scholarly journals Effect of neonatal dexamethasone treatment on cognitive abilities of adult male mice and gene expression in the hypothalamus

2019 ◽  
Vol 23 (4) ◽  
pp. 456-464
Author(s):  
N. P. Bondar ◽  
V. V. Reshetnikov ◽  
K. V. Burdeeva ◽  
T. I. Merkulova
Keyword(s):  
Hpa Axis ◽  
Adult Male ◽  
Early Life ◽  
Receptor Gene ◽  
Expression Level ◽  
Male Mice ◽  
Dexamethasone Treatment ◽  
Negative Feedback Regulation ◽  
Adult Mice ◽  
Glucocorticoid Receptor Gene

The early postnatal period is critical for the development of the nervous system. Stress during this period causes negative long-term effects, which are manifested at both behavioral and molecular levels. To simulate the elevated glucocorticoid levels characteristic of early-life stress, in our study we used the administration of dexamethasone, an agonist of glucocorticoid receptors, at decreasing doses at the first three days of life (0.5, 0.3, 0.1 mg/kg, s.c.). In adult male mice with neonatal dexamethasone treatment, an increase in the relative weight of the adrenal glands and a decrease in body weight were observed, while the basal level of corticosterone remained unchanged. Dexamethasone treatment in early life had a negative impact on the learning and spatial memory of adult mice in the Morris water maze. We analyzed the effect of elevated glucocorticoid levels in early life on the expression of the Crh, Avp, Gr, and Mr genes involved in the regulation of the HPA axis in the hypothalami of adult mice. The expression level of the mineralocorticoid receptor gene (Mr) was significantly downregulated, and the glucocorticoid receptor gene (Gr) showed a tendency towards decreased expression (p = 0.058) in male mice neonatally treated with dexamethasone, as compared with saline administration. The expression level of the Crh gene encoding corticotropin-releasing hormone was unchanged, while the expression of the vasopressin gene (Avp) was increased in response to neonatal administration of dexamethasone. The obtained results demonstrate a disruption of negative feedback regulation of the HPA axis, which involves glucocorticoid and mineralocorticoid receptors, at the level of the hypothalamus. Malfunction of the HPA axis as a result of activation of the glucocorticoid system in early life may cause the development of cognitive impairment in the adult mice. 

scholarly journals SUN-207 Modelling Long Term Glucocorticoid-Induced HPA Axis Suppression in Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nicola Romano ◽  
Peter James Duncan ◽  
Oscar Nolan ◽  
Paul Roussel Le Tissier ◽  
Mike Shipston ◽  
...  
Keyword(s):  
Drinking Water ◽  
Mouse Model ◽  
Hpa Axis ◽  
Adult Male ◽  
Male Mice ◽  
Dexamethasone Treatment ◽  
Mortality And Morbidity ◽  
Fold Reduction ◽  
The Uk

Abstract Glucocorticoids are prescribed for >3 months to 1% of the UK population. 10-50% of these long-term glucocorticoid treated patients develop persistent HPA axis suppression associated with mortality and morbidity. We have developed a mouse model of glucocorticoid-induced HPA axis dysfunction to determine the mechanisms resulting in persistent HPA axis suppression. Experiment 1: 36 C57BL/6 adult male mice received Dexamethasone (DEX,~10µg/day) or vehicle (CTL) via drinking water for 28 days, following which treatment was stopped and tissues were harvested at 0, 7 and 28 days. DEX suppressed waking serum corticosterone at days 0 and 7, recovering by day 28. Adrenal size remained lower 28 days following DEX withdrawal. DEX had no effect on whole pituitary pomc, nr3c1 or crhr1 expression, although avpr1b was increased at day 0. In the adrenal, hsd3b2 and cyp11a1 expression were reduced at time 0; normalising by 28 days. Experiment 2: 24 POMC-GFP male mice were treated as above. Tissues were collected at day 0 (n=6), 7 (n=3) and 10 (n=3) following withdrawal. Pooled corticotrophs (groups of 3) were isolated by FACS and RNA extracted for qPCR. DEX reduced corticotroph pomc expression at time 0 (x20 fold reduction), with x5 fold suppression at day 7, which recovered with evidence of compensation by day 10. DEX increased expression of avpr1b but not crhr1. CONCLUSION: 28 days dexamethasone treatment in mice suppresses the HPA axis. HPA suppression is evident 7 days following withdrawal of dexamethasone in the adrenal, corticotroph population and corticosterone production. Further analysis will determine mechanisms for delays in HPA axis recovery.

scholarly journals Early life trauma, depression and the glucocorticoid receptor gene – an epigenetic perspective

2015 ◽  
Vol 45 (16) ◽  
pp. 3393-3410 ◽  
Author(s):  
C. Smart ◽  
G. Strathdee ◽  
S. Watson ◽  
C. Murgatroyd ◽  
R. H. McAllister-Williams
Keyword(s):  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Early Life ◽  
Epigenetic Modification ◽  
Receptor Gene ◽  
Unipolar Depression ◽  
Tissue Cell ◽  
Glucocorticoid Receptor Gene ◽  
Early Life Trauma

Background.Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the ‘gold standard’ for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic–pituitary–adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life.Method.In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored.Results.Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges.Conclusions.The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.

scholarly journals Specific transgenerational imprinting effects of the endocrine disruptor methoxychlor on male gametes

Reproduction ◽  
2011 ◽  
Vol 141 (2) ◽  
pp. 207-216 ◽  
Author(s):  
Christelle Stouder ◽  
Ariane Paoloni-Giacobino
Keyword(s):  
Adult Male ◽  
Endocrine Disrupting Chemicals ◽  
Methylation Pattern ◽  
Imprinted Genes ◽  
Male Mice ◽  
Systematic Analysis ◽  
Adult Mice ◽  
Male Gametes ◽  
Pregnant Mice ◽  
Methylation Defects

Endocrine-disrupting chemicals (EDCs), among which methoxychlor (MXC), have been reported to affect the male reproductive system. This study evaluates the possible deleterious effects of MXC on imprinted genes. After administration of the chemical in adult male mice or in pregnant mice we analyzed by pyrosequencing possible methylation defects in two paternally imprinted (H19 and Meg3 (Gtl2)) and three maternally imprinted (Mest (Peg1), Snrpn, and Peg3) genes in the sperm and in the tail, liver, and skeletal muscle DNAs of the adult male mice and of the male offspring. MXC treatment of adult mice decreased the percentages of methylated CpGs of Meg3 and increased those of Mest, Snrpn, and Peg3 in the sperm DNA. MXC treatment of pregnant mice decreased the mean sperm concentrations by 30% and altered the methylation pattern of all the imprinted genes tested in the F1 offspring. In the latter case, MXC effects were transgenerational but disappeared gradually from F1 to F3. MXC did not affect imprinting in the somatic cells, suggesting that it exerts its damaging effects via the process of reprogramming that is unique to gamete development. A systematic analysis at the CpG level showed a heterogeneity in the CpG sensitivity to MXC. This observation suggests that not only DNA methylation but also other epigenetic modifications can explain the transgenerational effects of MXC. The reported effects of EDCs on human male spermatogenesis might be mediated by complex imprinting alterations analogous to those described in this study.

scholarly journals Developmental conditions modulate DNA methylation at the glucocorticoid receptor gene with cascading effects on expression and corticosterone levels in zebra finches

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Blanca Jimeno ◽  
Michaela Hau ◽  
Elena Gómez-Díaz ◽  
Simon Verhulst
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Early Life ◽  
Receptor Gene ◽  
Regulatory Region ◽  
Long Term Effects ◽  
Glucocorticoid Receptor Gene ◽  
Developmental Conditions

Abstract Developmental conditions can impact the adult phenotype via epigenetic changes that modulate gene expression. In mammals, methylation of the glucocorticoid receptor gene Nr3c1 has been implicated as mediator of long-term effects of developmental conditions, but this evidence is limited to humans and rodents, and few studies have simultaneously tested for associations between DNA methylation, gene expression and phenotype. Adverse environmental conditions during early life (large natal brood size) or adulthood (high foraging costs) exert multiple long-term phenotypic effects in zebra finches, and we here test for effects of these manipulations on DNA methylation and expression of the Nr3c1 gene in blood. Having been reared in a large brood induced higher DNA methylation of the Nr3c1 regulatory region in adulthood, and this effect persisted over years. Nr3c1 expression was negatively correlated with methylation at 2 out of 8 CpG sites, and was lower in hard foraging conditions, despite foraging conditions having no effect on Nr3c1 methylation at our target region. Nr3c1 expression also correlated with glucocorticoid traits: higher expression level was associated with lower plasma baseline corticosterone concentrations and enhanced corticosterone reactivity. Our results suggest that methylation of the Nr3c1 regulatory region can contribute to the mechanisms underlying the emergence of long-term effects of developmental conditions in birds, but in our system current adversity dominated over early life experiences with respect to receptor expression.

Prenatal maternal vaginal inflammation increases anxiety and alters HPA axis signalling in adult male mice

2019 ◽  
Vol 75 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Huan‐Li Wang ◽  
De‐En Pei ◽  
Ri‐Dong Yang ◽  
Chang‐Lan Wan ◽  
Yan‐Mei Ye ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Adult Male ◽  
Male Mice

scholarly journals Impact of mothers’ experience and early‐life stress on aggression and cognition in adult male mice

2019 ◽  
Vol 62 (1) ◽  
pp. 36-49 ◽  
Author(s):  
Vasiliy V. Reshetnikov ◽  
Yulia A. Ryabushkina ◽  
Natalia P. Bondar
Keyword(s):  
Adult Male ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Male Mice

Intrauterine growth retardation affects expression and epigenetic characteristics of the rat hippocampal glucocorticoid receptor gene

2010 ◽  
Vol 42 (2) ◽  
pp. 177-189 ◽  
Author(s):  
Xingrao Ke ◽  
Michelle E. Schober ◽  
Robert A. McKnight ◽  
Shannon O'Grady ◽  
Diana Caprau ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Growth Retardation ◽  
Intrauterine Growth Retardation ◽  
Receptor Gene ◽  
Altered Expression ◽  
Time Points ◽  
Intrauterine Growth ◽  
Mrna Variant ◽  
Glucocorticoid Receptor Gene

Studies in humans and rats suggest that intrauterine growth retardation (IUGR) permanently resets the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis reprogramming may involve persistently altered expression of the hippocampal glucocorticoid receptor (hpGR), an important regulator of HPA axis reactivity. Persistent alteration of gene expression, long after the inciting event, is thought to be mediated by epigenetic mechanisms that affect mRNA and mRNA variant expression. GR mRNA variants in both humans and rats include eleven 5′-end variants and GRα, the predominant 3′-end variant. The 3′-end variants associated with glucocorticoid resistance in humans (GRβ, GRγ, GRA, and GRP) have not been reported in rats. We hypothesized that in the rat hippocampus IUGR would decrease total GR mRNA, increase GRβ, GRγ, GRA, and GRP, and affect epigenetics of the GR gene at birth (D0) and at 21 days of life (D21). IUGR increased hpGR and exon 1.7 hpGR mRNA in males at D0 and D21, associated with increased trimethyl H3/K4 at exon 1.7 at both time points. IUGR also increased hpGRγ in males at D0 and D21, associated with increased acetyl H3/K9 at exon 3 at both time points. hpGRA increased in female IUGR rats at D0 and D21. In addition, our data support the existence of hpGRβ and hpGRP in the rat. IUGR has sex-specific, persistent effects on GR expression and its histone code. We speculate that postnatal changes in hippocampal GR variant and total mRNA expression may underlie IUGR-associated HPA axis reprogramming.

Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study

2015 ◽  
Vol 58 ◽  
pp. 46-50 ◽  
Author(s):  
Lisette J. van der Knaap ◽  
Albertine J. Oldehinkel ◽  
Frank C. Verhulst ◽  
Floor V.A. van Oort ◽  
Harriëtte Riese
Keyword(s):  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Receptor Gene ◽  
Gene Methylation ◽  
Glucocorticoid Receptor Gene

scholarly journals Osteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice

2006 ◽  
Vol 22 (3) ◽  
pp. 347-356 ◽  
Author(s):  
Amanda J Notini ◽  
Julie F McManus ◽  
Alison Moore ◽  
Mary Bouxsein ◽  
Mark Jimenez ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Bone Loss ◽  
Trabecular Bone ◽  
Adult Male ◽  
Receptor Gene ◽  
Androgen Receptor Gene ◽  
Male Mice ◽  
Trabecular Bone Loss
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