placenta's own metabolism. The aim of this study was to analyze how excess hydrocortisone affects placental glucose and lipid metabolism. Human placenta explants from term physiological pregnancies were cultured for 18 hours under different hydrocortisone concentrations (2.75, 5.5, and 55 mM; 1, 2, and 20 mg/ml). Placental glucose and lipid uptake and the metabolic partitioning of fatty acids were quantified by isotopic techniques, and expression of specific glucose transporter GLUT1 was quantified by western blot. Cell viability was assessed by MTT, immunohistochemistry and caspase activity. We found that excess hydrocortisone impairs glucose uptake and lipoprotein lipase (LPL) activity, coincident with a GC-dose dependent inhibition of fatty acid oxidation and esterification. None of the experimental conditions showed an increased cell death. In conclusion, our results show that GC overexposure exerts a dysfunctional effect on lipid transport and metabolism and glucose uptake in human placental explants. These findings could well be directly related to a reduced placental growth and possibly to a reduced supply of nutrients to the fetus and the consequent fetal growth retardation and metabolic programming.

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Section: Discussionsupporting

confidence: 88%

Excess Hydrocortisone Hampers Placental Nutrient Uptake Disrupting Cellular Metabolism

Mateos

Jiménez

Álvarez-Gil

et al. 2018

BioMed Research International

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“…Glucocorticoids are critical for implantation, fetal organ development, and survival during pregnancy and parturition [27]. However, excess glucocorticoid exposure suppresses the immune system and has adverse effects on placental proliferation, angiogenesis, and glucose transport [28,96,97]. The observation that a higher glucocorticoid receptor expression in term female placentas compared to term male placentas suggests the lower glucocorticoid exposure of female fetuses during pregnancy and an enhanced immune response, which may contribute to the increased survival rate of female fetuses in an aberrant intrauterine milieu [28].…”

Section: Discussionmentioning

confidence: 99%

Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth

Lien

Zhang

et al. 2021

IJMS

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A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB.

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“…Furthermore, placentae in Sub dams were found to be markedly smaller than in Dom dams on GD19, regardless of restraint (Figure 3(A)). Maternal corticosterone has been shown to contribute to placental angiogenesis (Korgun, Ozmen, Unek, & Mendilcioglu, 2012), and while the weight measurements taken in the current study were of entire placentae, GR activation has been shown to regulate development of the junctional zone in the mouse placenta (Cuffe et al, 2012), a phenomenon whose effects may concurrently impact total placental weight. Thus, the relatively low corticosterone concentrations among Naïve Sub mice appear to Figure 5.…”

Section: Discussionmentioning

confidence: 74%

“…In order to test a candidate biologic substrate potentially mediating the placental sensitivity to a PRS-induced elevation in maternal corticosterone, we measured placental GR protein levels on GD19. Placental GR is considered to possess a range of pleiotropic effects, enacting processes required for embryo implantation, as well as for proper growth and development of both the fetus and placenta (Korgun et al, 2012). Currently, Dom PRS placentae contained significantly more GR than did Dom Naïve (Figure 4(B)).…”

Section: Discussionmentioning

confidence: 99%

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

Gross

Romi

Gilimovich

et al. 2018

Stress

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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.

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The Effects of Glucocorticoids on Fetal and Placental Development

Cited by 10 publications

References 187 publications

Excess Hydrocortisone Hampers Placental Nutrient Uptake Disrupting Cellular Metabolism

Excess Hydrocortisone Hampers Placental Nutrient Uptake Disrupting Cellular Metabolism

Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth

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

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