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opencc-by-4.0Dec 2023View details →

Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids

Abstract: Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. In this study, we used single-cell and cell-type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics- with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GCs influenced lineage specification primarily by priming the inhibitory neuron lineage through key transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.

opencc-zeroMar 2024View details →

Baseline glucocorticoids alone do not predict reproductive success across years but in interaction with enzymatic antioxidants

Glucocorticoids are known to adjust organismal functions, such as metabolism, in response to environmental conditions. Therefore, these hormones are thought to play a key role in regulating the metabolically demanding aspects of reproduction, especially in variable environments. However, support for the hypothesis that variation in glucocorticoid concentrations predicts reproductive success is decidedly mixed. Two explanations may account for this discrepancy: a) glucocorticoids might not act independently but could interact with other physiological traits, jointly influencing reproduction, and b) such an association could become apparent primarily in challenging environments when glucocorticoid concentrations increase. To address these two possibilities, we determined natural variation in circulating baseline glucocorticoid concentrations in parental great tits (Parus major) alongside two physiological systems known to be related to an individual's metabolism: oxidative status parameters (i.e., concentrations of pro-oxidants, dietary, and enzymatic antioxidants) and body condition. These systems interact with glucocorticoids and can also influence reproductive success. We measured these variables in two breeding seasons that differed in environmental conditions. When accounting for the interaction of baseline glucocorticoids with other physiological traits, we found a positive relationship between baseline glucocorticoids and the number of fledglings in adult great tits. The strength of this relationship was more pronounced for those individuals who also had high concentrations of the enzymatic antioxidant glutathione peroxidase. When studied independently, glucocorticoids were not related to fitness proxies, even in the year with more challenging environmental conditions. Together, our study lends to support the hypothesis that glucocorticoids do not influence fitness alone, but in association with other physiological systems

opencc-by-4.0Nov 2023View details →

Morphing libraries, QSAR models, and compounds predicted to be active on the Glucocorticoid receptor (GR)

This repository contains datasets and files related to the computational drug discovery project of the chemical space exploration of the Glucocorticoid receptor. The accompanying Python code is freely available in the GitHub repository (<a title="https://github.com/Iagea/GRML_analyses" href="https://github.com/Iagea/GRML_analyses" target="_blank" rel="noreferrer noopener">https://github.com/Iagea/GRML_analyses</a>). Morphing Libraries: <ul> <li>GRML_library.csv: The GRML library is the collection of 999,015 virtual compounds generated by Molpher [1-2] starting from GR ligands with unique Bemis-Murcko scaffolds collected from the ChEMBL17 and IMG libraries.</li> <li>RML_library.csv: The RML library is the collection of 1,346,310 virtual compounds generated by Molpher starting from compounds with unique Bemis-Murcko scaffolds  randomly selected from the ZINC database.</li> </ul> IMG library: <ul> <li>IMG_non_proprietary.csv: The non-proprietary IMG library subset containing 12,956 compounds and their corresponding B-scores from the primary screen.</li> </ul> Molpher inputs: <ul> <li>GR_inputs.csv: The GR inputs are the ligands used to create the GRML library, 204 compounds from ChEMBL17 (95 compounds) and the non-proprietary dataset from IMG (109 compounds).</li> <li>Random_inputs.csv: The random inputs are 249 random ZINC compounds used to create the Random library.</li> </ul> Model's training sets: <ul> <li>Model33_training_set.csv: Random forest classification model training set, it includes 865 compounds; known GR actives and inactives from ChEMBL33 (738 compounds) and non-proprietary active ligands from the IMG library (127 compounds).</li> <li>Model17_training_set.csv: Random forest classification model training set, it includes 601 compounds; known GR actives and inactives from ChEMBL17 (474 compounds) and non-proprietary active ligands from the IMG library (127 compounds).</li> <li>RFR_training_set.csv: Random forest regression model training set, it includes 89 compounds; known GR actives and inactives from ChEMBL33 that fit into the GR pharmacophore with the four features we describe in our paper.</li> </ul> Models: <ul> <li>Model33.pkl: Python pickle file containing the trained Random forest classification models used along with Mondrian cross-conformal prediction to classify GR actives/inactives. This model was trained with ChEMBL33 and IMG libraries.</li> <li>Model17.pkl: Python pickle file containing the trained Random forest classification models used along with Mondrian cross-conformal prediction to classify GR actives/inactives. This model was trained with ChEMBL17 and IMG libraries.</li> <li>RFR_models.pkl: Python pickle file containing the 100 trained random forest regression models used to rank the proposed active morphs. These models were trained with the RFR_training_set.csv.</li> </ul> Active predicted morphs: <ul> <li>all_morphs_actives_predicted.xlsx: An Excel spreadsheet containing two sheets. 1) All 22,524 GRML active predicted morphs. 2) All 4,341 RML active predicted morphs. The QED, NIBR Severity Score, and Molskill Score are given for each morph.</li> </ul> Proposed GR active ligands: <ul> <li>designed_ligands.xlsx: An Excel spreadsheet containing two sheets. 1) All 54 designed GR ligands with their QED, NIBR severity score, MolSkill score, consensus ranking from the 100 RFR models, and the result of the manual annotation and remarks, if available. 2) The structure of the 54 ligands based on their manual annotation and presence or not in ChEMBL33 database.</li> </ul> Researchers and professionals in the field of drug discovery and cheminformatics may find these resources useful for further analysis and investigations. Bibliography [1] Hoksza, D., &Scaron;koda, P., Vor&scaron;ilák, M. et al. Molpher: a software framework for systematic chemical space exploration. J Cheminform 6, 7 (2014). https://doi.org/10.1186/1758-2946-6-7 [2] <a href="https://github.com/lich-uct/molpher-lib">https://github.com/lich-uct/molpher-lib</a>

opencc-by-4.0Nov 2021View details →

Data and code for: Viviparous mothers impose stronger glucocorticoid‐mediated maternal stress effects on their offspring than oviparous mothers

Data and code accompanying the manuscript "Viviparous mothers impose stronger glucocorticoid‐mediated maternal stress effects on their offspring than oviparous mothers", MacLeod KJ, While GM, Uller, T, Ecology & Evolution 2021. Code is in an R file - can be opened with any txt app. Metadata is in sheet 2 of the main data sheet (xlsx). Queries to kirstyjmacleod@gmail.com Publication abstract: Maternal stress during gestation has the potential to affect offspring development via changes in maternal physiology, such as increases in circulating levels of glucocorticoid hormones that are typical after exposure to a stressor. While the effects of elevated maternal glucocorticoids on offspring phenotype (i.e., “glucocorticoid‐mediated maternal effects”) have been relatively well established in laboratory studies, it remains poorly understood how strong and consistent such effects are in natural populations. Using a meta‐analysis of studies of wild mammals, birds, and reptiles, we investigate the evidence for effects of elevated maternal glucocorticoids on offspring phenotype and investigate key moderators that might influence the strength and direction of these effects. In particular, we investigate the potential importance of reproductive mode (viviparity vs. oviparity). We show that glucocorticoid‐mediated maternal effects are stronger, and likely more deleterious, in mammals and viviparous squamate reptiles compared with birds, turtles, and oviparous squamates. No other moderators (timing and type of manipulation, age at offspring measurement, or type of trait measured) were significant predictors of the strength or direction of the phenotypic effects on offspring. These results provide evidence that the evolution of a prolonged physiological association between embryo and mother sets the stage for maladaptive, or adaptive, prenatal stress effects in vertebrates driven by glucocorticoid elevation.

opencc-by-4.0Nov 2021View details →

Cell type specificity of glucocorticoid signaling in the adult mouse hippocampus

The present study is based on the 10X scRNA-seq dataset published by the Allen Institute for Brain Science and publicly available at: <a href="https://portal.brain-map.org/atlases-and-data/RNA-seq/mouse-whole-cortex-and-hippocampus-10x">https://portal.brain-map.org/atlases-and-data/RNA-seq/mouse-whole-cortex-and-hippocampus-10x</a>. The cells from the hippocampus region were selected from the gene count expression matrix and pre-processed in R v3.6.1 according to the Seurat v3.1.5 standard pre-processing workflow for quality control, normalization, and analysis of scRNA-seq data. Here we make the final seurat object and other datasets further used in the code (<a href="https://github.com/eviho/10XHip2021_VihoEMG">https://github.com/eviho/10XHip2021_VihoEMG</a>) available for download.

opencc-zeroJul 2024View details →

Data and code for: Previous assessments of faecal glucocorticoid metabolites in Cape Mountain zebra (Equus zebra zebra) were flawed

Steroid hormones, especially glucocorticoids (GCs), are widely used to assess physiological responses to stressors. As steroid hormones are heavily metabolised prior to excretion, it is essential to validate enzyme immunoassays (EIAs) for measuring faecal glucocorticoid metabolites (fGCMs). Although problems with unvalidated assays have been raised repeatedly, their use persists widely. Lea et al. (2017) used an unvalidated corticosterone assay (CJM006) to relate fGCM concentrations to habitat quality, demography, and population performance in the Cape mountain zebra (Equus zebra zebra). Here, we revisit their findings and evaluate the validity of their conclusions using a validated EIA. First, we evaluate the biological sensitivity of six EIAs (three group-specific metabolite assays and three corticosterone assays, including CJM006) through a biological validation experiment (translocation) for two sub-species of mountain zebra, Cape mountain and Hartmann's mountain zebra (E. z. hartmannae). Second, we reanalyse the faecal extracts from Lea et al. (2017) using a validated EIA. fGCM concentrations consistently increased following translocation, when using two 11-oxoaetiocholanolone (lab codes: 72T and 72a) and an 11ß-hydroxyaetiocholanolone (69a) EIA, but did not with three different corticosterone EIAs. All corticosterone EIAs (including CJM006) failed to detect an increase in fGCMs within the critical 48–72-hour period post translocation. Therefore, the CJM006 EIA utilised in Lea et al. (2017) does not sensitively measure hypothalamic-pituitary-adrenal (HPA) axis activity in CMZ faeces. Using a validated assay (72T), fGCM concentrations were no longer associated with adult sex ratio or habitat quality (measured by grassiness) and these variables were dropped from predictive models. fGCM concentrations now varied between seasons and were negatively associated with female fecundity (foal:mare ratio). Consequently, we can conclude that the results of the previous study are unreliable. We introduce the terms "insensitive" and "sub-optimal" to categorise assays that are tested but fail validation, and assays that are comparatively poor at detecting relevant hormone changes, respectively. We discuss how both "insensitive" and "sub-optimal" assays could lead to incorrect inferences about population stressors and counterproductive conservation recommendations. In this dataset, we provide all R code scripts, raw data and data to reproducible all results and figures in Previous assessments of faecal glucocorticoid metabolites in Cape Mountain zebra (Equus zebra zebra) were flawed. We have structured the project as an internally consistent directory with files corresponding to code, data, raw lab_ouputs, and figures.

opencc-by-4.0Aug 2021View details →

Data for: Context-dependent effects of glucocorticoids on the lizard gut microbiome

Data from: Context-dependent effects of glucocorticoids on the lizard gut microbiome (provisionally accepted, Molecular Ecology 2021)  Metadata is in Sheet 2. Address queries to kirstyjmacleod@gmail.com. Publication abstract: The vertebrate gut microbiota (bacterial, archaeal, and fungal communities of the gastrointestinal tract) can have profound effects on physiological processes of their hosts. Although relatively stable, changes in microbiome structure and composition occur due to changes in the environment, including exposure to stressors and associated increases in glucocorticoid hormones. Although a growing number of studies have linked stressor exposure to microbiome changes, few studies have experimentally explored the specific influence of glucocorticoids on the microbiome in wild animals, or across ecologically-important processes (e.g., reproductive stages). Here we tested the response of the gut microbiota of adult female Sceloporus undulatus across gestation to ecologically relevant elevations of a stress-relevant glucocorticoid hormone (CORT) in order to determine a) how experimentally elevated CORT influenced microbiome characteristics, and b) whether this relationship was dependent on reproductive context (i.e. whether females were gravid or not, and in those that were gravid, gestational stage). We show that the effects of CORT on gut microbiota are complex and depend on both gestational state and stage. CORT treatment altered microbial community membership and resulted in an increase in microbiome diversity in late-gestation females, and microbial community membership varied according to treatment. In non-gravid females, CORT treatment resulted in inter-individual variation in microbial communities, but this effect was not observed in late-gestation females.  Our results highlight the need for a more holistic understanding of the downstream physiological effects of glucocorticoids, as well as the importance of context (here, gestational state and stage) in interpreting stress effects in ecology.

ClinicalTrials.gov40/100

An Efficacy and Safety Trial of Intravenous Zoledronic Acid Twice Yearly in Osteoporotic Children Treated With Glucocorticoids

ClinicalTrials.gov study NCT00799266. IPD Sharing: UNDECIDED. Countries: 6. Publications: 1.

restrictedIPD-UNDECIDEDFeb 2026View details →

ClinicalTrials.gov40/100

1 Year Open-label Extension to CZOL446H2337 Safety and Efficacy Trial of Zoledronic Acid Twice Yearly in Osteoporotic Children Treated With Glucocorticoids

ClinicalTrials.gov study NCT01197300. IPD Sharing: YES. Countries: 6. Publications: 5.

controlledIPD-YESFeb 2026View details →

publicMar 2024View details →

Baseline glucocorticoids alone do not predict reproductive success across years but in interaction with enzymatic antioxidants

Open the record for dataset details and reuse information.

publicJul 2024View details →

Data and code for: Previous assessments of faecal glucocorticoid metabolites in Cape Mountain zebra (Equus zebra zebra) were flawed

Open the record for dataset details and reuse information.

zenodo36/100

Ensminger et al 2020 - Fecal glucocorticoid metabolites in harvested elk

Raw data for modeling fecal glucocorticoid metabolites in Ensminger et al. 2020.

opencc-by-4.0May 2020View details →

opencc-zeroJul 2020View details →

Data from: Increased glucocorticoid concentrations in early life cause mitochondrial inefficiency and short telomeres

Telomeres are DNA structures that protect chromosome ends. However, telomeres shorten during cell replication and at critically low lengths can reduce cell replicative potential, induce cell senescence and decrease fitness. Stress exposure, which elevates glucocorticoid hormone concentrations, can exacerbate telomere attrition. This phenomenon has been attributed to increased oxidative stress generated by glucocorticoids ("oxidative stress hypothesis"). We recently instead suggested that glucocorticoids increase telomere attrition during stressful periods by reducing the resources available for telomere maintenance through changes in the metabolic machinery ("metabolic telomere attrition hypothesis"). Here we tested whether experimental increases in glucocorticoid levels affected telomeres and mitochondrial function in wild great tit (Parus major) nestlings during the energy-demanding early growth. We monitored resulting corticosterone (Cort) concentrations in plasma, and in red blood cells telomere lengths and mitochondrial metabolism (metabolic rate, proton leak, oxidative phosphorylation, maximal mitochondrial capacity and mitochondrial inefficiency). We assessed oxidative damage caused by reactive oxygen species (ROS) metabolites as well as the total non-enzymatic antioxidant protection in plasma. Compared with control (Ctrl) nestlings, Cort-nestlings had higher baseline corticosterone, shorter telomeres and higher mitochondrial metabolic rate. Importantly, Cort-nestlings showed increased mitochondrial proton leak, leading to a decreased ATP production efficiency. Treatment groups did not differ in oxidative damage or antioxidants. Hence, glucocorticoid-induced telomere attrition is associated with changes in mitochondrial metabolism, but not with ROS production. These findings support the "metabolic telomere attrition hypothesis" which proposes an active regulation of telomere length by glucocorticoids during stressful periods, which is mediated through metabolic rearrangements.

opencc-zeroDec 2018View details →

Data from: The effects of stress and glucocorticoids on vocalizations: a test in North American red squirrels

Acoustic signaling is an important means by which animals communicate both stable and labile characteristics. Although it is widely appreciated that vocalizations can convey information on labile state, such as fear and aggression, fewer studies have experimentally examined the acoustic expression of stress state. The transmission of such public information about physiological state could have broad implications, potentially influencing the behavior and life history traits of neighbors. North American red squirrels (Tamiasciurus hudsonicus) produce vocalizations known as rattles that advertise territorial ownership. We examined the influence of changes in physiological stress state on rattle acoustic structure through the application of a stressor (trapping and handling the squirrels) and by provisioning squirrels with exogenous glucocorticoids (GCs). We characterized the acoustic structure of rattles emitted by these squirrels by measuring rattle duration, mean frequency, and entropy. We found evidence that rattles do indeed exhibit a "stress signature." When squirrels were trapped and handled, they produced rattles that were longer in duration with a higher frequency and increased entropy. However, squirrels that were administered exogenous GCs had similar rattle duration, frequency, and entropy as squirrels that were fed control treatments and unfed squirrels. Our results indicate that short-term stress does affect the acoustic structure of vocalizations, but elevated circulating GC levels do not mediate such changes.

opencc-zeroDec 2017View details →

Data from: Chronic anthropogenic noise disrupts glucocorticoid signaling and has multiple effects on fitness in an avian community

Anthropogenic noise is a pervasive pollutant that decreases environmental quality by disrupting a suite of behaviors vital to perception and communication. However, even within populations of noise-sensitive species, individuals still select breeding sites located within areas exposed to high noise levels, with largely unknown physiological and fitness consequences. We use a study system in the natural gas fields of northern New Mexico to test the prediction that exposure to noise causes glucocorticoid-signaling dysfunction and decreases fitness in a community of secondary cavity nesting birds. In accordance with these predictions, and across all species, we find strong support for noise exposure decreasing baseline corticosterone in adults and nestlings and, conversely, increasing acute stressor-induced corticosterone in nestlings. We also document fitness consequences with increased noise in the form of reduced hatching success in the western bluebird (Sialia mexicana), the species most likely to nest in noisiest environments. Nestlings of all three species exhibited accelerated growth of both feathers and body size at intermediate noise amplitudes compared to low or higher amplitudes. Our results are consistent with recent experimental laboratory studies, and show that noise functions as a chronic, inescapable stressor. Anthropogenic noise likely impairs environmental risk perception by species relying on acoustic cues, and, ultimately, leads to impacts on fitness. Our work, when taken together with recent efforts to document noise across the landscape, implies potential widespread, noise-induced chronic stress coupled with reduced fitness for many species reliant on acoustic cues.

opencc-zeroMar 2020View details →

Wild chimpanzees exhibit human-like aging of glucocorticoid regulation

Cortisol, a key product of the stress response, has critical influences on degenerative aging in humans. In turn, cortisol production is affected by senescence of the hypothalamic-pituitary-adrenal (HPA) axis, leading to progressive dysregulation and increased cortisol exposure. These processes have been studied extensively in industrialized settings, but few comparative data are available from humans and closely-related species living in natural environments, where stressors are very different. Here, we examine age-related changes in urinary cortisol in a 20-year longitudinal study of wild chimpanzees (N = 59 adults) in the Kanyawara community of Kibale National Park, Uganda. We tested for three key features of HPA aging identified in many human studies: increased average levels, a blunted diurnal rhythm, and enhanced response to stressors. Using linear mixed models, we found that aging was associated with a blunting of the diurnal rhythm and a significant linear increase in cortisol, even after controlling for changes in dominance rank. These effects did not differ by sex. Aging did not increase sensitivity to energetic stress or social status. Female chimpanzees experienced their highest levels of cortisol during cycling (versus lactation), and this effect increased with age. Male chimpanzees experienced their highest levels when exposed to sexually-attractive females, but this effect was diminished by age. Our results indicate that chimpanzees share some key features of HPA aging with humans. These findings suggest that impairments of HPA regulation are intrinsic to the aging process in hominids and are neither side effects of extended human lifespan nor of atypical environments.

opencc-zeroDec 2018View details →

Data from: Exogenous glucocorticoids amplify the costs of infection by reducing resistance and tolerance, but effects are mitigated by co-infection

Individual variation in parasite defenses, such as resistance and tolerance, can underlie heterogeneity in fitness and could influence disease transmission dynamics. Glucocorticoid hormone concentrations often change in response to fluctuating environmental conditions and mediate changes in immune function, resource allocation, and tissue repair. Thus, changes in glucocorticoid hormone concentrations might mediate individual variation in investment in resistance versus tolerance. In this study, we experimentally increased glucocorticoid concentrations in red-winged blackbirds (Agelaius phoeniceus) that were naturally infected with haemosporidian parasites and assessed changes in resistance and tolerance of infection. Glucocorticoid treatment increased burdens of Plasmodium, the parasite causing avian malaria, but only in the absence of co-infection with another Haemosporidian, Haemoproteus. Thus, glucocorticoids might reduce resistance to infection, but co-infection can mitigate the negative consequences of increased hormone concentrations. Glucocorticoid treatment also decreased tolerance of infection. We found no evidence that the inflammatory immune response or rate of red blood cell production underlie the effects of glucocorticoids on resistance and tolerance. Our findings suggest that exogenous glucocorticoids can increase the costs of haemosporidian infections by both increasing parasite numbers and reducing an individual's ability to cope with infection. These effects could scale up to impact populations of both host and parasite.