Maternal Corticosterone Research Articles

Maternal Baicalin Treatment Increases Fetal Lung Surfactant Phospholipids in Rats

Baicalin is a flavonoid compound purified from the medicinal plant Scutellaria baicalensis Georgi and has been reported to stimulate surfactant protein (SP)-A gene expression in human lung epithelial cell lines (H441). The aims of this study were to determine whether maternal baicalin treatment could increase lung surfactant production and induce lung maturation in fetal rats. This study was performed with timed pregnant Sprague-Dawley rats. One-day baicalin group mothers were injected intraperitoneally with baicalin (5 mg/kg/day) on Day 18 of gestation. Two-day baicalin group mothers were injected intraperitoneally with baicalin (5 mg/kg/day) on Days 17 and 18 of gestation. Control group mothers were injected with vehicle alone on Day 18 of gestation. On Day 19 of gestation, fetuses were delivered by cesarean section. Maternal treatment with 2-day baicalin significantly increased saturated phospholipid when compared with control group and total phospholipid in fetal lung tissue when compared with control and 1-day baicalin groups. Antenatal treatment with 2-day baicalin significantly increased maternal growth hormone when compared with control group. Fetal lung SP-A mRNA expression and maternal serum corticosterone levels were comparable among the three experimental groups. Maternal baicalin treatment increases pulmonary surfactant phospholipids of fetal rat lungs and the improvement was associated with increased maternal serum growth hormone. These results suggest that antenatal baicalin treatment might accelerate fetal rat lung maturation.

Elevated corticosterone levels in stomach milk, serum, and brain of male and female offspring after maternal corticosterone treatment in the rat

Early influences such as maternal stress affect the developmental outcome of the offspring. We created an animal model of postpartum depression/stress based on giving high levels of corticosterone (CORT) to the rat dam, which resulted in behavioral and neural changes in the offspring. This study investigated whether highly elevated levels of maternal CORT during pregnancy or the postpartum result in higher levels of CORT in the stomach milk, serum, and brain of offspring. Dams received daily injections of CORT (40 mg/kg) or oil (control) either during pregnancy (gestational days 10-20) or the postpartum (Days 2-21). Pups that were exposed to high gestational maternal CORT had higher CORT levels in serum, but not in stomach milk or brain, on postnatal day (PND) 1. However, on PND7, pups that were exposed to high postpartum maternal CORT had higher CORT levels in stomach milk and brain, but not in serum. Conversely on PND18, pups that were exposed to high postpartum maternal CORT had higher CORT levels in serum, but not in brain (prefrontal cortex, hypothalamus, or hippocampus). Moreover, 24 h after weaning, there were no significant differences in serum CORT levels between the groups. Thus, CORT given to the dam during pregnancy or the postpartum results in elevated levels of CORT in the offspring, but in an age- and tissue-dependent manner. Developmental exposure to high CORT could reprogram the HPA axis and contribute to the behavioral and neural changes seen in adult offspring.

Critical Age Windows for Neurodevelopmental Psychiatric Disorders: Evidence from Animal Models

A disruption in normal brain development has been hypothesized to contribute to the aetiology of major psychiatric disorders. According to the 'double-hit' hypothesis, mutant genes-based deviations, associated with specific environmental insults during brain development, may result in neurobehavioural disturbances. The existence of age windows of vulnerability to environmental conditions during brain maturation will be discussed, using as examples a series of studies we have performed during the last years. Major deviations from normative neurobehavioural trajectories have been reported in animal models following exposure to severe stress (either episodes of maternal separation, deprivation or corticosterone supplementation) early in infancy. Rodent models of difficult and/or stressful pregnancies, including obstetric complications (e.g. prenatal restrain stress or neonatal hypoxia) and gestational exposure to infection (e.g prenatal immune challenge), have been associated with profound long-lasting deficits in the offspring's emotional and social behaviour, and with immune and endocrine changes. More recently, adolescence, characterized by elevated rates of brain plasticity, has emerged as an additional period during which sensitivity to environmental influence (either adverse or stimulatory) is maximal. We have reported that both pharmacological (methylphenidate) and environmental (physical or social enrichment) interventions can be used to counteract the detrimental effects of earlier-origin developmental insults. Present findings indicate that these age periods (i.e. prenatal stage, early infancy and adolescence) do represent critical windows open to plastic changes and might be susceptible to both adverse and supportive shaping environmental forces. Taken together, age-related neuroplasticity might be considered not only as a risk factor for psychopathology but also as a potent mechanism for compensation. A better understanding of these critical periods of brain development is a concern for public health and may provide new insights into prevention strategies and into novel therapeutic approaches in neuropsychiatry.

Defining age limits of the sensitive period for attachment learning in rat pups.

Enhanced odor preference learning and attenuated fear learning characterizes rat pups' attachment learning Sensitive Period for learning the maternal odor. This period terminates at 10 days old (PN10) with increasing endogenous levels of the stress hormone, corticosterone. Increasing Sensitive Period pups' corticosterone prematurely terminates the Sensitive Period, while decreasing corticosterone in older pups delays Sensitive Period termination. Here we extend these findings and define the age range corticosterone alters learning and question whether corticosterone permanently terminates the Sensitive Period. Pups were odor-0.5 mA shock conditioned with either corticosterone increased (PN5-6; 4 mg/kg vs. saline) or decreased (PN15-16; naturally by maternal presence or corticosterone synthesis blocker, Metyrapone). Finally, PN7-8 pups were conditioned with corticosterone and reconditioned without corticosterone to assess whether the Sensitive Period was permanently terminated. Results indicate developmental limits for corticosterone regulation of pup learning are PN6 through PN15. Furthermore, inducing precocious corticosterone induced fear learning was not permanent, since reconditioning without corticosterone enabled odor preference learning. Results suggest pups are protected from learning aversions to maternal odor until approaching weaning.

Ethanol-induced inhibition of fetal hypothalamic–pituitary–adrenal axis due to prenatal overexposure to maternal glucocorticoid in mice

Prenatal ethanol exposure has been well documented to be one of the etiological factors responsible for intrauterine growth retardation (IUGR). Previous studies have shown that chronic ethanol exposure during pregnancy elevated the basic level of corticosterone in fetus. However, the potential mechanisms behind them are still unclear. The aim of the present study was to investigate the effects of prenatal ethanol exposure on maternal and fetal hypothalamic–pituitary–adrenal (HPA) axis as well as placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), and to clarify the mechanism of ethanol-induced IUGR. Pregnant mice were intragastricly administrated with ethanol at a dose of 6.4 g kg −1 d −1 from day 11 to 17 of gestation and parameters representing fetal growth and development were recorded either. The level of corticosterone in maternal serum was determined by ELISA kit. The mRNA expressions of steroidogenic acute regulatory protein (StAR) and cytochrome P450 cholesterol side chain cleavage (P450scc) both in maternal and fetal adrenal, and placental 11β-HSD-2 were detected by real-time quantitative PCR, respectively. The results showed that fetal body weight significantly decreased, and the incidence of IUGR was obviously increased after prenatal ethanol exposure. Maternal serum corticosterone level was elevated, and the expressions of StAR and P450scc were increased in maternal adrenal while decreased in fetal adrenal. The expression of placental 11β-HSD-2 was significantly reduced. These results suggest that prenatal ethanol exposure induces an inhibition of fetal HPA axis activity and IUGR occurs. The mechanism may be associated with ethanol-induced maternal HPA axis activation and high glucocorticoid condition, which impair the placental barrier, and lead to an overexposure of elevated maternal glucocorticoid to fetus, and eventually result in the inhibition of the fetal HPA axis.

Change in Body Mass Can Overrule the Effects of Maternal Testosterone on Primary Offspring Sex Ratio of First Eggs in Homing Pigeons

The phenomenon of primary offspring sex ratio adjustment is being extensively studied, yet knowledge of the underlying proximate mechanism is still mainly hypothetical. Female birds are the heterogametic sex, thus potentially controlling the sex of the gamete to be fertilized. In several bird species, independent studies showed effects of maternal plasma testosterone, corticosterone, or condition on primary offspring sex ratio. Our objective was to investigate the causal relation between these two maternal hormones, body condition, and offspring sex ratio in homing pigeons (Columba livia domestica). Following our earlier study, we again implanted females with testosterone and determined embryo sex of first eggs. To identify the pathway of sex ratio adjustment, we repeatedly measured not only maternal plasma testosterone and mass but also plasma corticosterone, cholesterol, and glucose, all indicators of body condition. We also calculated the temporal change in these parameters, which has been proposed to be a more accurate predictor of offspring sex ratio compared with the absolute values. Furthermore, we analyzed testosterone concentrations in outer yolk layers, which potentially influence the first meiotic division of the gamete. We found no relation between plasma parameter and embryo sex of first eggs; testosterone treatment did not affect any of the measured parameters. However, females that increased in mass produced more male embryos, irrespective of treatment group. Outer yolk layer testosterone concentrations did not differ between treatment groups or between male and female eggs. We propose that not only the absolute values but also the complex interactions between maternal hormones and body condition ultimately affect the mechanism of primary offspring sex manipulation.

Are increased concentrations of maternal corticosterone adaptive to offspring? A test using a placentotrophic lizard

Summary 1. Maternal hormones during embryogenesis act as a bridge between the maternal and the offspring environment and consequently may allow maternal pre‐programming of offspring phenotype to the environment, assuming that maternal environment is a reliable predictor of offspring environment. 2. We use an orthogonal experimental design in which we increase plasma corticosterone concentration (vs. control) in placentotrophic gravid female spotted skinks (Niveoscincus ocellatus) and their offspring. We hypothesize that high concentrations of maternal corticosterone allow offspring phenotype to be pre‐programmed to better cope with high concentrations of corticosterone after birth and, consequently, offspring would not suffer from its deleterious effects. We use growth as a measure of performance as corticosterone typically affects growth in reptiles. 3. High concentrations of maternal corticosterone had significant effects on offspring body condition at birth which could have resulted from corticosterone passing through the complex placenta and/or from the indirect effects of corticosterone on maternal body condition. 4. There was no indication of maternal pre‐programming to high concentrations of corticosterone postpartum: growth rate of offspring placed in the same treatment (corticosterone vs. control) than their mother was not different to growth rate of offspring placed in a different treatment than their mother. 5. Maternal pre‐programming to corticosterone may not have been selected for in this species either because maternal chronic stress is not a reliable predictor of offspring chronic stress or because maternal pre‐programming does not outweigh the costs of having reduced sensitivity to the hormone, resulting in slower, less appropriate reactions in stressful conditions. This study further demonstrates the highly versatile and context‐dependent nature of maternal effects and the trade‐offs between costs and benefits of maternal pre‐programming.

Differential effects of prenatal stress and glucocorticoid administration on postnatal growth and glucose metabolism in rats

Glucocorticoid administration during pregnancy programmes cardiovascular and metabolic functions in the adult offspring. Often, the control procedures are stressful per se and raise maternal glucocorticoid concentrations. This study compared the effects of maternal injection with dexamethasone (dex, 200 microg/kg) or saline with no treatment from 15 to 20 days of rat pregnancy on offspring growth and glucose metabolism. Near term, maternal corticosterone concentrations were higher in the saline-treated dams and lower in the dex-treated dams relative to untreated animals. In both male and female offspring, growth rate was measured for 14 weeks, and glucose tolerance was assessed between 12 and 13 weeks together with body fat content and plasma concentrations of insulin, leptin, and corticosterone between 14 and 15 weeks. Offspring liver was collected at different ages and was analyzed for glycogen content and gluconeogenic enzyme activity. Compared with untreated animals, both dex and saline treatments altered postnatal growth although adult body weight was unaffected. The two treatments had different effects on adult insulin concentrations and on hepatic glycogen content and gluconeogenic enzyme activities both pre- and postnatally. Relative to untreated animals, adult glucose tolerance was improved by maternal saline injection in males but not in females, while it was impaired in female offspring but not in male offspring of the dex-treated dams. Adult glucose tolerance was related to male body fat content but not to female body fat content. Dex and saline treatments of pregnant rats have differential sex-linked effects on the growth and glucose metabolism of their offspring, which indicates that the programming actions of natural and synthetic glucocorticoids may differ.

Maternal corticosterone but not testosterone level is associated with the ratio of second-to-fourth digit length (2D:4D) in field vole offspring ( Microtus agrestis)

The steroid environment encountered by a foetus can strongly affect its post-natal physiology and behaviour. It has been proposed that steroid concentrations experienced in utero could be estimated from adults by measuring their second-to-fourth digit length ratio (2D:4D). However, there is still little direct evidence that intra-uterine steroid levels affect individual 2D:4D. We examined whether maternal pre-pregnancy testosterone and corticosterone levels (as estimates of intra-uterine testosterone and corticosterone exposure) affected the 2D:4D of pups in non-domesticated field voles ( Microtus agrestis), measured by X-rays at the age of weaning (21 days). Furthermore, for the first time in a non-human species, we studied whether testosterone and corticosterone levels correlated with 2D:4D in adult females. We found that the maternal pre-pregnancy level of testosterone was not associated with offspring 2D:4D in either the left or the right paw. Instead, maternal pre-pregnancy corticosterone level was positively correlated with offspring 2D:4D in the right paw, but unrelated to 2D:4D in the left paw. In addition, the 2D:4D of adult females was not associated with either their circulating testosterone or corticosterone levels. Our results suggest that in field voles maternally administered testosterone is not a major determinant of offspring 2D:4D, whereas maternal stress appears to account for some of the variation in the 2D:4D of their offspring.

Influence of maternal corticosterone treatment on incubation length of eggs laid by Japanese quail hens selected for divergent adrenocortical stress responsiveness

1. Previous studies have shown that more yolk corticosterone is found in the eggs of random bred Japanese quail hens implanted with corticosterone during egg formation; both unstressed and stressed quail hens selected for exaggerated (high stress) rather than reduced (low stress) plasma corticosterone response to brief restraint deposit more corticosterone into their egg yolks. The length of egg incubation is also known to be shorter in eggs laid by high than low stress hens. 2. Here we investigated the interactive effects of quail stress line (low vs. high stress) with maternal corticosterone treatment (empty implant controls vs. corticosterone-implants) during egg formation on length of egg incubation. 3. Mean (±SEM) length of egg incubation for high stress control eggs (397⋅3 ± 0⋅4 h) was similarly shorter (by about 4.5 h) than that found for low stress control eggs (392⋅8 ± 0⋅2 h). In addition, on average, the incubation length of eggs laid by corticosterone-implanted hens (392⋅9 ± 0⋅5 h) was nearly 3 h shorter than that found for eggs laid by control hens (395⋅8 ± 0⋅2 h) regardless of stress line. 4. Line × hen-implant treatment effects on mean (±SEM) length of egg incubation partitioned in rank order as follows: low stress control (397⋅8 ± 0⋅5 h) > low stress corticosterone-implant (395⋅9 ± 0⋅7 h) > high stress control (393⋅8 ± 0⋅3 h) > high stress corticosterone-implant (391⋅2 ± 0⋅4 h). 5. Our original contention that selection for exaggerated adrenocortical responsiveness is associated with a reduction in the length of egg incubation was supported. Because maternal stress-induced elevations of yolk B are known to occur, the present findings of further shortenings of the hatching times of eggs of corticosterone-treated hens of both stress lines are also important to the poultry industry because they warn producers that unless stress in hens during egg formation is minimised, abbreviated egg incubation periods may result beyond the effects that a hen's genetic predisposition to adrenocortical stress responsiveness has on the length of egg incubation.

Influence of metyrapone treatment during pregnancy on the development and maturation of brain monoaminergic systems in the rat

This study examines the effect of reducing the corticosterone levels of gestating rat dams on the postnatal development and maturation of monoaminergic systems in their offspring's brains. Metyrapone, an inhibitor of CORT synthesis, was administered to pregnant rats from E0 to E17 of gestation. Monoamine concentrations were determined in male and female offspring at postnatal days (PN) 23 and 90 in the hippocampus, hypothalamus and striatum. Reducing maternal corticosterone (mCORT) during gestation led to alterations in dopamine and serotonin levels in all three brain areas studied at PN 23. Alterations persisted until at least PN 90 in the serotonergic systems; the dopamine content of the hippocampus also remained modified. Reduced mCORT during gestation also led to alterations in the development and maturation of the hypothalamic noradrenergic systems. Sexually dimorphic responses were observed in all these monoaminergic systems at different times. These results suggest that while they are still developing, brain monoaminergic systems are particularly sensitive to epigenetic influences. An adequate foetal level of CORT is required for the normal ontogeny of brain monoaminergic systems. The present data also provide that during the critical period of brain development, maternal CORT plays an important role in the sexual differentiation of monoaminergic systems, with particular influence on brain serotonergic neurones.

Maternal corticosterone reduces egg fertility and hatchability and increases the numbers of early dead embryos in eggs laid by quail hens selected for exaggerated adrenocortical stress responsiveness

Quail hens selected for exaggerated (HS, high stress) rather than reduced (LS, low stress) plasma corticosterone (B) response to brief restraint deposit more B into their egg yolks than do LS hens. Female progeny of HS hens implanted with B also show reduced egg production when compared with female offspring of LS- and HS-control and LS-B-implanted hens. Herein, LS and HS hens were implanted (s.c.) with empty (controls, CON) or B-filled silastic tubes to assess the interactive influences of maternal B-treatment with quail stress line on egg fertility (FERT), total egg hatchability (TOTHATCH) and fertile egg hatchability, and the percentages of embryonic mortality (early dead, ED; late dead) and pipped eggs. Mean FERT was dramatically reduced in eggs of HS compared with LS hens and B-implanted compared with CON-treated hens (P < 0.0001, both cases). Line x implant treatment FERT outcomes partitioned (P < 0.05) as follows: LS-B = LS-CON > HS-CON > HS-B. In addition, TOTHATCH was also affected by line (LS > HS; P < 0.0001) and implant treatment (CON > B-implant; P < 0.0002) and line x implant treatment TOTHATCH means differed (P < 0.05) as follows: LS-CON = LS-B = HS-CON > HS-B. Fertile egg hatchability was reduced (P < 0.05) in HS-B-treated hen eggs when compared with LS-B and HS-CON hen eggs and more (P < 0.05) ED embryos were found in eggs laid by HS-B-implanted hens than in any other treatment group. Late dead and pipped egg percentages were unaffected by any treatment. The findings are important to avian geneticists because they further emphasize the benefits that selection for reduced adrenocortical responsiveness has on hen reproductive performance. The maternal B findings also warn poultry and hatchery managers that unless hen stress during egg formation is avoided, negative consequences in FERT, TOTHATCH, and ED can result, particularly in hens genetically predisposed toward exaggerated adrenal stress responsiveness.

Effects of prenatal immune activation on hippocampal neurogenesis in the rat

Maternal infection during pregnancy has been associated with an increased risk for the development of schizophrenia, a disorder characterized by abnormalities in hippocampal morphology and function. Neurogenesis occurs in the hippocampus throughout development into adulthood and is believed to modulate hippocampal function. This study used a rat model in which bacterial endotoxin, lipopolysaccharide (LPS), is administered to pregnant dams, to test if prenatal immune activation has acute and/or long term effects on various phases of neurogenesis (proliferation, survival, differentiation) in the hippocampal dentate gyrus of offspring. When LPS was administered to dams on gestation days (GD) 15 and 16, there was decreased proliferation of dentate cells at postnatal day (PD) 14 and decreased survival of cells generated at PD14 in offspring. When prenatal exposure to LPS was later in pregnancy (GD 18 and 19), offspring showed decreased survival of cells generated both at the time of LPS exposure and at PD14. There was no change in cell proliferation or survival in adult offspring at PD60, with prenatal LPS exposure. Co-administration of the cyclo-oxygenase inhibitor, ibuprofen (IBU), together with prenatal LPS on GD 15 and 16, was unable to prevent the deficit in neuronal survival at PD14. IBU blocked LPS-induced fever but did not block LPS-induced increases in plasma cytokines and corticosterone in the pregnant dam. This indicates that deficits in neurogenesis caused by prenatal LPS are not mediated by LPS-induced fever or eicosanoid induction, but could be mediated by LPS-induced increases in maternal cytokines or corticosterone.

Sex-specific developmental plasticity in response to yolk corticosterone in an oviparous lizard

Corticosterone exposure during prenatal development as a result of maternal upregulation of circulating hormone levels has been shown to have effects on offspring development in mammals. Corticosterone has also been documented in egg yolk in oviparous vertebrates, but the extent to which this influences phenotypic development is less studied. We show that maternal corticosterone is transferred to egg yolk in an oviparous lizard (the mallee dragon, Ctenophorus fordi Storr), with significant variation among clutches in hormone levels. Experimental elevation of yolk corticosterone did not affect hatching success, incubation period or offspring sex ratio. However, corticosterone did have a sex-specific effect on skeletal growth during embryonic development. Male embryos exposed to relatively high levels of corticosterone were smaller on average than control males at hatching whereas females from hormone-treated eggs were larger on average than control females. The data thus suggest that males are not just more sensitive to the detrimental effects of corticosterone but rather that the sexes may have opposite responses to corticosterone during development. Positive selection on body size at hatching for both sexes in this species further suggests that increased corticosterone in egg yolk may have sex-specific fitness consequences, with potential implications for sex allocation and the evolution of hormone-mediated maternal effects.

Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11β‐hydroxysteroid dehydrogenase type 2

Prenatal stress (PS) produces persistent abnormalities in anxiety-related behaviors, stress responsivity, susceptibility to psychopathology and hippocampal changes in adult offspring. The hippocampus shows a remarkable degree of structural plasticity, notably in response to stress and glucocorticoids. We hypothesized that PS would differentially affect hippocampal neurogenesis in rats selectively bred for genetic differences in anxiety-related behaviors and stress responsivity. Pregnant dams of high anxiety-related behavior (HAB) and low anxiety-related behavior (LAB) strains were stressed between days 5 and 20 of pregnancy. The survival of newly generated hippocampal cells was found to be significantly lower in 43-day-old HAB than in LAB male offspring of unstressed pregnancies. PS further reduced newly generated cell numbers only in HAB rats, and this was paralleled by a reduction in doublecortin-positive cell numbers, indicative of reduced neurogenesis. As maternal plasma corticosterone levels during PS were similar in both strains, we examined placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which catalyses rapid inactivation of maternal corticosterone to inert 11-dehydrocorticosterone and thus serves as a physiological 'barrier' to maternal glucocorticoids. PS significantly increased placental 11beta-HSD2 activity in LAB, but not HAB, rats. We conclude that PS differentially affects the number of surviving newly generated cells and neurogenesis in HAB and LAB rats. The high sensitivity of hippocampal neurogenesis to PS in HAB rats is paralleled by a failure to increase placental 11beta-HSD2 activity after stress rather than by different maternal corticosterone responses. Hence, stress-induced placental 11beta-HSD2 expression may be critical in protecting the fetal brain from maternal stress-induced effects on adult neurogenesis.

Reciprocal Changes in Maternal and Fetal Metabolism of Corticosterone in Rat During Gestation

The objective of this study was to investigate the role of 11beta-hydroxysteroid dehydrogenases (11HSD1 and 11HSD2) in determining the fetal concentration of glucocorticoids. The expression patterns for mRNA abundance, protein level, and enzyme activities of placental and fetal 11HSD1 and 11HSD2 were assessed from embryonic day 13 (E13) to day 21 (E21; term E22). The transplacental passage of maternal corticosterone and its contribution to fetal glucocorticoids was also studied. Placental 11HSD1 mRNA decreased between days E13 and E14 and then remained at much lower values up to E21. Similarly, NADP+-dependent 11beta-oxidation and 11-reduction were lower in late gestation. In contrast, placental 11HSD2 mRNA and protein decreased between E13 and E21. Dithiothreitol increased the activity of 11HSD2 and the output of 11-dehydrocorticosterone into fetal circulation.The fetal activity of 11HSD1 increased and 11HSD2 decreased between E16 and E21. The final third of gestation is accompanied by reciprocal changes in placental and fetal metabolism of corticosterone due to changes in 11HSD1 and 11HSD2 not only at the level of transcription but also at a posttranslational level.

Characterization of mice deficient in Melanocortin 2 receptor on a B6/Balbc mix background

We have previously reported that Melanocortin 2 receptor (MC2R(-/-)) deficient mice on B6 N5 generations exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata (zF) and lack of detectable levels of corticosterone, and reduced serum concentrations of aldosterone and epinephrine. All MC2R(-/-) mice on B6/N8 background die within 2 days after birth, while about half of the MC2R(-/-) mice on B6/Balbc mix background survived to adulthood. Both male and female MC2R(-/-) mice were fertile, suggesting that normal development and function of reproductive organs. MC2R(-/-) mice delivered from MC2R(-/-) dams failed to survive due to lung failure, suggesting that fetal or maternal corticosterone is essential for lung maturation. MC2R(-/-) mice failed to activate the hypothalamic-pituitary-adrenal axis in response to both immune and non-immune stimuli. MC2R(-/-) mice maintained glomerular structure and achieved electrolyte homeostasis by the activation of the renin-angiotensin-aldosterone system under low aldosterone and undetectable levels of corticosterone.

Effects of maternal corticosterone and stress on behavioral and hormonal indices of formalin pain in male and female offspring of different ages

In previous studies, we showed for the first time that prenatal stress in rats produces long-term alterations of formalin-induced pain behavior that are dependent on age and sex, and we demonstrated an important role of the serotonergic system in mechanisms of prenatal stress (Butkevich, I.P. and Vershinina, E.A., 2001; Butkevich, I.P. and Vershinina, E.A., 2003; Butkevich, I.P., Mikhailenko, V.A., Vershinina, E.A., Khozhai, L.I., Grigorev, I.P., Otellin, V.A., 2005; Butkevich, I.P., Mikhailenko, V.A., Khozhai, L.I., Otellin, V.A., 2006). In the present study, we focus on the influence of the maternal corticosterone milieu and its role in the effects of stress during pregnancy on formalin-induced pain and the corticosterone response to it in male and female offspring of different ages. For this purpose, we used adrenalectomy (AD) in female rats 3–4 weeks before mating (as distinct from AD typically performed at the beginning of pregnancy). Since AD is considered a reliable method to treat hypercortisolism, researches on the effects of long-term AD in dams on the systems responsible for adaptive behavior in offspring are important (such studies are not described in the literature). The results demonstrate that the differences in the corticosterone response to injection of formalin and saline are obvious in 90-day-old (adult) female offspring but masked in 25-day-old ones. AD promoted the corticosterone response to formalin-induced pain but not to injection of saline in prenatally non-stressed female offspring of both ages. Prenatal stress canceled the differences in corticosterone response to injection of formalin and saline in 25-day-old offspring of AD dams and in adult offspring of sham-operated (SH) dams but caused similar differences in adult offspring of AD dams. Sex differences were found in basal corticosterone levels in AD prenatally stressed rats of both age groups, with a higher level in females, and in the corticosterone response to formalin-induced pain in the adult rats of all groups investigated, with higher corticosterone levels in females. In regard to pain behavior, AD induced significant changes in flexing + shaking in prenatally non-stressed adult offspring and canceled the differences in this behavior between non-stressed and stressed 25-day-old offspring. There were sex differences in pain behavior of the adult rats: greater flexing + shaking in AD non-stressed males but in SH non-stressed females; greater licking in prenatally-stressed AD and SH females. These results indicate that the long-term influences of maternal corticosterone on formalin-induced pain and the corticosterone response to it are determined by the sex and age of the offspring and suggest that other mechanisms, including serotonergic ones revealed in our previous studies, are involved in the effects of prenatal stress on inflammatory pain behavior.

Influences of Maternal Corticosterone and Selection for Contrasting Adrenocortical Responsiveness in Japanese Quail on Developmental Instability of Female Progeny

Differences in developmental instability were assessed in female offspring of Japanese quail hens selected for reduced (low stress, LS) or exaggerated (high stress, HS) plasma corticosterone (B) response to stress and treated with a placebo or B during egg formation. Hens of each line were implanted (s.c.) with either a silastic tube containing no B (controls) or one filled with B. Female chicks hatched from each of the 4 line × implant treatment combinations were retained for examination of 3 bilateral traits at 130 d of age: length of the tibiotarsus, middle toe length, and distance between the auditory canal and the nares (face length, FL). Greater bilateral trait size variances were associated with measurement of tibiotarsus length (P < 0.04) and middle toe length (P < 0.06) in the HS line, supporting our previous findings in the opposite sex that developmental instability (i.e., fluctuating asymmetry, FA) of certain morphological traits is more pronounced in HS than LS adult quail. The HS quail are also known to exhibit greater adrenocortical responsiveness to a wide range of stressors, and they are more easily frightened than LS birds. Therefore, the line differences in FA (HS > LS) found previously in males and herein in females may simply reflect the differential responsiveness of the birds to chronic social and physical environmental stressors. In addition, the present study detected more (albeit marginally so, P < 0.06) bilateral variability (i.e., heightened FA) in FL of quail hatched from mothers treated with B, a finding entirely due to the very high FL variance observed in the female offspring of B-treated HS hens. Because others have found in ovo B treatment to be associated with heightened FA in chick tarsus bone length and because we have also demonstrated that greater yolk B deposition occurs in eggs from both unstressed and stressed HS quail hens than their LS counterparts, the present maternal B treatment may be acting independently, or in combination with HS genomic effects, to adversely affect developmental stability.

The effects of maternal corticosterone levels on offspring behavior in fast- and slow-growth garter snakes ( Thamnophis elegans)

During embryonic development, viviparous offspring are exposed to maternally circulating hormones. Maternal stress increases offspring exposure to corticosterone and this hormonal exposure has the potential to influence developmental, morphological and behavioral traits of the resulting offspring. We treated pregnant female garter snakes ( Thamnophis elegans) with low levels of corticosterone after determining both natural corticosterone levels in the field and pre-treatment levels upon arrival in the lab. Additional measurements of plasma corticosterone were taken at days 1, 5, and 10 during the 10-day exposure, which occurred during the last third of gestation (of 4-month gestation). These pregnant snakes were from replicate populations of fast- and slow-growth ecotypes occurring in Northern California, with concomitant short and long lifespans. Field corticosterone levels of pregnant females of the slow-growth ecotype were an order of magnitude higher than fast-growth dams. In the laboratory, corticosterone levels increased over the 10 days of corticosterone manipulation for animals of both ecotypes, and reached similar plateaus for both control and treated dams. Despite similar plasma corticosterone levels in treated and control mothers, corticosterone-treated dams produced more stillborn offspring and exhibited higher total reproductive failure than control dams. At one month of age, offspring from fast-growth females had higher plasma corticosterone levels than offspring from slow-growth females, which is opposite the maternal pattern. Offspring from corticosterone-treated mothers, although unaffected in their slither speed, exhibited changes in escape behaviors and morphology that were dependent upon maternal ecotype. Offspring from corticosterone-treated fast-growth females exhibited less anti-predator reversal behavior; offspring from corticosterone-treated slow-growth females exhibited less anti-predator tail lashing behavior.