Fetal endocrine axes mRNA expression levels are related to sex and intrauterine position.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. METHODS: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. RESULTS: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males', but in the last trimester of pregnancy, male components were more related to each other than female's. CONCLUSIONS: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development.

Sex differences in binge drinking-related higher morning cortisol levels and in prospective association with future alcohol intake.

AIMS: Peripheral cortisol represents one biological measure of the hypothalamic-pituitary-adrenal (HPA) axis, a significant component of the stress system, which is altered by chronic alcohol consumption. However, whether heavy alcohol use affects the HPA axis differentially between the sexes and whether basal cortisol levels are a biomarker of prospective alcohol intake is unknown. METHODS: We recruited light moderate (LM) and binge-heavy (BH) drinkers of alcohol (n = 118). Repeated fasting morning cortisol levels were studied over a 2-hour period to assess basal levels while participants underwent a neuroimaging scan. RESULTS: Significantly higher average cortisol levels in BH compared to LM groups across four timepoints were observed (P < .018). Overall sex differences were observed with women showing higher initial cortisol levels at the first timepoint with a blunted decrease over the morning relative to men (P < .003). Average morning cortisol differentially predicted prospective future 30-day daily reports of alcohol consumption by sex and group, such that LM males had a positive significant relationship and BH males had a negative non-significant relationship between cortisol and drinking. CONCLUSIONS: Findings indicate that morning plasma cortisol is upregulated in the BH vs. LM group. Although females had higher initial morning cortisol levels, BH males showed a dysregulated negative relationship between stress and binge drinking in contrast to the LM group. Future work should further investigate the role of cortisol and other stress hormones as biomarkers of problematic drinking behaviors in men and women.

Manipulation of a social signal affects DNA methylation of a stress-related gene in a free-living bird.

Social status directly affects the health of humans and other animals. Low status individuals receive more antagonistic encounters, have fewer supportive relationships and have worse health outcomes. However, the physiological and cellular processes that mediate the relationship between the social environment and health are incompletely known. Epigenetic regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine pathway that activates in response to stressors, may be one process that is sensitive to the social environment. Here, we experimentally manipulated plumage, a key social signal in female tree swallows (Tachycineta bicolor) and quantified methylation of four genes in the HPA axis before and after treatment. We found that dulling the white breast plumage affected methylation in one gene, CRHR1; however, the effect depended on the original brightness of the bird. Methylation in this gene was correlated with baseline corticosterone levels, suggesting that DNA methylation of CRHR1 helps regulate glucocorticoid production in this species. Methylation in two other genes, FKBP5 and GR, changed over the course of the experiment, independent of treatment. These results show that methylation of these genes is labile into adulthood and suggest that epigenetic regulation of the HPA axis could help birds respond to current environmental conditions.

The oral microbiome is associated with HPA axis response to a psychosocial stressor.

Intense psychosocial stress during early life has a detrimental effect on health-disease balance in later life. Simultaneously, despite its sensitivity to stress, the developing microbiome contributes to long-term health. Following stress exposure, HPA-axis activation regulates the "fight or flight" response with the release of glucose and cortisol. Here, we investigated the interaction between the oral microbiome and the stress response. We used a cohort of 115 adults, mean age 24, who either experienced institutionalisation and adoption (n = 40) or were non-adopted controls (n = 75). Glucose and cortisol measurements were taken from participants following an extended socially evaluated cold pressor test (seCPT) at multiple time points. The cohort´s oral microbiome was profiled via 16S-V4 sequencing on microbial DNA from saliva and buccal samples. Using mixed-effect linear regressions, we identified 12 genera that exhibited an interaction with host's cortisol-glucose response to stress, strongly influencing intensity and clearance of cortisol and glucose following stress exposure. Particularly, the identified taxa influenced the glucose and cortisol release profiles and kinetics following seCPT exposure. In conclusion, our study provided evidence for the oral microbiome modifying the effect of stress on the HPA-axis and human metabolism, as shown in glucose-cortisol time series data.

Distinct saliva DNA methylation profiles in relation to treatment outcome in youth with posttraumatic stress disorder.

In youth with posttraumatic stress disorder (PTSD) non-response rates after treatment are often high. Epigenetic mechanisms such as DNA methylation (DNAm) have previously been linked to PTSD pathogenesis, additionally DNAm may affect response to (psychological) therapies. Besides investigating the direct link between DNAm and treatment response, it might be helpful to investigate the link between DNAm and previously associated biological mechanisms with treatment outcome. Thereby gaining a deeper molecular understanding of how psychotherapy (reflecting a change in the environment) relates to epigenetic changes and the adaptability of individuals. To date, limited research is done in clinical samples and no studies have been conducted in youth. Therefore we conducted a study in a Dutch cohort of youth with and without PTSD (n = 87, age 8-18 years). We examined the cross-sectional and longitudinal changes of saliva-based genome-wide DNA methylation (DNAm) levels, and salivary cortisol secretion. The last might reflect possible abbreviations on the hypothalamic-pituitary- adrenal (HPA) axis. The HPA-axis is previously linked to DNAm and the development and recovery of PTSD. Youth were treated with 8 sessions of either Eye Movement Reprocessing Therapy (EMDR) or Trauma Focused Cognitive behavioral Therapy (TF-CBT). Our epigenome wide approach showed distinct methylation between treatment responders and non-responders on C18orf63 gene post-treatment. This genomic region is related to the PAX5 gene, involved in neurodevelopment and inflammation response. Additionally, our targeted approach indicated that there were longitudinal DNAm changes in successfully treated youth at the CRHR2 gene. Methylation at this gene was further correlated with cortisol secretion pre- and post-treatment. Awaiting replication, findings of this first study in youth point to molecular pathways involved in stress response and neuroplasticity to be associated with treatment response.

Intermittent pulses of methylprednisolone with low-dose prednisone attenuate lupus symptoms in B6.MRL-Faslpr/J mice with fewer glucocorticoid side effects.

Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant medications and remain the cornerstone of systemic lupus erythematosus (SLE) therapy. However, ongoing exposure to GCs has the potential to elicit multiple adverse effects. Considering the irreplaceability of GCs in SLE therapy, it is important to explore the optimal regimen of GCs. Here, we compared the long-term efficacy and safety of pulsed and oral GC therapy in a lupus-prone mouse model. Mice were grouped using a randomized block design. We monitored survival rates, proteinuria, serum autoantibodies, and complement 3 (C3) levels up to 28 weeks of age, and assessed renal damage, bone quality, lipid deposition in the liver and marrow, glucose metabolic parameters, and levels of hormones of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, we explored the mechanisms underlying the superior efficacy of the pulse regimen over oral prednisone regimen. We found that both GC regimens alleviated the poor survival rate, proteinuria, and glomerulonephritis, while also reducing serum autoantibodies and increasing the level of C3. The pulsed GC regimen showed less resistance to insulin, less suppression of the HPA axis, less bone loss, and less bone marrow fat deposition than the oral GC regimen. Additionally, GC-induced leucine zipper (GILZ) was significantly overexpressed in the GC pulse group. These results suggest that the GC pulse regimen ameliorated symptoms in lupus-prone mice, with fewer side effects, which may be related to GILZ overexpression. Our findings offer a potentially promising GC treatment option for SLE.

Fibromyalgia pathogenesis explained by a neuroendocrine multistable model.

Fibromyalgia (FM) is a central disorder characterized by chronic pain, fatigue, insomnia, depression, and other minor symptoms. Knowledge about pathogenesis is lacking, diagnosis difficult, clinical approach puzzling, and patient management disappointing. We conducted a theoretical study based on literature data and computational analysis, aimed at developing a comprehensive model of FM pathogenesis and addressing suitable therapeutic targets. We started from the evidence that FM must involve a dysregulation of central pain processing, is female prevalent, suggesting a role for the hypothalamus-pituitary-gonadal (HPG) axis, and is stress-related, suggesting a role for the HP-adrenocortical (HPA) axis. Central pathogenesis was supposed to involve a pain processing loop system including the thalamic ventroposterolateral nucleus (VPL), the primary somatosensory cortex (SSC), and the thalamic reticular nucleus (TRN). For decreasing GABAergic and/or increasing glutamatergic transmission, the loop system crosses a bifurcation point, switching from monostable to bistable, and converging on a high-firing-rate steady state supposed to be the pathogenic condition. Thereafter, we showed that GABAergic transmission is positively correlated with gonadal-hormone-derived neurosteroids, notably allopregnanolone, whereas glutamatergic transmission is positively correlated with stress-induced glucocorticoids, notably cortisol. Finally, we built a dynamic model describing a multistable, double-inhibitory loop between HPG and HPA axes. This system has a high-HPA/low-HPG steady state, allegedly reached in females under combined premenstrual/postpartum brain allopregnanolone withdrawal and stress condition, driving the thalamocortical loop to the high-firing-rate steady state, and explaining the connection between endocrine and neural mechanisms in FM pathogenesis. Our model accounts for FM female prevalence and stress correlation, suggesting the use of neurosteroid drugs as a possible solution to currently unsolved problems in the clinical treatment of the disease.

A kidney-hypothalamus axis promotes compensatory glucose production in response to glycosuria.

The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Slc2a2 (also known as Glut2) knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in the body's defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal Slc2a2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving the efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria but are met with a compensatory increase in endogenous glucose production.

The Interaction of Vasopressin with Hormones of the Hypothalamo-Pituitary-Adrenal Axis: The Significance for Therapeutic Strategies in Cardiovascular and Metabolic Diseases.

A large body of evidence indicates that vasopressin (AVP) and steroid hormones are frequently secreted together and closely cooperate in the regulation of blood pressure, metabolism, water-electrolyte balance, and behavior, thereby securing survival and the comfort of life. Vasopressin cooperates with hormones of the hypothalamo-pituitary-adrenal axis (HPA) at several levels through regulation of the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and multiple steroid hormones, as well as through interactions with steroids in the target organs. These interactions are facilitated by positive and negative feedback between specific components of the HPA. Altogether, AVP and the HPA cooperate closely as a coordinated functional AVP-HPA system. It has been shown that cooperation between AVP and steroid hormones may be affected by cellular stress combined with hypoxia, and by metabolic, cardiovascular, and respiratory disorders; neurogenic stress; and inflammation. Growing evidence indicates that central and peripheral interactions between AVP and steroid hormones are reprogrammed in cardiovascular and metabolic diseases and that these rearrangements exert either beneficial or harmful effects. The present review highlights specific mechanisms of the interactions between AVP and steroids at cellular and systemic levels and analyses the consequences of the inappropriate cooperation of various components of the AVP-HPA system for the pathogenesis of cardiovascular and metabolic diseases.

Prediction of suicidal thoughts and behaviors based on the diurnal cortisol pattern and THC dosage in continued cannabis users, a 5 year population-based matched cohort study.

It appears that the THC dosage is the link between dysregulation of the hypothalamic pituitary adrenal (HPA) axis and suicidal thoughts and behaviors (STB). We proposed a new model to understand the underlying pathophysiological mechanism of STB based on the interaction of cortisol and THC dosage. From September 1, 2019, to January 1, 2024, we conducted a population-based, matched-pair, nested case-control study resulting from a three-wave complete longitudinal, multicenter cohort study on a sample of congress 60 clients. A total of 368 male continued cannabis users (CCu) were allocated to four categories, including low, moderate and high THC dosages and relapse, using optimal matching. Several HPA axis measures were analyzed in the saliva using liquid chromatography with tandem mass spectrometry (LC-MS-MS), and carboxylic acids levels in the urine were assessed via gas chromatography/mass spectrometry (GC-MS). We used structural equation modeling (SEM) to examine the relationship between the variables of interest and the model fit test, and used the Akaike information criterion (AIC) to compare the model fit and select the best-fitting model. Population attributable fractions (PAFs) and cumulative risk score were also calculated for the best-fitting pattern. The analysis showed that the likelihood of STB in individuals with a cortisol awakening response (CAR) and a blunted diurnal cortisol slope (DCS) and higher area under the curve (AUC) who reported heavy cannabis use was more than three times higher than the control group (OR 3.2, 95 % CI 2.4-4.1). These findings indicate the importance of the specific cortisol secretion pattern in the increased clinical expression of STB and may be an important factor for guiding preventive efforts in this area.

HPA activity mediates the link between trait impulsivity and boredom.

Boredom, a complex emotional state with implications for mental health and well-being, has garnered attention across disciplines, yet remains relatively understudied in psychiatric research. Here, we explored the intricate relationship between trait-impulsivity, stress, and boredom across two studies. Participants completed self-report measures of trait-impulsivity and boredom and boredom-inducing tasks. Study 1, involving 80 participants (42 women and 38 men, aged 20-63), replicates previous findings, by demonstrating that impulsive individuals report greater boredom following a boring task. Study 2 then extends this, using 20 participants (9 women and 12 men, aged 18-24), to show that hypothalamic-pituitary-adrenal (HPA) axis activity, specifically heightened salivary cortisol responses, mediate the link between impulsivity and boredom following a boring task. Collectively, these results demonstrate that HPA axis activity may underline the relationship between trait-impulsivity and boredom by extending previous work and offering a novel insight into potential mechanisms. These findings offer promise for personalised interventions, designed for high impulsivity individuals, to alleviate the negative impacts of boredom and potentially break the identified feedback loop.

Salivary uric acid dynamics are associated with stress response hormones among African Americans in an urban sample.

Acute physiological responses to psychosocial stressors are a potential pathway underlying racial disparities in stress-related illnesses. Uric acid (UA) is a potent antioxidant that has been linked to disparities in stress-related illnesses, and recent research has shown that UA is responsive to acute social stress. However, an examination of the relationships between the purinergic system and other commonly measured stress systems is lacking. Here, we measure and characterize associations of salivary uric acid (sUA) with markers of hypothalamic-pituitary-adrenal (HPA) axis activation, sympathetic-adreno-medullar (SAM) axis activation, and acute inflammation. A community sample of 103 African Americans (33 male, 70 female) completed the Trier Social Stress Test to induce social-evaluative threat. Passive drool collected before, during, and after the stressor task provided salivary reactivity measures of UA (sUA), cortisol, dehydroepiandrosterone sulfate (DHEAS), salivary alpha amylase (sAA - a surrogate marker of SAM activity) and C-reactive protein (sCRP). Multiple regressions revealed that total activation of cortisol, DHEAS, and sCRP were each positively associated with higher total activation of sUA. Additionally, DHEAS reactivity was positively associated with sUA reactivity. Relationships between HPA-axis markers and sUA were especially observed among younger and male participants. Overall, findings suggest potential coordination of stress systems with sUA in response to acute stress, which may further the contributions of biological stress processes to racial health disparities.

Is social disadvantage a chronic stressor? Socioeconomic position and HPA axis activity among older adults living in England.

INTRODUCTION: Living in socioeconomic disadvantage has been conceptualised as a chronic stressor, although this contradicts evidence from studies using hair cortisol and cortisone as a measure of hypothalamus-pituitary-adrenal (HPA)1 axis activity. These studies used complete case analyses, ignoring the impact of missing data for inference, despite the high proportion of missing biomarker data. The methodological limitations of studies investigating the association between socioeconomic position (SEP)2 defined as education, wealth, and social class and hair cortisol and cortisone are considered in this study by comparing three common methods to deal with missing data: (1) Complete Case Analysis (CCA),3 (2) Inverse Probability Weighting (IPW) 4and (3) weighted Multiple Imputation (MI).5 This study examines if socioeconomic disadvantage is associated with higher levels of HPA axis activity as measured by hair cortisol and cortisone among older adults using three approaches for compensating for missing data. METHOD: Cortisol and cortisone levels in hair samples from 4573 participants in the 6th wave (2012-2013) of the English Longitudinal Study of Ageing (ELSA)6 were examined, in relation to education, wealth, and social class. We compared linear regression models with CCA, weighted and multiple imputed weighted linear regression models. RESULTS: Social groups with certain characteristics (i.e., ethnic minorities, in routine and manual occupations, physically inactive, with poorer health, and smokers) were less likely to have hair cortisol and hair cortisone data compared to the most advantaged groups. We found a consistent pattern of higher levels of hair cortisol and cortisone among the most socioeconomically disadvantaged groups compared to the most advantaged groups. Complete case approaches to missing data underestimated the levels of hair cortisol in education and social class and the levels of hair cortisone in education, wealth, and social class in the most disadvantaged groups. CONCLUSION: This study demonstrates that social disadvantage as measured by disadvantaged SEP is associated with increased HPA axis activity. The conceptualisation of social disadvantage as a chronic stressor may be valid and previous studies reporting no associations between SEP and hair cortisol may be biased due to their lack of consideration of missing data cases which showed the underrepresentation of disadvantaged social groups in the analyses. Future analyses using biosocial data may need to consider and adjust for missing data.

Should we routinely assess hypothalamic-pituitary-adrenal axis in pediatric patients with Prader-Willi syndrome?

Background: It has been reported that central adrenal insufficiency (CAI) in pediatric patients (pts) with Prader-Willi syndrome (PWS) may be a potential cause of their sudden death. In addition, the risk of CAI may increase during treatment with recombinant human growth hormone (rhGH). Objective: To prevent both over- and undertreatment with hydrocortisone, we evaluated the prevalence of CAI in a large multicenter cohort of pediatric pts with PWS analyzing adrenal response in the low-dose ACTH test (LDAT) and/or the glucagon stimulation test (GST) and reviewing the literature. Methods: A total of 46 pts with PWS were enrolled to the study, including 34 treated with rhGH with a median dose of 0.21 mg/kg/week. LDAT was performed in 46 pts, and GST was carried out in 13 pts. Both tests were conducted in 11 pts. The tests began at 8:00 a.m. Hormones were measured by radioimmunoassays. Serum cortisol response >181.2 ng/mL (500 nmol/L) in LDAT and >199.3 ng/mL (550 nmol/L) in GST was considered a normal response. Additionally, cortisol response delta (the difference between baseline and baseline) >90 ng/mL and doubling/tripling of baseline cortisol were considered indicators of normal adrenal reserve. Results: Three GSTs were not diagnostic (no hypoglycemia obtained). LDAT results suggested CAI in four pts, but in two out of four pts, and CAI was excluded in GST. GST results suggested CAI in only one patient, but it was excluded in LDAT. Therefore, CAI was diagnosed in 2/46 pts (4.3%), 1 treated and 1 untreated with rhGH, with the highest cortisol values of 162 and 175 ng/dL, but only in one test. However, in one of them, the cortisol delta response was >90 ng/mL and peak cortisol was more than tripled from baseline. Finally, CAI was diagnosed in one patient treated with rhGH (2.2%). Conclusion: We present low prevalence of CAI in pediatric pts with PWS according to the latest literature. Therefore, we do not recommend to routinely screen the function of the hypothalamic-pituitary-adrenal axis (HPAA) in all pts with PWS, both treated and untreated with rhGH. According to a review of the literature, signs and symptoms or low morning ACTH levels suggestive of CAI require urgent and appropriate diagnosis of HPAA by stimulation test. Our data indicate that the diagnosis of CAI should be confirmed by at least two tests to prevent overtreatment with hydrocortisone.

Neurochemical and genetic factors in panic disorder: a systematic review.

This systematic review addresses the complex nature of Panic Disorder (PD), characterized by recurrent episodes of acute fear, with a focus on updating and consolidating knowledge regarding neurochemical, genetic, and epigenetic factors associated with PD. Utilizing the PRISMA methodology, 33 original peer-reviewed studies were identified, comprising 6 studies related to human neurochemicals, 10 related to human genetic or epigenetic alterations, and 17 animal studies. The review reveals patterns of altered expression in various biological systems, including neurotransmission, the Hypothalamic-Pituitary-Adrenal (HPA) axis, neuroplasticity, and genetic and epigenetic factors leading to neuroanatomical modifications. Noteworthy findings include lower receptor binding of GABAA and serotonin neurotransmitters in the amygdala. The involvement of orexin (ORX) neurons in the dorsomedial/perifornical region in triggering panic reactions is highlighted, with systemic ORX-1 receptor antagonists blocking panic responses. Elevated Interleukin 6 and leptin levels in PD patients suggest potential connections between stress-induced inflammatory changes and PD. Brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) signaling are implicated in panic-like responses, particularly in the dorsal periaqueductal gray (dPAG), where BDNF's panicolytic-like effects operate through GABAA-dependent mechanisms. GABAergic neurons' inhibitory influence on dorsomedial and posterior hypothalamus nuclei is identified, potentially reducing the excitability of neurons involved in panic-like responses. The dorsomedial hypothalamus (DMH) is highlighted as a specific hypothalamic nucleus relevant to the genesis and maintenance of panic disorder. Altered brain lactate and glutamate concentrations, along with identified genetic polymorphisms linked to PD, further contribute to the intricate neurochemical landscape associated with the disorder. The review underscores the potential impact of neurochemical, genetic, and epigenetic factors on the development and expression of PD. The comprehensive insights provided by this systematic review contribute to advancing our understanding of the multifaceted nature of Panic Disorder and pave the way for targeted therapeutic strategies.

Effects of improved on-farm crop storage on DNA methylation of mothers and their infants: evidence from a randomized controlled trial in Kenya.

BACKGROUND: Stress during pregnancy can lead to adverse maternal and infant health outcomes through epigenetic changes in the hypothalamic-pituitary-adrenal axis. Among farmers in low-income countries, one important stressor is food insecurity, which can be reduced using hermetic storage bags. This study aimed to determine, for the first time, whether a hermetic storage bag intervention during pregnancy positively affects maternal and infant DNA methylation of the hypothalamic-pituitary-adrenal axis-related genes FKBP5 and NR3C1. We further analyzed whether anthropometrics, stress, and mental health were associated with DNA methylation. METHODS: This study was part of a larger matched-pair randomized controlled trial focusing on the impact of improved on-farm storage on food security, poverty, and net income of smallholder farming households. A total of N = 149 mothers were recruited by telephone and invited to attend a study appointment at health facilities in Kakamega County, Western Kenya, with their infants in April or May 2021. During the appointment, anthropometric measurements were taken, questionnaires on stress and mental health were administered, and saliva samples were collected. Logistic and multiple linear regression were used to examine the effect of the intervention and related measures on DNA methylation. RESULTS: Mothers in the intervention group showed higher mean NR3C1 methylation levels than those in the control group, corrected for multiple testing. Maternal postpartum body mass index was positively associated with infant NR3C1 CpG3 DNA methylation. The more stressful life events a mother had experienced in the previous 12 months (including during pregnancy), the lower her FKBP5 CpG3 methylation levels. CONCLUSIONS: Food insecurity and stressful life events during pregnancy seem to exert significant effects on maternal DNA methylation. While these stressors did not appear to impact infant DNA methylation in the present study, maternal postpartum body mass index was significantly related to infant methylation. These findings suggest that while infants may be protected from excessive maternal glucocorticoids by placental barrier activity, maternal metabolic status is still reflected in their epigenetic make-up. Trial registration This study was part of a larger matched-pair randomized controlled trial on the impact of improved on-farm crop storage on welfare, nutrition, and human health. Registration can be found in the American Economic Association (AEA) RCT Registry, RCT ID: AEARCTR-0005845.

The Influence of Maternal Hypoxia and Buspirone during Pregnancy on Cognitive Abilities and a Stress Response in Adult Male Offspring.

Spatial learning, memory, and reactivity of the hypothalamic-pituitary-adrenocortical system (HPA axis) were studied in adult male rats, whose mothers during pregnancy were subjected to acute moderate normobaric hypoxia, or repeated injections of buspirone, an agonist of type 1A serotonergic receptors (5HT1A), or their combination. Prenatal treatment with buspirone in rats with prenatal hypoxia impaired learning ability during the first day of 5-day training. A decrease in the effectiveness of long-term memory in comparison with short-term memory was revealed in two groups of rats: prenatal treatment with buspirone in combination with hypoxia and injection of physiological saline without hypoxia. The effectiveness of long-term memory and the level of corticosterone in response to stress did not differ between the groups, which can indicate adaptation of the 5HT1A receptor and the HPA axis to the prenatal buspirone and normobaric hypoxia during ontogeny.

Glucose attenuates the long-term adverse neurodevelopment effect of neonate pain stimulus via CRF/GR in rats.

BACKGROUND: Neonates undergo numerous painful procedures throughout their hospitalization. Repeated procedural pain may cause adverse long-term effects. Glucose as a non-pharmacological analgesia, is used for neonate pain management. In this study, potential mechanism of attenuate pain induced by glucose in neurodevelopment effect of neonate pain stimulus was investigated. METHODS: Neonatal rats to perform a repetitive injury model and glucose intervention model in the postnatal day 0-7(P0-7). Pain thresholds were measured by von Frey test weekly. The puberty behavioral outcome, tissue loss and protein expression in hippocampus were analyzed. RESULTS: Oral administration of glucose after repeated pain stimulation can maintain the hippocampal structure in, and reduce the expressions of corticotropin releasing factor (CFR) and glucocorticoid receptor (GR), therefore, resulted in long-term threshold of pain and cognitive improvement. CONCLUSION: Exposure to neonatal repeated procedural pain causes persistent mechanical hypersensitivity and the dysfunction of spatial memory retention at puberty. In addition, glucose can relieve these adverse effects, possibly via decreasing CRF/GR levels to change the hypothalamus-pituitary-adrenal (HPA) axis.

Exploring the interplay between stress mediators and skin microbiota in shaping age-related hallmarks: A review.

Psychological stress is a major contributing factor to several health problems (e.g., depression, cardiovascular disease). Around 35 % of the world's population suffers from it, including younger generations. Physiologically, stress manifests through neuroendocrine pathways (Hypothalamic-Pituitary-Adrenal (HPA) axis and Sympathetic-Adrenal-Medullary (SAM) system) which culminate in the production of stress mediators like cortisol, epinephrine and norepinephrine. Stress and its mediators have been associated to body aging, through molecular mechanisms such as telomere attrition, mitochondrial dysfunction, cellular senescence, chronic inflammation, and dysbiosis, among others. Regarding its impact in the skin, stress impacts its structural integrity and physiological function. Despite this review focusing on several hallmarks of aging, emphasis was placed on skin microbiota dysbiosis. In this line, several studies, comprising different age groups, demographic contexts and body sites, have reported skin microbiota alterations associated with aging, and some effects of stress mediators on skin microbiota have also been reviewed in this paper. From a different perspective, since it is not a "traditional" stress mediator, oxytocin, a cortisol antagonist, has been related to glucorticoids inhibition and to display positive effects on cellular aging. This hormone dysregulation has been associated to psychological issues such as depression, whereas its upregulation has been linked to positive social interaction.