Effects of psychogenic stress on oxidative stress and antioxidant capacity at different growth stages of rats: Experimental study.

This study examined the psychogenic stress (PS) effects on changes in oxidative stress and the antioxidant capacity of an organism at different growth stages. The experimental animals were male Wistar rats of five different ages from growth periods (GPs) to old age. The growth stages were randomly classified into control (C) and experimental (PS) groups. The PS was performed using restraint and water immersion once daily for 3 h for 4 weeks. Reactive oxygen metabolites (d-ROMs) and the biological antioxidant potential (BAP) were measured before and after the experiment. In addition, the liver and adrenal glands were removed, and the wet weight was measured. The d-ROM and BAP of all growth stages given PS increased significantly. The d-ROM in the C group without PS increased significantly in GPs while decreased significantly in old-aged rats. In addition, the BAP of the C group in GP and early adulthood were all significantly elevated. There were significant differences in organ weights between the C and PS groups at all growth stages. Oxidative stress and antioxidant capacity differed depending on the organism's developmental status and growth stage, and PS also showed different effects. In particular, the variability in oxidative stress was remarkable, suggesting that the effect of PS was more significant in the organism's immature organs.

Intergenerational genetic programming mechanism and sex differences of the adrenal corticosterone synthesis dysfunction in offspring induced by prenatal ethanol exposure.

We previously found that prenatal ethanol exposure (PEE) induced adrenal dysplasia in offspring, which was related to intrauterine maternal glucocorticoid overexposure. This study investigated the intergenerational genetic effect and sex differences of PEE-induced changes in the synthetic function of adrenal corticosterone in offspring, and to clarify the intrauterine origin programming mechanism. Wistar pregnant rats were gavaged with ethanol (4 g/kg bw/d) from gestation day (GD) 9-20, and F1 generation was born naturally. The F1 generation female rats in the PEE group were mated with normal male rats to produce F2 generation. Serum and adrenal glands of fetal rats and F1/F2 adult rats were collected at GD20 and postnatal week 28. PEE increased the serum corticosterone level, while diminishing the expression of adrenal steroid synthases of fetal rats. Moreover, PEE enhanced the mRNA expression of GR and HDAC1, but inhibited the mRNA expression of SF1 and reduced the H3K9ac level of P450scc in the fetal adrenal gland. In PEE adult offspring of F1 and F2 generation the serum corticosterone level, the H3K9ac level of P450scc and its expression were decreased in males but were increased in females. In NCI-H295R cells, cortisol reduced the production of endogenous cortisol, down-regulated SF1, and up-regulated HDAC1 expression by activating GR, and decreased H3K9ac level and expression of P450scc. In conclusion, PEE could induce adrenal dysplasia in offspring with sex differences and intergenerational genetic effects, and the adrenal insufficiency in male offspring was related to the induction of low functional genetic programming of P450scc by intrauterine high corticosterone through the GR/SF1/HDAC1 pathway.

Selection and verification of the combination of reference genes for RT-qPCR analysis in rat adrenal gland development.

Quantitative reverse transcription polymerase chain reaction (RT-qPCR) is commonly used for gene expression analysis, and the accuracy of its results depends greatly on chosen reference genes. Adrenal gland is the core of the occurrence and development of fetal-originated adult diseases. Its dysplasia or dysfunction may increase susceptibility to adult disease, which has apparent sex differences. To explore the optimal combination of reference genes for RT-qPCR in female and male rats adrenal development, we selected seven reference genes (GAPDH, ß-actin, etc.), and use RT-qPCR to detect genes expression during different stages of rats adrenal development under physiological conditions. Then we analysed data using GeNorm, NormFinder and BestKeeper to select the optimal combination of reference genes. Further, we used the intrauterine growth retardation (IUGR) model of rat caused by prenatal caffeine exposure (PCE) to verify the stability and accuracy of the selected combination of reference genes under physiological conditions. The results showed that TBP + ß-actin could be the optimal combination of reference genes for fetal rat adrenals under physiological conditions, without obvious sex differences. In infancy and adolescence, the optimal combination of reference genes for adrenals had sex differences, and females were GAPDH + ß-actin, while males were GAPDH + SDHA. In PCE model, the optimal combination of reference genes was consistent with physiological conditions. Using combination of reference genes to analyze target genes can improve the accuracy of the results. In summary, this study provided reliable combination of reference genes for RT-qPCR and experimental supports for researches on adrenal development.

Update on adrenarche.

PURPOSE OF REVIEW: Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when dehydroepiandrosterone sulfate (DHEAS) concentrations increase. This review provides an update on adrenal steroidogenesis and the differential diagnosis of premature development of pubic hair. RECENT FINDINGS: The complexity of adrenal steroidogenesis has increased with recognition of the alternative 'backdoor pathway' and the 11-oxo-androgens pathways. Traditionally, sulfated steroids such as DHEAS have been considered to be inactive metabolites. Recent data suggest that intracellular sulfated steroids may function as tissue-specific intracrine hormones particularly in the tissues expressing steroid sulfatases such as ovaries, testes, and placenta. SUMMARY: The physiologic mechanisms governing the onset of adrenarche remain unclear. To date, no validated regulatory feedback mechanism has been identified for adrenal C19 steroid secretion. Available data indicate that for most children, premature adrenarche is a benign variation of development and a diagnosis of exclusion. Patients with premature adrenarche tend to have higher BMI values. Yet, despite greater knowledge about C19 steroids and zona reticularis function, much remains to be learned about adrenarche.

Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment.

Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. The current study focuses on the exposure impact of mixtures of EDCs that better mimics the real-life situation. We herein describe a mixture of phthalates, pesticides and bisphenol A (mixture N1) detected in pregnant women of the SELMA cohort and associated with language delay in their children. To study the long-term impact of developmental exposure to N1 on brain physiology and behavior we administered this mixture to mice throughout gestation at doses 0×, 0.5×, 10×, 100× and 500× the geometric mean of SELMA mothers' concentrations, and examined their offspring in adulthood. Mixture N1 exposure increased active coping during swimming stress in both sexes, increased locomotion and reduced social interaction in male progeny. The expression of corticosterone receptors, their regulator Fkbp5, corticotropin releasing hormone and its receptor, oxytocin and its receptor, estrogen receptor beta, serotonin receptors (Htr1a, Htr2a) and glutamate receptor subunit Grin2b, were modified in the limbic system of adult animals, in a region-specific, sexually-dimorphic and experience-dependent manner. Principal component analysis revealed gene clusters associated with the observed behavioral responses, mostly related to the stress axis. This integration of epidemiology-based data with an experimental model increases the evidence that prenatal exposure to EDC mixtures impacts later life brain functions.

Expression of Toll-like receptors 4 and 7 in murine peripheral nervous system development.

BACKGROUND: Toll-Like Receptors (TLRs) play a critical role in the innate and adaptive immune system. They are the mammalian orthologs of Drosophila melanogaster protein Toll, which has been proved to have an early morphogenetic role in invertebrate embryogenesis that in the adult switches to an immune function. AIM: The aim of this study was to evaluate the expression of TLR4 and TLR7 during dorsal root ganglia (DRG), paravertebral ganglia (PVG), and enteric nervous system (ENS) murine development. METHODS: Mouse embryos from different stages (i.e. E12 to E18) were processed for immunolocalization analysis on formalin-fixed paraffin-embedded sections, and isolated intestine were processed for whole-mount preparations. RESULTS: We observed a differentially regulated expression of TLR4 and TLR7 during embryogenesis and an overall increased expression of both receptors during development. While TLR4 was detectable in neurons of DRG and PVG starting from E14 and only from E18 in the ENS, TLR7 was already expressed in scattered neurons of all the investigated regions at E12. CONCLUSIONS: TLR4 and TRL7 expression temporal patterns suggest a morphogenetic role for these receptors in the development of neural crest derivatives in mammals.

DHEAS and Human Development: An Evolutionary Perspective.

Adrenarche, the post-natal rise of DHEA and DHEAS, is unique to humans and the African Apes. Recent findings have linked DHEA in humans to the development of the left dorsolateral prefrontal cortex (LDPFC) between the ages of 4-8 years and the right temporoparietal junction (rTPJ) from 7 to 12 years of age. Given the association of the LDLPFC with the 5-to-8 transition and the rTPJ with mentalizing during middle childhood DHEA may have played an important role in the evolution of the human brain. I argue that increasing protein in the diet over the course of human evolution not only increased levels of DHEAS, but linked meat consumption with brain development during the important 5- to-8 transition. Consumption of animal protein has been associated with IGF-1, implicated in the development of the adrenal zona reticularis (ZR), the site of DHEAS production. In humans and chimps, the zona reticularis emerges at 3-4 years, along with the onset of DHEA/S production. For chimps this coincides with weaning and peak synaptogenesis. Among humans, weaning is completed around 2 ½ years, while synaptogenesis peaks around 5 years. Thus, in chimpanzees, early cortical maturation is tied to the mother; in humans it may be associated with post-weaning provisioning by others. I call for further research on adrenarche among the African apes as a critical comparison to humans. I also suggest research in subsistence populations to establish the role of nutrition and energetics in the timing of adrenarche and the onset of middle childhood.

Exploration of cardiometabolic and developmental significance of angiotensinogen expression by cells expressing the leptin receptor or agouti-related peptide.

Angiotensin II (ANG II) Agtr1a receptor (AT1A) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor (Lepr) and agouti-related peptide (Agrp). Agtr1a expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT1A signaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen (Agt, encoding AGT) with mice expressing Cre-recombinase via the Lepr or Agrp promoters to cause cell-specific deletions of Agt (AgtLepr-KO and AgtAgrp-KO mice, respectively). AgtLepr-KO mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, AgtAgrp-KO mice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body Agt deficiency or Agt disruption in albumin (Alb)-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult AgtAgrp-KO mice exhibited normal circulating AGT protein and hepatic Agt mRNA expression but reduced Agt mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that Agrp and Alb are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both Agrp-Cre and Alb-Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of Agt is critically required for normal renal development and survival.

The Unique Role of 11-Oxygenated C19 Steroids in Both Premature Adrenarche and Premature Pubarche.

INTRODUCTION: Recent studies have shown 11-oxygenated androgens (11oAs) are the dominant androgens in premature adrenarche (PA). Our objective was to compare 11oAs and conventional androgens in a well-defined cohort of children with PA or premature pubarche (PP) and correlate these androgens with metabolic markers. METHODS: A prospective cross-sectional study was conducted at a university hospital. Fasting early morning serum steroids (including 11oAs) and metabolic biomarkers were compared and their correlations determined in children ages 3-8 years (F) or 3-9 years (M) with PA or PP (5 M and 15 F) and healthy controls (3 M and 8 F). RESULTS: There were no differences between PA, PP, and controls or between PA and PP subgroups for sex, BMI z-score, or criteria for childhood metabolic syndrome. Dehydroepiandrosterone sulfate (DHEAS) was elevated only in the PA subgroup, as defined. 11oAs were elevated versus controls in PA and PP although no differences in 11oAs were noted between PA and PP. Within the case cohort, there was high correlation of T and A4 with 11-ketotestosterone and 11ß-hydroxyandrostenedione. While lipids did not differ, median insulin and HOMA-IR were higher but not statistically different in PA and PP. CONCLUSIONS: PA and PP differ only by DHEAS and not by 11oAs or insulin sensitivity, consistent with 11oAs - rather than DHEAS - mediating the phenotypic changes of pubarche. Case correlations suggest association of 11oAs with T and A4. These data are the first to report the early morning steroid profiles including 11oAs in a well-defined group of PA, PP, and healthy children.

Embryonic Development and Adult Regeneration of the Adrenal Gland.

The adrenal gland plays a pivotal role in an organism's health span by controlling the endocrine system. Decades of research on the adrenal gland have provided multiscale insights into the development and maintenance of this essential organ. A particularly interesting finding is that founder stem/progenitor cells participate in adrenocortical development and enable the adult adrenal cortex to regenerate itself in response to hormonal stress and injury. Since major advances have been made in understanding the dynamics of the developmental process and the remarkable regenerative capacity of the adrenal gland, understanding the mechanisms underlying adrenal development, maintenance, and regeneration will be of interest to basic and clinical researchers. Here, we introduce the developmental processes of the adrenal gland and discuss current knowledge regarding stem/progenitor cells that regulate adrenal cortex remodeling and regeneration. This review will provide insights into the fascinating ongoing research on the development and regeneration of the adrenal cortex.

Assessment of adrenal function at birth using adrenal glucocorticoid precursor to product ratios to predict short-term neonatal outcomes.

BACKGROUND: Most neonatal outcomes in neonates are related to normal adrenal gland function. Assessment of adrenal function in a sick preterm neonate remains a challenge, thus we hypothesized that adrenal steroid precursors to their product ratios have a direct relationship with neonatal outcomes. METHODS: We studied demographics of pregnancy and neonatal outcomes in 99 mother-infant pairs (24-41 weeks) and assayed 7 glucocorticoid precursors in the cortisol biosynthesis/degradation pathway. We correlated antenatal factors and short-term neonatal outcomes with these precursors and their ratios to assess maturity of individual enzymes. RESULTS: We found no correlation between cortisol levels with antenatal factors and outcomes. Antenatal steroid use impacted several cortisol precursors. 17-OH pregnenolone-to-cortisol ratio at birth was the best predictor of short-term neonatal outcomes, such as hypotension, RDS, IVH and PDA. A cord blood 17-OH pregnenolone:cortisol ratio of <0.21 predicts which neonate will have a normal outcome with a high sensitivity and specificity. CONCLUSIONS: Maternal factors and antenatal steroids impact neonatal adrenal function and leads to maturation of adrenal function. 17-OH pregnenolone:cortisol ratio and not cortisol is the best predictor of adrenal function. Adrenal function can be assessed by evaluating the profile of adrenal steroids.

Prenatal glucocorticoids exposure and fetal adrenal developmental programming.

Clinically, we apply synthetic glucocorticoids to treat fetal and maternal diseases, such as premature labor and autoimmune diseases. Although its clinical efficacy is positive, the fetus will be exposed to exogenous synthetic glucocorticoids. Prenatal adverse environments (such as xenobiotics exposure, malnutrition, infection, hypoxia and stress) can cause fetuses overexposure to excessive endogenous maternal glucocorticoids. The level of glucocorticoids is the key to fetal tissue maturation and postnatal fate. A large number of studies have found that prenatal glucocorticoids exposure can lead to fetal adrenal dysplasia and dysfunction, continuing after birth and even into adulthood. As the core organ of fetal-originated adult diseases, fetal adrenal dysplasia is closely related to the susceptibility and occurrence of multiple chronic diseases, and there are also obvious gender differences. However, its intrauterine programming mechanisms have not been fully elucidated. This review summarizes recent advances in prenatal glucocorticoids exposure and fetal adrenal developmental programming alterations, which is of great significance for explaining adrenal developmental toxicity and the intrauterine origin of fetal-originated adult diseases.

Sympathectomy-induced blood pressure reduction in adult normotensive and hypertensive rats is counteracted by enhanced cardiovascular sensitivity to vasoconstrictors.

The effect of chemical sympathectomy on cardiovascular parameters and the compensatory role of adrenal hormones, the renin-angiotensin system, and cardiovascular sensitivity to vasoconstrictors were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sympathectomy was induced in 20-week-old rats by daily intraperitoneal guanethidine administration (30 mg/kg b.w.) for 2 weeks. Basal blood pressure (BP), heart rate (HR), and restraint stress-induced cardiovascular changes were measured by radiotelemetry. The BP response to catecholamines was determined in rats with implanted catheters. Sympathectomy decreased BP only transiently, and after 14-day guanethidine treatment, BP returned to basal values in both strains. Sympathectomy permanently lowered HR, improved baroreflex sensitivity, and decreased the low-frequency domain of systolic blood pressure variability (a marker of vascular sympathetic activity). Guanethidine also attenuated the BP and HR responses to restraint stress. On the other hand, the BP response to catecholamines was augmented in sympathectomized rats, and this was not due to the de novo synthesis of vascular adrenergic receptors. Sympathectomy caused adrenal enlargement, enhanced the expression of adrenal catecholamine biosynthetic enzymes, and elevated plasma adrenaline levels in both strains, especially in WKY rats. Guanethidine also increased the plasma levels of aldosterone and corticosterone in WKY rats only. In conclusion, sympathectomy produced a transient decrease in BP, a chronic decrease in HR and improvement in baroreflex sensitivity. The effect of sympathectomy on BP was counteracted by increased vascular sensitivity to catecholamines in WKY rats and SHRs and/or by the enhanced secretion of adrenal hormones, which was more pronounced in WKY rats.

Ontogeny of the adrenocortical response in an extremely altricial bird.

Life history theory predicts that physiological and behavioral responsiveness to stress should be delayed in development until the benefits of heightened reactivity outweigh the costs of potentially chronic glucocorticoid levels. Birds often acquire stress-responsiveness at locomotor independence, however, both stress-responsiveness and locomotor ability are delayed in birds with altricial developmental strategies. Parrots (Psittacidae) are extremely altricial, but it is not known whether they also postpone physiological responsiveness to stress until locomotor independence. We quantified individual variation in baseline and stress-induced plasma corticosterone (CORT) concentrations, the main avian glucocorticoid, in wild green-rumped parrotlets (Forpus passerinus) of Venezuela at four stages of nestling development. Parrotlet neonates are very underdeveloped and compete for parental care among extreme sibling size hierarchies, a competitive scenario that might benefit from early hypothalamic-pituitary-adrenal (HPA) functionality. Nestlings that underwent a standardized restraint stress-treatment showed higher average CORT concentrations compared to baseline in all age groups sampled, and exhibited no evidence of age-related changes in the stress response. This is 2 weeks before locomotor independence and earlier than previously documented for altricial species. Results suggest that precocity of HPA function may be advantageous to growth and survivorship in extremely altricial birds.

Hyperthermia-induced seizures followed by repetitive stress are associated with age-dependent changes in specific aspects of the mouse stress system.

Stress is among the most frequently self-reported factors provoking epileptic seizures in children and adults. It is still unclear, however, why some people display stress-sensitive seizures and others do not. Recently, we showed that young epilepsy patients with stress-sensitive seizures exhibit a dysregulated hypothalamic-pituitary-adrenal (HPA)-axis. Most likely, this dysregulation gradually develops, and is triggered by stressors occurring early in life (early-life stress [ELS]). ELS may be particularly impactful when overlapping with the period of epileptogenesis. To examine this in a controlled and prospective manner, the present study investigated the effect of repetitive variable stressors or control treatment between postnatal day (PND) 12 and 24 in male mice exposed on PND10 to hyperthermia (HT)-induced prolonged seizures (control: normothermia). A number of peripheral and central indices of HPA-axis activity were evaluated at pre-adolescent and young adult age (ie, at PND25 and 90, respectively). At PND25 but not at PND90, body weight gain and absolute as well as relative (to body weight) thymus weight were reduced by ELS (vs control), whereas relative adrenal weight was enhanced, confirming the effectiveness of the stress treatment. Basal and stress-induced corticosterone levels were unaffected, though, by ELS at both ages. HT by itself did not affect any of these peripheral markers of HPA-axis activity, nor did it interact with ELS. However, centrally we did observe age-specific interaction effects of HT and ELS with regard to hippocampal glucocorticoid receptor mRNA expression, neurogenesis with the immature neurone marker doublecortin and the number of hilar (ectopic) granule cells using Prox1 staining. This lends some support to the notion that exposure to repetitive stress after HT-induced seizures may dysregulate central components of the stress system in an age-dependent manner. Such dysregulation could be one of the mechanisms conferring higher vulnerability of individuals with epilepsy to develop seizures in the face of stress.

The Adrenal Clock Prevents Aberrant Light-Induced Alterations in Circadian Glucocorticoid Rhythms.

The glucocorticoid (GC) rhythm is entrained to light-dark (LD) cycles via a molecular clock in the suprachiasmatic nucleus (SCN) and is maintained by an adrenal clock synchronized by SCN-dependent signals. Targeted deletion of the core clock gene Bmal1 can disrupt adrenal clock function. The requirement of the adrenal clock to stabilize the circadian GC rhythm during exposure to aberrant LD cycles was determined using novel aldosterone synthase (AS)Cre/+::Bmal1Fl/Fl mice in which Bmal1 deletion occurred during postnatal adrenal transdifferentiation. To examine whether adrenal Bmal1 deletion results in loss of the adrenal clock, mice were crossed with mPER2::Luciferase (mPER2Luc/+) mice. Adrenals from ASCre/+::Bmal1+/+::PER2Luc/+ [control (CTRL)] mice show mPER2Luc rhythms ex vivo, whereas slices from ASCre/+::Bmal1Fl/Fl::PER2Luc/+ [knockout (KO)] mice show dampened rhythms. To monitor corticosterone rhythmicity, mice were implanted with subcutaneous microdialysis probes and sampled at 60-minute intervals for up to 3 days under 12:12-hour [τ (T) 24] LD or 3.5:3.5-hour (T7) LD cycles. Corticosterone rhythms were entrained to T24 LD in CTRL and KO mice. Under T7 LD, circadian corticosterone rhythms persisted in most CTRL mice but not KO mice. Hyperadrenocorticism also was observed in KO mice under T7 LD, reflected by increased corticosterone peak amplitude, total daily corticosterone, and responses to ACTH. Analysis of dysregulated adrenal genes in KO mice exposed to aberrant light identified candidates involved in cholesterol metabolism and trafficking, including steroidogenic acute regulatory protein, which could increase steroidogenesis. Our results show that the adrenal clock functions to buffer steroidogenic responses to aberrant light and stabilize circadian GC rhythmicity.

The Rise, Fall, and Resurrection of 11-Oxygenated Androgens in Human Physiology and Disease.

The 11-oxyandrogens, particularly 11-ketotestosterone, have been recognized as a biologically important gonadal androgen in teleost (bony) fishes for decades, and their presence in human beings has been known but poorly understood. Today, we recognize that 11-oxyandrogens derive from the human adrenal glands and are major bioactive androgens, particularly in women and children. This article will review their biosynthesis and metabolism, abundance in normal and pathologic states, and potential as biomarkers of adrenal developmental changes and disease. Specifically, 11-oxyandrogens are the dominant active androgens in many patients with 21-hydroxylase deficiency.

Adrenocortical development: Lessons from mouse models.

The adrenocortical gland undergoes structural and functional remodelling in the fetal and postnatal periods. After birth, the fetal zone of the gland undergoes rapid involution in favor of the definitive cortex, which reaches maturity with the emergence of the zona reticularis(zR) at the adrenarche. The mechanisms underlying the adrenarche, the process leading to pre-puberty elevation of plasma androgens in higher primates, remain unknown, largely due to lack of any experimental model. By following up fetal and definitive cortex cell lines in mice, we showed that activation of protein kinase A (PKA) signaling mainly impacts the adult cortex by stimulating centripetal regeneration, with differentiation and then conversion of the zona fasciculata into a functional zR. Animals developed Cushing syndrome associated with primary hyperaldosteronism, suggesting possible coexistence of these hypersecretions in certain patients. Remarkably, all of these traits were sex-dependent: testicular androgens promoted WNT signaling antagonism on PKA, slowing cortical renewal and delaying onset of Cushing syndrome and the establishment of the zR in male mice, this being corrected by orchidectomy. In conclusion, zR derives from centripetal conversion of the zona fasciculata under cellular renewal induced by PKA signaling, determining the size of the adult cortex. Finally, we demonstrated that this PKA-dependent mobilization of cortical progenitors is sexually dimorphic and could, if confirmed in humans, account for female preponderance in adrenocortical pathologies.

Transcriptome Profile in Unilateral Adrenalectomy-Induced Compensatory Adrenal Growth in the Rat.

Compensatory adrenal growth evoked by unilateral adrenalectomy (hemiadrenalectomy) constitutes one of the most frequently studied in vivo models of adrenocortical enlargement. This type of growth has been quite well characterized for its morphological, biochemical, and morphometric parameters. However, the molecular basis of compensatory adrenal growth is poorly understood. Therefore, the aim of this study was to investigate the rat adrenal transcriptome profile during the time of two previously described adrenocortical proliferation waves at 24 and 72 h after unilateral adrenalectomy. Surgical removal of the left adrenal or a sham operation was accomplished via the classic dorsal approach. As expected, the weight of the remaining right adrenal glands collected at 24 and 72 h after hemiadrenalectomy increased significantly. The transcriptome profile was identified by means of Affymetrix® Rat Gene 2.1 ST Array. The general profiles of differentially expressed genes were visualized as volcano plots and heatmaps. Detailed analyzes consisted of identifying significantly enriched gene ontological groups relevant to adrenal physiology, by means of DAVID and GOplot bioinformatics tools. The results of our studies showed that compensatory adrenal growth induced by unilateral adrenalectomy exerts a limited influence on the global transcriptome profile of the rat adrenal gland; nevertheless, it leads to significant changes in the expression of key genes regulating the circadian rhythm. Our results confirm also that regulation of compensatory adrenal growth is under complex and multifactorial control with a pivotal role of neural regulatory mechanisms and a supportive role of other components.