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Fetal glucocorticoid synthesis is required for development of fetal adrenal medulla and hypothalamus feedback suppression.

ABSTRACT: During pregnancy, fetal glucocorticoid is derived from both maternal supply and fetal secretion. We have created mice with a disruption of the Cyp11a1 gene resulting in loss of fetal steroid secretion but preserving the maternal supply. Cyp11a1null embryos have appreciable although lower amounts of circulating corticosterone, the major mouse glucocorticoid, suggesting that transplacental corticosterone is a major source of corticosterone in fetal circulation. These embryos thus provide a means to examine the effect of fetal glucocorticoids. The adrenal in Cyp11a1 null embryos was disorganized with abnormal mitochondria and oil accumulation. The adrenal medullary cells did not express phenylethanolamine N-methyltransferase and synthesized no epinephrine. Cyp11a1 null embryos had decreased diencephalon Hsd11b1, increased diencephalon Crh, and increased pituitary Pomc expression, leading to higher adrenocorticotropin level in the plasma. These data indicate blunted feedback suppression despite reasonable amounts of circulating corticosterone. Thus, the corticosterone synthesized in situ by the fetus is required for negative feedback suppression of the hypothalamus-pituitary-adrenal axis and for catecholamine synthesis in adrenal medulla.

SUBMITTER: Huang CC

PROVIDER: S-EPMC3512012 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Fetal glucocorticoid synthesis is required for development of fetal adrenal medulla and hypothalamus feedback suppression.

Huang Chen-Che Jeff CC Shih Meng-Chun Monica MC Hsu Nai-Chi NC Chien Yu Y Chung Bon-chu BC

Endocrinology 20120907 10

During pregnancy, fetal glucocorticoid is derived from both maternal supply and fetal secretion. We have created mice with a disruption of the Cyp11a1 gene resulting in loss of fetal steroid secretion but preserving the maternal supply. Cyp11a1null embryos have appreciable although lower amounts of circulating corticosterone, the major mouse glucocorticoid, suggesting that transplacental corticosterone is a major source of corticosterone in fetal circulation. These embryos thus provide a means t ...[more]

PMID: 22962254

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Project description:BackgroundGender, genetic makeup, and prior experience interact to determine physiological responses to an external perceived stressor. Here, we investigated the contribution of both genetic variants and promoter methylation of the NR3C1 (glucocorticoid receptor) gene to the cardiovascular and hypothalamus-pituitary-adrenal (HPA) axis response to the socially evaluated cold pressor test (seCPT).ResultsTwo hundred thirty-two healthy participants were recruited and underwent the experiment. They were randomly assigned to either the seCPT group (cold water) or a control group (warm water). The seCPT group had a clear stress reaction; salivary cortisol levels and peak systolic and diastolic blood pressure all increased significantly compared to the control group. GR genotype (TthIIII, NR3C1-I, 1H, E22E, R23K, BclI and 9beta) and methylation data were obtained from 218 participants. Haplotypes were built from the GR genotypes, and haplotype 2 (minor allele of BclI) carriers had a higher cortisol response to the seCPT in comparison to non-carriers (20.77 ± 13.22; 14.99 ± 8.42; p = 0.034), as well as independently of the experimental manipulation, higher baseline heart rate (72.44 ± 10.99; 68.74 ± 9.79; p = 0.022) and blood pressure (115.81 ± 10.47; 111.61 ± 10.74; p = 0.048). Average methylation levels throughout promoter 1F and 1H were low (2.76 and 1.69 %, respectively), but there was a strong correlation between individual CpGs and the distance separating them (Pearson's correlation r = 0.725, p = 3.03 × 10(-26)). Higher promoter-wide methylation levels were associated with decreased baseline blood pressure, and when incorporated into a linear mixed effect model significantly predicted lower systolic and diastolic blood pressure evolution over time in response to the experimental manipulation. The underlying genotype significantly predicted methylation levels; particularly, the homozygous BclI minor allele was associated with higher methylation in promoter 1H (p = 0.042).ConclusionsThis is one of the first studies linking epigenetic modifications of the GR promoter, receptor genotype and physiological measures of the stress response. At baseline, there were clear genetic and epigenetic effects on blood pressure. The seCPT induced a strong cardiovascular and HPA axis response, and both systems were affected by the functional genetic variants, although methylation also predicted blood pressure reactivity. The return to baseline was predominantly influenced by the genomic sequence. Overall, the physiological response to the seCPT is controlled by an exquisite mix of genetic and epigenetic factors.

Project description:Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11?-hydroxysteroid dehydrogenase-2 (11?-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11?-HSD-2, promote the expression of 11?-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11?-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in elucidating the developmental toxicity of caffeine and in exploring the fetal origin of adult HPA axis dysfunction and metabolic syndrome susceptibility for offspring with IUGR induced by caffeine.

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Fetal glucocorticoid synthesis is required for development of fetal adrenal medulla and hypothalamus feedback suppression.

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Fetal glucocorticoid synthesis is required for development of fetal adrenal medulla and hypothalamus feedback suppression.

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