Maternal Corticosterone Research Articles

Placental O-GlcNAc-transferase expression and interactions with the glucocorticoid receptor are sex specific and regulated by maternal corticosterone exposure in mice

Maternal stress programs offspring disease in a sexually dimorphic manner with males often more adversely affected. Previous studies of maternal glucocorticoid exposure suggest male vulnerability may derive from placental alterations. The hexosamine signalling pathway and O-linked glycosylation (O-GlcNAcylation) are part of an essential adaptive survival response in healthy cells. The key enzyme involved is O-linked-N-acetylglucosamine transferase (OGT), a gene recently identified as a sex-specific placental biomarker of maternal stress. Using a mouse model of maternal corticosterone (Cort) exposure, we examined components of hexosamine biosynthesis/signalling and O-GlcNAcylation in whole placentae at E14.5. Our results demonstrate sex-specific differences in OGT levels and O-GlcNAcylation during Cort exposure which impacts on key mediators of cell survival, in particular AKT as well as the stress responsive OGT/GR transrepression complex. In male placentae only, Cort exposure increased Akt O-GlcNacylation which correlated with decreased phosphorylation. Female placentae had higher basal OGT and OGT/GR complex compared with male placentae. Cort exposure did not alter these levels in female placentae but increased global O-GlcNacylation. In male placentae Cort increased OGT and OGT/GR complex with no change in global O-GlcNacylation. These findings suggest that sex-specific differences in placental OGT play a key role in the sexually dimorphic responses to stress.

Prenatal Stress Reduces Learning and Memory in Pre-pubertal, Young, and Adult Rats of Both Sexes

Prenatal stress (PS) induced by immobilization produces deficiencies in spatial learning and information retrieval. These deficiencies seem to be larger in males than in females, and have been explained as an effect of fetal exposure to high concentrations of maternal corticosterone during stress response.

Maternal corticosterone exposure has transgenerational effects on grand-offspring.

The hormone fluctuations that an animal experiences during ovulation can have lifelong effects on developing offspring. These hormones may act as an adaptive mechanism, allowing offspring to be 'pre-programmed' to survive in an unstable environment. Here, we used a transgenerational approach to examine the effects of elevated maternal corticosterone (CORT) on the future reproductive success of female offspring. We show that female zebra finches (Taeniopygia guttata) exposed to embryonic CORT produce daughters that have equal reproductive success (clutch sizes, fertility, hatching success) compared with the daughters produced from untreated mothers, but their offspring had accelerated post-hatching growth rates and were significantly heavier by nutritional independence. Although there was no significant effect on primary offspring sex ratio, females from CORT-treated mothers produced significantly female-biased clutches by nutritional independence. To the best of our knowledge, this is the first record of a transgenerational sex ratio bias in response to elevated maternal CORT in any avian species.

Endogenous Corticosterone Elevations Five Hours Prior to Ovulation do not Influence Offspring Sex Ratios in Zebra Finches

Previous research suggests that environmental and social factors can drive female birds to bias offspring sex ratios. The underlying mechanisms controlling these adjustments remain unclear. Results from experimental and correlative research suggest that maternal corticosterone plays an important role in this process. Since females are the heterogametic sex in birds, corticosterone may potentially bias offspring sex ratios during meiotic segregation, through non-random segregation of sex chromosomes. In a previous study, we showed that pharmacological elevations of corticosterone near the time of meiotic segregation exerted an effect on offspring sex ratio, causing female Zebra Finches ( Taeniopygia guttata) to produce significantly more males. Here, we aimed to determine whether endogenous elevations in the physiological range have similar effects on offspring sex. First we examined offspring sex ratio in relation to baseline corticosterone levels to determine if natural variation in circulating corticosterone near the time of meiotic segregation is related to offspring sex ratio. Next, we used a 5-minute bag handling protocol to induce corticosterone elevations 5 hours prior to ovulation. Maternal baseline corticosterone levels did not correlate with average clutch sex ratios. In addition, the sex ratios produced by females exposed to handling stress did not differ from sex ratios produced by unmanipulated females. Together these results suggest that physiological levels of endogenous corticosterone, both baseline and acutely elevated near the time of sex determination may not be involved in the adjustment of primary sex ratios in Zebra Finches.

Compensating for a stressful start: maternal corticosterone, offspring survival, and size at fledging in the Zebra Finch, Taeniopygia guttata

All organisms are exposed to a variety of physical, environmental and psychological challenges throughout their lives. We administered repeated oral doses of the stress hormone corticosterone (CORT) to ovulating Zebra Finches (Taeniopygia guttata) in order to mimic a disruptive environment, and investigated the effect on their reproductive output as well as outcomes for their offspring. Although females treated with CORT produced larger clutches than control females, hatching success was significantly reduced in the CORT-treated group, though there was no evidence of bias in offspring sex-ratio. Both treatment and sex had an effect on the size of chicks at hatching and their growth rate. Chicks from the experimental group were smaller at hatching than control chicks but grew faster. Similarly, male chicks were smaller than female chicks at hatching but grew faster than females. However, there was no significant difference in overall condition at nutritional independence, indicating that increased growth rates resulted from compensatory growth. These results have broad evolutionary implications, as maternal CORT is capable of affecting viability of eggs and offspring phenotype, even when maternal diet and body condition remain unchanged. As such, glucocorticoids may play a role in regulating population productivity and offspring phenotype, which provides a promising area for further research into the effects of maternal stress on adult offspring in successive generations.

Effects of maternal stress during pregnancy on learning and memory via hippocampal BDNF, Arc (Arg3.1) expression in offspring.

The intrauterine environment has a significant long-term impact on individual's life, this study was designed to investigate the effect of stress during pregnancy on offspring's learning and memory abilities and analyze its mechanisms from the expression of BDNF and Arc in the hippocampus of the offspring. A rat model of maternal chronic stress during pregnancy was mating from 3rd day during been subjecting to chronic unpredictable mild stress (CUMS). The body weights and behavioral changes were recorded, and plasma corticosterone levels were determined by radioimmunoassay. The learning and memory abilities of the offspring were measured by Morris water maze testing from PND 42. The expression of hippocampal BDNF and Arc mRNA and protein were respectively measured using RT-PCR and Western blotting. Results indicated that an elevation was observed in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy, a reduction in the crossing and rearing movement times and the preference for sucrose. The body weight of maternal stress's offspring was lower than the control group, and the plasma corticosterone level was increased. Chronic stress during pregnancy had a significant impact on the spatial learning and memory of the offspring. The expression of BDNF mRNA and protein, Arc protein in offspring of maternal stress during pregnancy was attenuated and some relationships existed between these parameters. Collectively, these findings disclose that long-time maternal stress during pregnancy could destroy spatial learning and memory abilities of the offspring, the mechanism of which is related to been improving maternal plasma corticosterone and reduced hippocampal BDNF, Arc of offspring rats.

Maternal testosterone and placental function: Effect of electroacupuncture on placental expression of angiogenic markers and fetal growth

Women with polycystic ovary syndrome (PCOS) have elevated circulating androgens during pregnancy and are at an increased risk of adverse pregnancy outcomes. Here we tested the hypotheses that maternal androgen excess decrease placental and fetal growth, and placental expression of markers of steroidogenesis, angiogenesis and sympathetic activity, and that acupuncture with low-frequency electrical stimulation prevents these changes. Pregnant rats were exposed to vehicle or testosterone on gestational day (GD)15-19. Low-frequency electroacupuncture (EA) or handling, as a control for the EA procedure, was given to control or testosterone exposed dams on GD16-20. On GD21, blood pressure was measured and maternal blood, fetuses and placentas collected. Placental steroid receptor expression and proteins involved in angiogenic, neurotrophic and adrenergic signaling were analyzed.EA did not affect any variables in control rats except maternal serum corticosterone, which was reduced. EA in testosterone exposed dams compared with controls increased systolic pressure by 30%, decreased circulating norepinephrine and corticosterone, fetal and placental weight and placental VEGFR1 and proNGF protein expression, and increased the VEGFA/VEGFR1 ratio, mature NGF (mNGF) and the mNGF/proNGF ratio.In conclusion, low-frequency EA in control animals did not have any negative influence on any of the studied variables. In contrast, EA in pregnant dams exposed to testosterone increased blood pressure and impaired placental growth and function, leading to decreased fetal growth.

Maternal corticosterone deposition in avian yolk: Influence of laying order and group size in a joint-nesting, cooperatively breeding species

Glucocorticoid hormones play a key role in day-to-day adjustments to fluctuating metabolic needs. These hormones also mediate physiological and behavioral responses to stressful events, allowing individuals to cope with stressors. Various environmental insults, such as a food shortages, predation attempts, and agonistic encounters often elevate plasma glucocorticoid levels in vertebrates. Because exposure to maternally-derived (via circulation or egg) glucocorticoids may be detrimental to the developing embryo, maternal stress can have negative carryover effects on offspring fitness. We examined corticosterone, the primary avian glucocorticoid, concentrations in egg yolk in a plural-breeding, joint-nesting species, the smooth-billed ani (Crotophaga ani), in which females compete among themselves to lay eggs in the final incubated clutch. We investigated whether yolk corticosterone levels varied with laying order and group size. Because egg-laying competition leads to physiological and social stress that is intensified with group size and laying order, we predicted that yolk corticosterone levels should increase from the early to the late egg-laying period and from single female to multi-female groups. In this two-year field study, we found that yolk corticosterone levels of late-laid eggs within the communal clutch were higher in multi-female groups than in single female groups. Results from this study suggest that laying females experience higher levels of stress in multi-female groups and that this maternal stress influences yolk corticosterone concentrations. This study identifies a novel cost of group-living in plural-breeding cooperatively breeding birds, namely an increase in yolk corticosterone levels with group size that may result in detrimental effects on offspring development.

Maternal corticosterone exposure in the mouse programs sex-specific renal adaptations in the renin-angiotensin-aldosterone system in 6-month offspring.

Short‐term maternal corticosterone (Cort) administration at mid‐gestation in the mouse reduces nephron number in both sexes while programming renal and cardiovascular dysfunction in 12‐month male but not female offspring. The renal renin–angiotensin–aldosterone system (RAAS), functions in a sexually dimorphic manner to regulate both renal and cardiovascular physiology. This study aimed to identify if there are sex‐specific differences in basal levels of the intrarenal RAAS and to determine the impact of maternal Cort exposure on the RAAS in male and female offspring at 6 months of age. While intrarenal renin concentrations were higher in untreated females compared to untreated males, renal angiotensin II concentrations were higher in males than females. Furthermore, basal plasma aldosterone concentrations were greater in females than males. Cort exposed male but not female offspring had reduced water intake and urine excretion. Cort exposure increased renal renin concentrations and elevated mRNA expression of Ren1, Ace2, and Mas1 in male but not female offspring. In addition, male Cort exposed offspring had increased expression of the aldosterone receptor, Nr3c2 and renal sodium transporters. In contrast, Cort exposure increased Agtr1a mRNA levels in female offspring only. This study demonstrates that maternal Cort exposure alters key regulators of renal function in a sex‐specific manner at 6 months of life. These finding likely contribute to the disease outcomes in male but not female offspring in later life and highlights the importance of renal factors other than nephron number in the programming of renal and cardiovascular disease.

Influence of the rearing system on yolk corticosterone concentration in captive Greater Rheas (Rhea americana).

Many environmental conditions elevate plasma corticosterone in laying birds, leading to elevated hormone accumulation in the egg. We investigated whether maternal yolk corticosterone levels in Greater Rheas differ between fresh eggs collected from an intensive (IRS) and a semi-extensive (SRS) rearing system. After HPLC validation, yolk corticosterone was measured using a corticosterone (125) I radio-immunoassay kit. Results (mean ± SE) showed that eggs collected from the IRS exhibited a significantly higher corticosterone concentration than eggs from SRS (89.88 ± 8.93 vs. 45.41 ± 5.48 ng/g yolk, respectively). Our findings suggest that rearing conditions under an intensive scheme (e.g., small pens with bare ground, no direct foraging and handling) might be perceived as more stressful for Greater Rhea females than semi-extensive rearing conditions (e.g., low animal density distributed in extensive areas and direct foraging), which would result in the transfer of higher yolk corticosterone levels. A better understanding of environmental conditions and female traits that affect yolk corticosterone deposition provides a background for future studies concerning the roles of maternal corticosterone on offspring development. Zoo Biol. 35:246-250, 2016. © 2016 Wiley Periodicals, Inc.

Pregnancy-induced adaptations of the central circadian clock and maternal glucocorticoids.

Maternal physiological adaptations, such as changes to the hypothalamic-pituitary-adrenal (HPA) axis, are central to pregnancy success. Circadian variation of the HPA axis is dependent on clock gene rhythms in the hypothalamus, but it is not known whether pregnancy-induced changes in maternal glucocorticoid levels are mediated via this central clock. We hypothesized that hypothalamic expression of clock genes changes across mouse pregnancy and this is linked to altered HPA activity. The anterior hypothalamus and maternal plasma were collected from C57Bl/6J mice prior to pregnancy and on days 6, 10, 14 and 18 of gestation (term=d19), across a 24-h period (0800, 1200, 1600, 2000, 0000, 0400 h). Hypothalamic expression of clock genes and Crh was determined by qPCR, plasma ACTH concentration measured by Milliplex assay and plasma corticosterone concentration by LC-MS/MS. Expression of all clock genes varied markedly across gestation, most notably at mid-gestation when levels of each gene were elevated. The pregnancy-induced increase in maternal corticosterone levels (by up to 14-fold on day 14) was not accompanied by a parallel shift in plasma ACTH (28% lower on day 14 compared with non-pregnant levels). Moreover, while circadian rhythmicity in corticosterone was maintained up to day 14 of gestation, this was effectively lost by day 18. Overall, our data show that the central circadian clock undergoes marked adaptations throughout mouse pregnancy, changes that are likely to contribute to maternal physiological adaptations. Importantly, however, neither hypothalamic clock genes nor plasma ACTH levels appear to drive the marked increase in maternal corticosterone after mid-gestation.

Resveratrol partially prevents oxidative stress and metabolic dysfunction in pregnant rats fed a low protein diet and their offspring.

Protein restriction in pregnancy produces maternal and offspring metabolic dysfunction potentially as a result of oxidative stress. Data are lacking on the effects of inhibition of oxidative stress. We hypothesized that maternal resveratrol administration decreases oxidative stress, preventing, at least partially, maternal low protein-induced maternal and offspring metabolic dysfunction. In the present study, pregnant wistar rats ate control (C) (20% casein) or a protein-restricted (R) (10% casein) isocaloric diet. Half of each group received resveratrol orally, 20 mg kg(-1) day(-1), throughout pregnancy. Post-delivery, mothers and offspring ate C. Oxidative stress biomarkers and anti-oxidant enzymes were measured in placenta, maternal and fetal liver, and maternal serum corticosterone at 19 days of gestation (dG). Maternal (19 dG) and offspring (postnatal day 110) glucose, insulin, triglycerides, cholesterol, fat and leptin were determined. R mothers showed metabolic dysfunction, increased corticosterone and oxidative stress and reduced anti-oxidant enzyme activity vs. C. R placental and fetal liver oxidative stress biomarkers and anti-oxidant enzyme activity increased. R offspring showed higher male and female leptin, insulin and corticosterone, male triglycerides and female fat than C. Resveratrol decreased maternal leptin and improved maternal, fetal and placental oxidative stress markers. R induced offspring insulin and leptin increases were prevented and other R changes were offspring sex-dependent. Resveratrol partially prevents low protein diet-induced maternal, placental and sex-specific offspring oxidative stress and metabolic dysfunction. Oxidative stress is one mechanism programming offspring metabolic outcomes. These studies provide mechanistic evidence to guide human pregnancy interventions when fetal nutrition is impaired by poor maternal nutrition or placental function.

Water deprivation increases maternal corticosterone levels and enhances offspring growth in the snake Vipera aspis.

Circulating glucocorticoid (GC) levels may increase as a result of reproductive effort or in response to unpredictable events. However, GC secretion can vary with the availability of vital trophic resources such as energy. While water represents another critical resource, the impact of water deprivation on GC secretion during reproduction has not yet been thoroughly investigated. Here, we examined the effects of water deprivation on plasma corticosterone (CORT) concentrations of female aspic vipers (Vipera aspis), and determined the impacts of water deprivation on offspring traits. We exposed both pregnant and non-reproductive females to a 20-day water deprivation and compared their pre- and post-deprivation CORT levels with those of control females. At the end of the treatment, only water-deprived pregnant females showed a significant increase in CORT levels. In pregnant females, changes in baseline CORT level were correlated with changes in female hydration state. Changes in baseline CORT levels were also negatively influenced by maternal reproductive effort in pregnant control females, while such a relationship was not apparent in pregnant water-deprived females. Finally, we found that offspring from water-deprived females had higher growth rates than offspring from control females. Offspring growth was also positively correlated with changes in both maternal osmolality and baseline CORT levels. Together, our results suggest that dehydration increases maternal CORT levels, which may subsequently influence offspring development. Further long-term field studies are therefore required to assess whether there is an adaptive significance of this response.

Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis

Postpartum depression (PPD) affects approximately 15% of mothers, disrupts maternal care, and can represent a form of early life adversity for the developing offspring. Intriguingly, male and female offspring are differentially vulnerable to the effects of PPD. Antidepressants, such as fluoxetine, are commonly prescribed for treating PPD. However, fluoxetine can reach offspring via breast milk, raising serious concerns regarding the long-term consequences of infant exposure to fluoxetine. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum stress/depression) and concurrent maternal postpartum fluoxetine on behavioral, endocrine, and neural measures in adult male and female offspring. Female Sprague–Dawley dams were treated daily with either CORT or oil and fluoxetine or saline from postnatal days 2–23, and offspring were weaned and left undisturbed until adulthood. Here we show that maternal postpartum fluoxetine increased anxiety-like behavior and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback in adult male, but not female, offspring. Furthermore, maternal postpartum fluoxetine increased the density of immature neurons (doublecortin-expressing) in the hippocampus of adult male offspring but decreased the density of immature neurons in adult female offspring. Maternal postpartum CORT blunted HPA axis negative feedback in males and tended to increase density of immature neurons in males but decreased it in females. These results indicate that maternal postpartum CORT and fluoxetine can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and adult hippocampal neurogenesis and that adult male and female offspring are differentially affected by these maternal manipulations.

Prenatal alcohol exposure and prenatal stress differentially alter glucocorticoid signaling in the placenta and fetal brain

Adverse intrauterine environments increase vulnerability to chronic diseases across the lifespan. The hypothalamic–pituitary–adrenal (HPA) axis, which integrates multiple neuronal signals and ultimately controls the response to stressors, may provide a final common pathway linking early adversity and adult diseases. Both prenatal alcohol exposure (PAE) and prenatal stress (PS) induce a hyperresponsive HPA phenotype in adulthood. As glucocorticoids are pivotal for the normal development of many fetal tissues including the brain, we used animal models of PAE and PS to investigate possible mechanisms underlying fetal programing of glucocorticoid signaling in the placenta and fetal brain at gestation day (GD) 21. We found that both PAE and PS dams had higher corticosterone (CORT) levels than control dams. However, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme levels were increased in PAE and unchanged in PS placentae, although there were no differences in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) levels. Moreover, only PAE fetuses showed decreased body weight and increased placental weight, and hence a lower fetal/placental weight ratio, a marker of placenta efficiency, compared to all other prenatal groups. Importantly, PAE and PS differentially altered corticosteroid receptor levels in placentae and brains. In the PS condition, maternal CORT was negatively correlated with both 11β-HSD1 and mineralocorticoid receptor (MR) protein levels in male and female placentae, whereas in the PAE condition, there were trends for a positive correlation between maternal CORT and 11β-HSD1, regardless of sex, and a negative correlation between maternal alcohol intake and MR in male placentae. In fetal brains, sexually dimorphic changes in MR and glucocorticoid receptor (GR) levels, and the MR/GR ratio seen in C fetuses were absent in PAE and PS fetuses. In addition, PS but not PAE female fetuses had higher MR and lower GR expression levels in certain limbic areas compared to C female fetuses. Thus the similar adult HPA hyperresponsive phenotype in PAE and PS animals likely occurs through differential effects on glucocorticoid signaling in the placenta and fetal brain.

The placental sulfate transporter, Slc13a4, is critical for skeletal development in mice.

The placental sulfate transporter, Slc13a4, is critical for skeletal development in mice.

Maternal corticosterone exposure in the mouse causes sex specific alterations in placental OGT and O-linked glycosylation.

Maternal corticosterone exposure in the mouse causes sex specific alterations in placental OGT and O-linked glycosylation.

Vitamin D Deficiency in BALB/c Mouse Pregnancy Increases Placental Transfer of Glucocorticoids.

The prevalence of vitamin D deficiency in pregnancy is increasing and implicated in adverse consequences for the health of offspring in later life. The aim of this study was to determine whether vitamin D deficiency increases fetal exposure to glucocorticoids, which are known to alter fetal development and result in adverse adult health outcomes. Female BALB/c mice were placed on either a vitamin D control (2195 IU/kg) or deficient (0 IU/kg) diet for 5 weeks before and during pregnancy. Maternal serum, placentas and fetal brains were collected at embryonic day 14.5 or 17.5 for morphological and gene expression analysis. Vitamin D deficiency during pregnancy increased maternal corticosterone concentrations and reduced placental weight. Maternal vitamin D deficiency decreased placental expression of 11β-hydroxysteroid dehydrogenase type II, which inactivates glucocorticoids thereby protecting the fetus from inappropriate glucocorticoid exposure. There was a corresponding increase in placental and fetal expression of the highly glucocorticoid-sensitive factor glucocorticoid-induced leucine zipper. Furthermore, placental expression of the angiogenic factor vascular endothelial growth factor-A was reduced in vitamin D-deficient pregnancies, with a corresponding decline in fetal capillary volume within the placenta. Overall, we show that prenatal vitamin D deficiency leads to an increase in maternal corticosterone, alterations in genes indicative of increased fetal glucocorticoid exposure and impairment in placental vascular development. Thus, the long-term adverse health consequences of vitamin D deficiency during early development may not just be due to alteration in direct vitamin D-related pathways but also altered fetal glucocorticoid exposure.

Maternal high-fat diet acts as a stressor increasing maternal glucocorticoids’ signaling to the fetus and disrupting maternal behavior and brain activation in C57BL/6J mice

Maternal diet during pregnancy can impact maternal behavior as well as the intrauterine environment, playing a critical role in programming offspring's physiology. In a preliminary study, we found a strong association between high-fat diet (HFD) during pregnancy and increased cannibalistic episodes and dams' mortality during late pregnancy and parturition. Based upon these data, we hypothesized that HFD during pregnancy could negatively affect neuroendocrine and metabolic regulations occurring during the final stages of pregnancy, thereby disrupting maternal behavior. To test this hypothesis, female C57BL/6J mice were fed HFD or control diet for 11 weeks until three days before the expected delivery date. Basal corticosterone plasma levels and brain levels of c-Fos were measured both before and after delivery, in addition to leptin levels in the adipose tissue. Dam's emotional behavior and social anxiety, in addition to locomotor activity were assessed before parturition. Data show that HFD led to aberrant maternal behavior, dams being characterized by behaviors related to aggression toward an unfamiliar social stimulus in the social avoidance test, in addition to decreased locomotor activity. Neural activity in HFD dams was reduced in the olfactory bulbs, a crucial brain region for social and olfactory recognition hence essential for maternal behavior. Furthermore, HFD feeding resulted in increased circulating levels of maternal corticosterone and decreased levels of leptin. In addition, the activity of the protective 11β-dehydrogenase-2 (11β-HSD-2) barrier in the placenta was decreased together with 11β-dehydrogenase-1 (11β-HSD-1) gene expression. Overall, these data suggest that HFD acts as a stressful challenge during pregnancy, impairing the neuroendocrine system and the neural activity of brain regions involved in the processing of relevant olfactory stimuli, with negative consequences on maternal physiology and behavior.

Retracted: Experimental evidence that maternal corticosterone controls adaptive offspring sex ratios

Retracted: Experimental evidence that maternal corticosterone controls adaptive offspring sex ratios