Maternal Corticosterone Research Articles

Prenatal stress induces sex- and tissue-specific alterations in insulin pathway of Wistar rats offspring.

Prenatal stress may lead to tissue and sex-specific cardiometabolic disorders in the offspring through imbalances in the insulin signaling pathway. Therefore, we aimed to determine the sex-specific adaptations of prenatal stress on the insulin signaling pathway of cardiac and hepatic tissue of adult offspring Wistar rats. Wistar pregnant rats were divided into control and stress groups. Unpredictable stress protocol was performed from the 14th to the 21st day of pregnancy. After lactation, the dams were euthanized and blood was collected for corticosterone measurement and the offspring were separated into four groups according to sex and intervention (n=8/group). At 90 days old, the offspring were submitted to an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). After euthanasia blood collection was used for biochemical analysis and the left ventricle and liver were used for protein expression and histological analysis. Stress increased maternal corticosterone levels, and in the offspring, decreased glucose concentration in both OGTT and ITT, reduced insulin receptor (Irβ) and insulin receptor substrate-1 (IRS1) activation and reduced insulin receptor inhibition (PTP1B) in the liver of male offspring at 90 days old, without repercussions in cardiac tissue. Moreover, female offspring submitted to prenatal stress exhibited reduced fatty acid uptake, with lower hepatic CD36 expression, reduced high density lipoprotein (cHDL) and increased Castelli risk indexes I and II. Unpredictable prenatal stress evoked reduced insulin sensitivity and liver-specific impairment in insulin signaling activation in male while increasing markers of cardiovascular risk in females.

Social transmission of inflammation in mice

The ability to detect and respond to sickness in others promotes survival. Here we show that mouse dams respond to immune challenged pups by mirroring their inflammatory response. Dams with pups subjected to immune challenge displayed a marked induction of inflammatory mediators in both the brain and the periphery, accompanied by an increase in maternal behaviors and corticosterone levels. This social transmission of inflammation did not require physical contact, and it contributed to the stress hormone response in the dams. In adult dyads, interaction with an immune challenged cagemate did not elicit robust inflammatory signaling but induced an increased responsiveness to a subsequent immune challenge. The identification of social transmission of inflammation, or inflammatory responsiveness, may open new avenues for research on social behavior, just like the description of similar phenomena such as observational fear and transmitted pain has done.

Maternally derived avian corticosterone affects offspring genome-wide DNA methylation in a passerine species.

Avian embryos develop in an egg composition which reflects both maternal condition and the recent environment of their mother. In birds, yolk corticosterone (CORT) influences development by impacting pre- and postnatal growth, as well as nestling stress responses and development. One possible mechanism through which maternal CORT may affect offspring development is via changes to offspring DNA methylation. We sought to investigate this, for the first time in birds, by quantifying the impact of manipulations to maternal CORT on offspring DNA methylation. We non-invasively manipulated plasma CORT concentrations of egg-laying female zebra finches (Taeniopygia castanotis) with an acute dose of CORT administered around the time of ovulation and collected their eggs. We then assessed DNA methylation in the resulting embryonic tissue and in their associated vitelline membrane blood vessels, during early development (5 days after lay), using two established methods - liquid chromatography-mass spectrometry (LC-MS) and methylation-sensitive amplification fragment length polymorphism (MS-AFLP). LC-MS analysis showed that global DNA methylation was lower in embryos from CORT-treated mothers, compared to control embryos. In contrast, blood vessel DNA from eggs from CORT-treated mothers showed global methylation increases, compared to control samples. There was a higher proportion of global DNA methylation in the embryonic DNA of second clutches, compared to first clutches. Locus-specific analyses using MS-AFLP did not reveal a treatment effect. Our results indicate that an acute elevation of maternal CORT around ovulation impacts DNA methylation patterns in their offspring. This could provide a mechanistic understanding of how a mother's experience can affect her offspring's phenotype.

FRI386 Effects Of Maternal Sucrose Intake During Pregnancy On Steroids In The Placenta And Fetal Brain Of Rats

Abstract Disclosure: M.M. Jung: None. D.R. Seib: None. H.W. Chen: None. M. Idrissi: None. K.K. Soma: None. Intake of added sugars such as sucrose (table sugar) is high globally. Many people consume more than 20% of their daily calories as added sugars. High-sucrose consumption alters steroids and the brain. In rats, a human-relevant level of maternal sucrose intake starting 10 weeks before, during, and after pregnancy decreases maternal corticosterone in the serum but increases corticosterone in the blood and brain of the adult female offspring. Similarly, rat dams fed a high-sucrose diet starting 10 weeks before and during gestation have elevated 11-dehydrocorticosterone (DHC) in the serum and amniotic fluid and reduced testosterone and androstenedione in the labyrinth/junctional zone and decidua, respectively. Aldosterone is also elevated in the amniotic fluid, fetal blood, and fetal brain (nucleus accumbens, NAc). Thus, it is clear that maternal sucrose intake alters both maternal and offspring steroids, and has long-term, sex-specific endocrine effects. However, it is unclear how maternal sucrose consumption specifically during pregnancy impacts the offspring development. Our study investigates how maternal sucrose intake during pregnancy affects steroids in the placenta and fetal brain. We hypothesize that maternal sucrose intake is a metabolic stressor that will alter steroid signalling in the placenta and the developing brain. We fed female Long-Evans rats either a high-sucrose diet (26% kcal sucrose) or an isocaloric, macro/micro-nutrient-matched control diet (1% kcal sucrose) starting embryonic day 0 (E0; the day of pregnancy confirmation) (n=15/group). On E19, we collected maternal serum, amniotic fluid, placenta, fetal blood, and fetal brain. We will microdissect the placenta (decidua and labyrinth/junctional zone) and fetal brain (prefrontal cortex, NAc, ventral tegmental area, hippocampus, and hypothalamus) and measure a panel of 15 steroids using highly specific and sensitive liquid chromatography-tandem mass spectrometry. Maternal sucrose intake did not alter maternal food intake, body weight, and litter size, but increased the percentage of male offspring. We are currently analyzing the steroid data. We predict that maternal sucrose intake during pregnancy will increase anti-inflammatory steroids (corticosterone, DHC, and aldosterone) in the maternal blood, amniotic fluid and fetal brain, and decrease androgens in the placenta. We will also measure steroidogenic enzymes in the placenta and fetal brain. Our findings will clarify how maternal sucrose intake impacts both the placenta and fetal development. Moreover, our results will examine whether sucrose exposure during pregnancy is the underlying mechanism for the endocrine effects observed in the fetal and adult offspring. This study will provide more insight into the relationship between nutrition, the nervous system, and the endocrine system. Presentation: Friday, June 16, 2023

From maternal glucocorticoid and thyroid hormones to epigenetic regulation of offspring gene expression: An experimental study in a wild bird species.

Offspring phenotype at birth is determined by its genotype and the prenatal environment including exposure to maternal hormones. Variation in both maternal glucocorticoids and thyroid hormones can affect offspring phenotype, but the underlying molecular mechanisms, especially those contributing to long-lasting effects, remain unclear. Epigenetic changes (such as DNA methylation) have been postulated as mediators of long-lasting effects of early-life environment. In this study, we determined the effects of elevated prenatal glucocorticoid and thyroid hormones on handling stress response (breath rate) as well as DNA methylation and gene expression of glucocorticoid receptor (GR) and thyroid hormone receptor (THR) in great tits (Parus major). Eggs were injected before incubation onset with corticosterone (the main avian glucocorticoid) and/or thyroid hormones (thyroxine and triiodothyronine) to simulate variation in maternal hormone deposition. Breath rate during handling and gene expression of GR and THR were evaluated 14 days after hatching. Methylation status of GR and THR genes was analyzed from the longitudinal blood cells sampled 7 and 14 days after hatching, as well as the following autumn. Elevated prenatal corticosterone level significantly increased the breath rate during handling, indicating an enhanced metabolic stress response. Prenatal corticosterone manipulation had CpG-site-specific effects on DNA methylation at the GR putative promoter region, while it did not significantly affect GR gene expression. GR expression was negatively associated with earlier hatching date and chick size. THR methylation or expression did not exhibit any significant relationship with the hormonal treatments or the examined covariates, suggesting that TH signaling may be more robust due to its crucial role in development. This study provides some support to the hypothesis suggesting that maternal corticosterone may influence offspring metabolic stress response via epigenetic alterations, yet their possible adaptive role in optimizing offspring phenotype to the prevailing conditions, context-dependency, and the underlying molecular interplay needs further research.

The effects of pre-hatch elevated corticosterone and post-hatch restrictive food availability on the HPA axis development of mallard ducks (Anas platyrhynchos)

Environmental changes can be stressors (altered habitat and food supply, climate change, etc.) to wild animals. Stressors trigger the hypothalamic pituitary adrenal (HPA) axis to release corticosterone (CORT) which modifies energy homeostasis. During nesting, stressed females can deposit increased concentrations of CORT into eggs, altering egg viability and offspring characteristics, constituting a significant mechanism regulating population productivity in subsequent generations. In this study, increased maternal disposition of CORT was mimicked through a 15 ng/g in ovo injection of CORT into mallard duck eggs. Growth and HPA axis function were measured during post-hatch development. For growth, changes in mass were compared at hatch, 7 weeks and 11 weeks. The HPA axis was assessed at seven weeks by measuring CORT at baseline, followed by restraint stress, dexamethasone (negative feedback) and ACTH (maximal adrenal capacity) challenges. At eleven weeks of age, ducks were subjected to a 6-day 25% feed reduction to simulate a poor quality environment to evaluate response to a chronic stressor by comparing CORT at baseline and after restraint stress. Growth and CORT concentration did not differ between treatments at seven weeks or after feed restriction (11 weeks). The CORT dosage administered did not appear to affect HPA axis development in ducklings. Mallards are a highly adaptable species and may have overcome any early alterations to their phenotype. Further research is needed to determine the effects of increased maternal CORT on growth and the development of the HPA axis in ducks. Summary statementThis study examines how maternal stress (simulated through elevated corticosterone in ovo) and post-hatch chronic stressors (food restriction) affect the development of the HPA axis in a precocial bird.

Postnatal melatonin administration to stressed dams for ameliorating risk-taking behaviour in rat pups through maternal care improvement.

Anxiety often occurs both concurrently and sequentially in childhood and adolescence in association with prenatal stress, which may reduce the quality of maternal care and then cause mood disorders among children in later life. Against this background, melatonin, as a powerful antioxidant, was used in the present study to ameliorate risk-taking behaviour induced by pure maternal care in rat pups. The Wistar rat dams recruited in this study were exposed to restraint stress from gestational day (GD) 11 until delivery. They further received melatonin (10mg/kg) during the postnatal days (PNDs) 0-7 by intraperitoneal (IP) injections at 4:00 PM. The pregnant rats were then divided into four groups, namely, control, stress, stress + melatonin and melatonin, and their maternal behaviour and corticosterone levels were measured. In the offspring, the outcomes of some behavioural tasks, including the elevated plus-maze (EPM) and open-field (OF) tests were ultimately assessed. The study results revealed that the quantity and quality of maternal care significantly declined and the plasma corticosterone levels compounded in the stressed dams. Melatonin treatment, however, improved their nursing behaviour and reduced their plasma corticosterone levels. The offspring performance in two tasks also showed an upward trend in risk-taking behaviour in the stress group, and melatonin administration ameliorated the effects of stress and lessened their anxiety-like behaviour. It was concluded that prenatal restraint stress could impair stress responses and quality of maternal care, whereas postnatal melatonin administration potentially contributed to the normalization of stress reaction and anxiolysis.

The effects of chronic unpredicted mild stress on maternal negative emotions and gut microbiota and metabolites in pregnant rats.

Chronic long-term stress is associated with a range of disorders, including depression and a variety of other chronic illnesses. It is well known that maternal exposure to psychosocial stress during pregnancy significantly increases the likelihood of adverse pregnancy outcomes. The gut microbiota has been a popular topic, it is a key mediator of the gut-brain axis and plays an important role in human health; changes in the gut microbiota have been related to chronic stress-induced health impairment, however, the relationship between maternal negative emotions and abnormal gut microbiota and its metabolites during maternal exposure to chronic stress during pregnancy remains unclear. Pregnant rats were subjected to chronic unpredicted mild stress (CUMS) to establish the rat model of chronic stress during pregnancy. The behavioral changes were recorded using sucrose preference test (SPT) and open-field test (OFT), plasma corticosterone levels were determined by radioimmunoassay, and a comprehensive method combining 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics was used to study the effects of stress during pregnancy on the function of intestinal microbiota and its metabolites. Chronic stress during pregnancy not only increased maternal plasma corticosterone (P < 0.05), but also caused maternal depression-like behaviors (P < 0.05). Chronic stress during pregnancy changed the species composition at the family level of maternal gut microbiota, the species abundance of Ruminococcaceae in the stress group (23.45%) was lower than the control group (32.67%) and the species abundance of Prevotellaceae in the stress group (10.45%) was higher than the control group (0.03%) (P < 0.05). Vertical locomotion and 1% sucrose preference percentage in pregnant rats were negatively correlated with Prevotellaceae (r=-0.90, P<0.05). Principal component analysis with partial least squares discriminant analysis showed that the integration points of metabolic components in the stress and control groups were completely separated, indicating that there were significant differences in the metabolic patterns of the two groups, and there were seven endogenous metabolites that differed (P < 0.05). The negative emotional behaviors that occur in pregnant rats as a result of prenatal chronic stress may be associated with alterations in the gut microbiota and its metabolites. These findings provide a basis for future targeted metabolomics and gut flora studies on the effects of chronic stress during pregnancy on gut flora.

Prolonged maternal exposure to glucocorticoids alters selenoprotein expression in the developing brain.

Aberrant activation of the stress-response system in early life can alter neurodevelopment and cause long-term neurological changes. Activation of the hypothalamic-pituitary-adrenal axis releases glucocorticoids into the bloodstream, to help the organism adapt to the stressful stimulus. Elevated glucocorticoid levels can promote the accumulation of reactive oxygen species, and the brain is highly susceptible to oxidative stress. The essential trace element selenium is obtained through diet, is used to synthesize antioxidant selenoproteins, and can mitigate glucocorticoid-mediated oxidative damage. Glucocorticoids can impair antioxidant enzymes in the brain, and could potentially influence selenoprotein expression. We hypothesized that exposure to high levels of glucocorticoids would disrupt selenoprotein expression in the developing brain. C57 wild-type dams of recently birthed litters were fed either a moderate (0.25 ppm) or high (1 ppm) selenium diet and administered corticosterone (75 μg/ml) via drinking water during postnatal days 1 to 15, after which the brains of the offspring were collected for western blot analysis. Glutathione peroxidase 1 and 4 levels were increased by maternal corticosterone exposure within the prefrontal cortex, hippocampus, and hypothalamus of offspring. Additionally, levels of the glucocorticoid receptor were decreased in the hippocampus and selenoprotein W was elevated in the hypothalamus by corticosterone. Maternal consumption of a high selenium diet independently decreased glucocorticoid receptor levels in the hippocampus of offspring of both sexes, as well as in the prefrontal cortex of female offspring. This study demonstrates that early life exposure to excess glucocorticoid levels can alter selenoprotein levels in the developing brain.

Transgenerational effects of maternal corticosterone across early life in a viviparous snake

Glucocorticoids (GCs) are central mediators of vertebrate responses to intrinsic and extrinsic stimuli. Among the sources of variation in circulating GCs are transgenerational effects mediated by mothers. Here we studied potential maternal effects mediated by GCs on offspring phenotype in a live-bearing reptile, the western terrestrial garter snake (Thamnophis elegans). We evaluated the association between baseline corticosterone (CORT) levels during gestation (i.e., preparturition) in field-captured mothers and 1) reproductive success and offspring sex ratios, 2) birth phenotypic traits of offspring born under common-garden laboratory conditions, and 3) neonate (age 3 months) and juvenile (age 12 months) traits of offspring raised under two thermal regimes (‘warm’ and ‘cool’) during their first year of life. Reproductive success and offspring sex ratios were not associated with preparturition maternal CORT, but pregnant snakes with higher CORT levels gave birth to smaller, lighter offspring, which tended to grow faster to age three months. Neonate baseline CORT varied with preparturition maternal CORT in a sex-specific manner (positive trend for females, negative for males). Maternal CORT effects on offspring phenotype were no longer detectable in juveniles at age one year. Instead, juvenile phenotypes were most influenced by rearing environment, with offspring raised under the cool regime showing higher baseline CORT and slower growth than those raised under warmer conditions. Our findings support the notion that offspring phenotype might be continuously adjusted in response to environmental cues —both pre- and post-natal— and that the strength of maternal CORT effects declines as offspring develop and experience unique environmental challenges. Our results contribute to a growing literature on transgenerational effects of hormones and help to fill a gap in our knowledge of these effects in ectothermic amniotes.

Sex ratios and the city: Secondary offspring sex ratios, parental corticosterone, and parental body condition in an urban-adapted bird

The Trivers–Willard hypothesis states that mothers should adjust their offspring sex ratio according to their own condition and the environment they face during breeding. Past tests of this hypothesis have focused on how natural variation in weather, food availability, or predation pressure shapes sex allocation trade-offs. However, anthropogenic activities, such as urbanization, can alter all of the above characteristics presenting animals with novel challenges in optimizing their brood sex ratio. Previous research has examined how urban living influences individual body condition in several bird taxa, but few have explored subsequent impacts on secondary offspring sex ratio. One likely mediator of the link between environmental conditions, parental condition, and sex ratios is corticosterone (CORT), the primary glucocorticoid in birds. Research on CORT’s influence on sex ratios has focused solely on maternal CORT. However, for species with biparental care, paternal CORT or the similarity of maternal and paternal phenotypes may also help ensure that offspring demand matches parental care quality. To test these hypotheses, we explore offspring secondary sex ratios in European starlings (Sturnus vulgaris). We did not find an effect of site or parental body condition on the production of the more costly sex (males). Instead, we found preliminary evidence suggesting that the similarity of maternal and paternal CORT levels within a breeding pair may increase the likelihood of successfully fledging sons. Maternal and paternal CORT were not significant predictors of secondary sex ratio, suggesting that parental similarity, rather than parental CORT alone, could play a role in shaping secondary offspring sex ratios, but additional work is needed to support this pattern. Starlings are considered an urban-adapted species, making them a compelling model for future studies of the relationship between urbanization, parental body condition, and sex ratios.

Contribution of hippocampal BDNF/CREB signaling pathway and gut microbiota to emotional behavior impairment induced by chronic unpredictable mild stress during pregnancy in rats offspring.

BackgroundNumerous studies have shown that exposure to prenatal maternal stress (PMS) is associated with various psychopathological outcomes of offspring. The accumulating evidence linking bacteria in the gut and neurons in the brain (the microbiota-gut-brain axis) has been aconsensus; however, there is a lack of research on the involvement mechanism of gut microbiota in the regulation of the BDNF/CREB signaling pathway in the hippocampus of prenatally stressed offspring.MethodsPregnant rats were subjected to chronic unpredictable mild stress (CUMS) to establish the prenatal maternal stress model. The body weight was measured and the behavioral changes were recorded. Offspring were tested to determine emotional state using sucrose preference test (SPT), open-field test (OFT) and suspended tail test (STT). Gut microbiota was evaluated by sequencing the microbial 16S rRNA V3–V4 region, and the interactive analysis of bacterial community structure and diversity was carried out. The expression of hippocampal BDNF, TrkB and CREB mRNA and proteins were respectively measured using RT-PCR and Western blotting.ResultsPrenatal maternal stress increased maternal plasma corticosterone levels, slowed maternal weight gain and caused depression-like behaviors (all P < 0.05). In offspring, prenatal maternal stress increased plasma corticosterone levels (P < 0.05) and emotional behavior changes (depression-like state) were observed (P < 0.05). The species abundance, diversity and composition of the offspring’s gut microbiota changed after the maternal stress during pregnancy (P < 0.05). Compared with the control group’s offspring, the species abundance of Lactobacillaceae was dropped, while the abundance of the Muribaculaceae species abundance was risen. Concurrent, changes in the hippocampal structure of the offspring and decreases in expression of BDNF/CREB signaling were noted (P < 0.05).ConclusionsPrenatal maternal stress leads to high corticosterone status and abnormal emotion behavior of offspring, which may be associated with the abnormal BDNF/CREB signaling in hippocampus of offspring caused by the change of gut microbiota composition.

Fitness Costs of Maternal Ornaments and Prenatal Corticosterone Manifest as Reduced Offspring Survival and Sexual Ornament Expression.

Colorful traits (i.e., ornaments) that signal quality have well-established relationships with individual condition and physiology. Furthermore, ornaments expressed in females may have indirect fitness effects in offspring via the prenatal physiology associated with, and social consequences of, these signaling traits. Here we examine the influence of prenatal maternal physiology and phenotype on condition-dependent signals of their offspring in adulthood. Specifically, we explore how prenatal maternal testosterone, corticosterone, and ornament color and size correlate with female and male offspring survival to adulthood and ornament quality in the lizard Sceloporus undulatus. Offspring of females with more saturated badges and high prenatal corticosterone were less likely to survive to maturity. Badge saturation and area were negatively correlated between mothers and their male offspring, and uncorrelated to those in female offspring. Maternal prenatal corticosterone was correlated negatively with badge saturation of male offspring in adulthood. Our results indicate that maternal ornamentation and prenatal concentrations of a stress-relevant hormone can lead to compounding fitness costs by reducing offspring survival to maturity and impairing expression of a signal of quality in surviving males. This mechanism may occur in concert with social costs of ornamentation in mothers. Intergenerational effects of female ornamentation and prenatal stress may be interdependent drivers of balancing selection and intralocus sexual conflict over signaling traits.

Prenatal yolk corticosterone exposure promotes skeletal growth and induces oxidative imbalance in yellow-legged gull embryos.

Maternally derived hormones induce variation in offspring phenotype, with consequences that can carry over into post-natal life and even into adulthood. In birds, maternal egg corticosterone (CORT) is known to exert contrasting effects on offspring morphology, physiology and behaviour after hatching. However, information on the effects of CORT exposure on pre-hatching embryonic development is limited. We experimentally increased yolk CORT levels in yellow-legged gull (Larus michahellis) eggs, and assessed the effects on embryo pre-hatching development and oxidative status of brain and liver. CORT-supplemented embryos reached a larger skeletal size and liver mass compared with controls. Embryos from CORT-injected last-laid eggs showed decreased activity of the hepatic antioxidant enzymes superoxide dismutase and catalase, while intermediate-laid eggs showed increased levels of lipid peroxidation. However, elevated yolk CORT did not affect oxidative stress endpoints in the brain. Our results indicate that elevated yolk CORT levels affect prenatal embryo development by promoting skeletal growth, and induce laying sequence- and organ-specific oxidative imbalance, with potential adverse consequences during postnatal life, especially for late-hatched offspring.

Changes in maternal fecal corticosterone metabolites across lactation and in response to chronic stress

Maternal exposure to stressors during lactation has previously been demonstrated to impact various aspects of milk synthesis and to have long-term physiological effects on offspring. Much of the current literature investigating the effects of stress during lactation has used acute stressors, and the studies investigating the effects of chronic stressors largely focus on neurological changes. Further, temporal variation in glucocorticoids across lactation in response to stressors has rarely been assessed. The present work uses a novel male intruder paradigm to model the effects of chronic stress on maternal fecal corticosterone metabolites (FCMs) in Sprague-Dawley rats across lactation. FCM levels were elevated in chronically-stressed mothers relative to the control group. Further, FCMs in the stress group were time-dependent either due to repeated exposure to the stressor or lactation stage. Together, this work demonstrates the efficacy of this established paradigm in increasing circulating glucocorticoids in lactating rats. These results highlight the need for repeated temporal sampling, as glucocorticoid levels in response to a chronic stressor may change across lactation.

Experimental manipulation of maternal corticosterone: Hormone transfer to the yolk in the zebra finch Taeniopygia guttata

Maternally-derived hormones affect offspring physiological and behavioural phenotype, plausibly as an adaptive response to maternal environmental conditions. Corticosterone (CORT), the principal avian glucocorticoid produced in response to stress, is recognised as a potential mediator of such maternal reproductive effects. Maternally-derived yolk CORT is implicated in mediating offspring growth and hatchling begging behaviour. However, determining the potential for maternal effects in opportunistic breeders subject to variable environments relies on understanding whether natural variation in maternal circulating hormones may directly impact the embryo during development. Therefore, we tested whether elevated maternal CORT concentrations increase yolk CORT concentrations in zebra finch (Taeniopygia guttata) eggs. We remotely dosed breeding females with biologically-relevant doses of CORT, or the oil vehicle, 0–3 h prior to the predicted time of ovulation, and allowed pairs to produce two clutches, one under each treatment, in a crosswise, balanced design. CORT dosing elevated maternal plasma CORT and increased mean yolk CORT by a factor of 1.75 compared to the egg yolks of control mothers. Importantly, CORT concentrations did not differ between inner and outer layers of yolk. We found no egg lay order effect and maternal CORT dosing did not influence reproductive outputs (clutch initiation date, clutch size or egg mass). Our results confirm the direct impact of biologically-relevant increases in maternal CORT on yolk CORT, providing evidence that maternal CORT concentrations during yolk deposition to the follicle alters embryonic exogenous CORT exposure. Further research is required to determine the impact of maternal CORT on embryonic developmental programming.

Maternal fluoxetine reduces hippocampal inflammation and neurogenesis in adult offspring with sex-specific effects of periadolescent oxytocin

Untreated perinatal depression can have severe consequences for the mother and her children. However, both the efficacy to mothers and safety to exposed infants of pharmacological antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been questioned. We previously reported that maternal SSRI exposure increased hippocampal IL-1β levels, which may be tied to limited efficacy of SSRIs during the postpartum to the dam but is not yet known whether maternal postpartum SSRIs affect the neuroinflammatory profile of adult offspring. In addition, although controversial, perinatal SSRI exposure has been linked to increased risk of autism spectrum disorder (ASD) in children. Oxytocin (OT) is under investigation as a treatment for ASD, but OT is a large neuropeptide that has difficulty crossing the blood–brain barrier (BBB). TriozanTM is a nanoformulation that can facilitate OT to cross the BBB. Thus, we investigated the impact of maternal postpartum SSRIs and offspring preadolescent OT treatment on adult offspring neuroinflammation, social behavior, and neurogenesis in the hippocampus. Using a model of de novo postpartum depression, corticosterone (CORT) was given in the postpartum to the dam with or without treatment with the SSRI, fluoxetine (FLX) for 21 days postpartum. Offspring were then subsequently treated with either OT, OT + TriozanTM, or vehicle for 10 days prior to adolescence (PD25-34). Maternal FLX decreased hippocampal IL-10 and IL-13 and neurogenesis in both sexes, whereas maternal CORT increased hippocampal IL-13 in both sexes. Maternal CORT treatment shifted the neuroimmune profile towards a more proinflammatory profile in offspring hippocampus, whereas oxytocin, independent of formulation, normalized this profile. OT treatment increased hippocampal neurogenesis in adult males but not in adult females, regardless of maternal treatment. OT treatment increased the time spent with a novel social stimulus animal (social investigation) in both adult male and female offspring, although this effect depended on maternal CORT. These findings underscore that preadolescent exposure to OT can reverse some of the long-lasting effects of postpartum maternal CORT and FLX treatments in the adult offspring. In addition, we found that maternal treatments that reduce (CORT) or increase (FLX) hippocampal inflammation in dams resulted in opposing patterns of hippocampal inflammation in adult offspring.

Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams

Perinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40 mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10 mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes in the postpartum. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Dexamethasone-induced intrauterine growth restriction modulates expression of placental vascular growth factors and fetal and placental growth.

Prenatal exposure to glucocorticoids (GC) is a central topic of interest in medicine since GCs are essential for the maturation of fetal organs and intrauterine growth. Synthetic glucocorticoids, which are used in obstetric practice, exert beneficial effects on the fetus, but have also been reported to lead to intrauterine growth retardation (IUGR). In this study, a model of growth restriction in mice was established through maternal administration of dexamethasone during late gestation. We hypothesised that GC overexposure may adversely affect placental angiogenesis and fetal and placental growth. Female BALB/c mice were randomly assigned to control or dexamethasone treatment, either left to give birth or euthanised on days 15, 16, 17 and 18 of gestation followed by collection of maternal and fetal tissue. The IUGR rate increased to 100% in the dexamethasone group (8 mg/kg body weight on gestational days 14 and 15) and pups had clinical features of symmetrical IUGR at birth. Dexamethasone administration significantly decreased maternal body weight gain and serum corticosterone levels. Moreover, prenatal dexamethasone treatment not only induced fetal growth retardation but also decreased placental weight. In IUGR placentas, VEGFA protein levels and mRNA expression of VEGF receptors were reduced and NOS activity was lower. Maternal dexamethasone administration also reduced placental expression of the GC receptor, αGR. We demonstrated that maternal dexamethasone administration causes fetal and placental growth restriction. Furthermore, we propose that the growth retardation induced by prenatal GC overexposure may be caused, at least partially, by an altered placental angiogenic profile.

Impact of constant light exposure during pregnancy on skin of neonatal New Zealand rabbits: structural and ultrastructural study.

Continuous industrial productivity and modern societies have resulted in excess artificial light. The altered circadian rhythm causes many diseases. During intrauterine life, the mother's maternal melatonin rhythm has a major role in influencing organ development. The aim of this study was to investigate the effect of maternal exposure to constant light on the structure and ultrastructure of neonatal skin. Twenty pregnant New Zealand rabbits were divided into two groups (n=10 each): control group (12-h light/dark) and constant light group (24-h light). Plasma maternal melatonin and corticosterone during pregnancy were determined. At the end of the experiment, the dorsal skin of the neonates of both groups was collected and prepared for histological, morphometric, and transmission electron microscopic study. Histological and morphometric results of skin of neonates from the constant light group revealed statistically significantly reduced epidermal thickness, decreased number of hair follicle, increased surface area of collagen, and decreased proliferating cell nuclear antigen (PCNA) positive cells. Ultrastructural examination showed wide intercellular spaces and disrupted desmosomal junctions in the epidermis. Earlier stages of hair follicles were also observed with indented shrunken nuclei, vacuolization, and swollen mitochondria. Dermal fibroblasts with dilated cisternae of rough endoplasmic reticulum containing electron-dense material were detected. Maternal melatonin was significantly reduced in the constant light group while maternal corticosterone showed no significant difference between groups. Therefore, normal maternal circadian rhythm is a key factor for the integrity of neonatal skin structure.