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1.
Toxicol Lett ; 351: 155-162, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34517056

RESUMO

Perfluorooctanoic acid (PFOA), a member of the Per- and polyfluoroalkyl substances, is a highly persistent "forever" chemicals with increasing concern for its potential health effects. However, the mechanisms of PFOA immunotoxic effects are poorly understood. We assessed the antibody response to a physiological antigen stimulation and associated cytokine response upon PFOA exposure. The significant decrease in the IgM antibody response to the T cell dependent antigen keyhole limpet hemocyanin (KLH) at a dose lower than the previously documented LOAEL was accompanied by a significant reduction of the Th2 serum cytokines IL-5 and IL-13, a non-significant dose-response reduction of IL-4, a significant reduction of the Th1 cytokine IL-12, and a non-significant dose-response increase in IL-2 and IFNγ. PFOA significantly decreased the pro-inflammatory cytokines IL-17α and IL-1α, decreased (non-significantly but dose-response) IL-6, and a significantly increased TNFα. Overall, the modulation of serum Th1/Th2 cytokines could explain the reduction in antibody response, pointing to a potential role for T helper cells in the immunotoxicity of PFOA. Further, the higher than anticipated weight loss and increased liver weight, compared to previous studies using similar doses, highlight the potential importance of the route and duration of exposure, contributing to the total accumulated dose, in assessing the toxicity of PFOA.


Assuntos
Caprilatos/toxicidade , Citocinas/metabolismo , Fluorcarbonetos/toxicidade , Imunoglobulina M/metabolismo , Animais , Corticosterona/metabolismo , Citocinas/genética , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hemocianinas/imunologia , Camundongos
2.
Chem Biol Interact ; 345: 109564, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34161785

RESUMO

Suppressive effect of bis (3-amino-2-pyridine) diselenide (BAPD) on psychiatric disorders - atopic dermatitis (AD) comorbidity in mice was investigated. To sensitize the animals, 2,4-dinitrochlorobenzene (DNCB) was applied to their dorsal skin on days 1-3. Mice were challenged with DNCB on their ears and dorsal skin on days 14, 17, 20, 23, 26, and 29. BAPD and Dexamethasone were administered to the animals, from days 14-29, and skin severity scores and behavioral tests were determined. Oxidative stress and inflammatory parameters were evaluated on the dorsal skin of mice. Na+, K+-ATPase activity and corticosterone levels were determined in hippocampus/cerebral cortex and plasma of mice, respectively. BAPD improved cutaneous damage, scratching behavior, inflammatory and oxidative stress markers. BAPD showed anxiolytic- and antidepressant-like effects and restored Na+, K+-ATPase activity and corticosterone levels. The present study was performed using female mice due the susceptibility for this disease. But, the evaluation of AD model in male mice would help to verify whether the male gender has the same predisposition to present this pathology. Our data demonstrated the suppressive effect of BAPD on psychiatric disorders - AD comorbidity by regulating inflammatory and oxidative status in mice.


Assuntos
Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/epidemiologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Siloxanas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Comorbidade , Corticosterona/sangue , Corticosterona/metabolismo , Dermatite Atópica/complicações , Dermatite Atópica/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/complicações , Transtornos Mentais/complicações , Transtornos Mentais/metabolismo , Camundongos , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Siloxanas/uso terapêutico
3.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071053

RESUMO

Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Pregnanolona/fisiologia , Adaptação Fisiológica , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Doença Crônica , Corticosterona/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Retroalimentação Fisiológica , Feminino , Agonistas de Receptores de GABA-A/uso terapêutico , Humanos , Masculino , Modelos Biológicos , Pregnanolona/biossíntese , Receptores de GABA-A/fisiologia , Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Ácido gama-Aminobutírico/fisiologia
4.
Environ Toxicol Pharmacol ; 86: 103662, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33878450

RESUMO

Although considerable inter-individual variability exists in health effects associated with air pollutant exposure, underlying reasons remain unclear. We examined whether innate differences in stress axis function modify lung glucocorticoid and macrophage responses to ozone (O3). Highly-stress responsive Fischer (F344) and less responsive Lewis (LEW) rats were exposed for 4 h by nose-only inhalation to air or O3 (0.8 ppm). Ozone increased corticosterone recovered by bronchoalveolar lavage in both strains (F344 > LEW). Higher corticosterone in F344 was associated with a blunted response to O3 of macrophage pro-inflammatory genes compared to LEW. Pharmacological inhibition of O3-dependent corticosterone production in F344 enhanced the inflammatory gene response to O3, mimicking the LEW phenotype. Examination of potential impacts of glucocorticoids on macrophage function using a human monocyte-derived macrophage cell line (THP-1) showed that cortisol modified phagocytosis in a macrophage phenotype-dependent manner. Overall, our data implicate endogenous glucocorticoids in the regulation of pulmonary macrophage responses to O3.


Assuntos
Poluentes Atmosféricos/toxicidade , Pulmão/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Ozônio/toxicidade , Animais , Líquido da Lavagem Broncoalveolar/química , Corticosterona/metabolismo , Glucocorticoides/metabolismo , Humanos , Pulmão/metabolismo , Macrófagos/metabolismo , Masculino , Fagocitose/efeitos dos fármacos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Estresse Fisiológico , Células THP-1
5.
PLoS One ; 16(4): e0249281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33852609

RESUMO

Muskoxen (Ovibos moschatus), a taxonomically unique Arctic species, are increasingly exposed to climate and other anthropogenic changes. It is critical to develop and validate reliable tools to monitor their physiological stress response in order to assess the impacts of these changes. Here, we measured fecal glucocorticoid metabolite (FGM) levels in response to the administration of adrenocorticotropic hormone (ACTH) in the winter (1 IU/kg) and summer (2 IU/kg) using two enzyme immunoassays, one targeting primarily cortisol and the other targeting primarily corticosterone. Fecal cortisol levels varied substantially within and among individuals, and none of the animals in either challenge showed an increase in fecal cortisol following the injection of ACTH. By contrast, two of six (winter) and two of five (summer) muskoxen showed a clear response in fecal corticosterone levels (i.e., maximal percentage increase as compared to time 0 levels > 100%). Increases in fecal corticosterone post-ACTH injection occurred earlier and were of shorter duration in the summer than in the winter and fecal corticosterone levels were, in general, lower during the summer. These seasonal differences in FGM responses may be related to the use of different individuals (i.e., influence of sex, age, social status, etc.) and to seasonal variations in the metabolism and excretion of glucocorticoids, intestinal transit time, voluntary food intake, and fecal output and moisture content. Results from this study support using FGMs as a biomarker of hypothalamic-pituitary-adrenal axis activity in muskoxen, advance our understanding of the physiological adaptations of mammals living in highly seasonal and extreme environments such as the Arctic, and emphasize the importance of considering seasonality in other species when interpreting FGM levels.


Assuntos
Fezes/química , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Ruminantes/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Animais , Corticosterona/análise , Corticosterona/metabolismo , Glucocorticoides/análise , Hidrocortisona/análise , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Estações do Ano
6.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921780

RESUMO

Glucocorticoids (GCs) are hormones that are released in response to stressors and exhibit many activities, including immunomodulatory and anti-inflammatory activities. They are primarily synthesized in the adrenal gland but are also produced in peripheral tissues via regeneration of adrenal 11-oxo metabolites or by de novo synthesis from cholesterol. The present study investigated the influence of the microbiota on de novo steroidogenesis and regeneration of corticosterone in the intestine of germ-free (GF) and specific pathogen-free mice challenged with a physical stressor (anti-CD3 antibody i.p. injection). In the small intestine, acute immune stress resulted in increased mRNA levels of the proinflammatory cytokines IL1ß, IL6 and Tnfα and genes involved in de novo steroidogenesis (Stard3 and Cyp11a1), as well as in regeneration of active GCs from their 11-oxo metabolites (Hsd11b1). GF mice showed a generally reduced transcriptional response to immune stress, which was accompanied by decreased intestinal corticosterone production and reduced expression of the GC-sensitive marker Fkbp5. In contrast, the interaction between stress and the microbiota was not detected at the level of plasma corticosterone or the transcriptional response of adrenal steroidogenic enzymes. The results indicate a differential immune stress-induced intestinal response to proinflammatory stimuli and local corticosterone production driven by the gut microbiota.


Assuntos
Corticosterona/metabolismo , Microbioma Gastrointestinal/fisiologia , Intestino Delgado/metabolismo , 11-beta-Hidroxiesteroide Desidrogenases/genética , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Masculino , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Esteroides/metabolismo , Espectrometria de Massas em Tandem
7.
J Steroid Biochem Mol Biol ; 210: 105845, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33652098

RESUMO

Orthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD + LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.


Assuntos
Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/química , Receptores de Mineralocorticoides/metabolismo , Regulação Alostérica , Animais , Corticosterona/metabolismo , Corticosterona/farmacologia , Relação Dose-Resposta a Droga , Evolução Molecular , Células HEK293 , Antagonistas de Hormônios/farmacologia , Humanos , Hidrocortisona/metabolismo , Hidrocortisona/farmacologia , Mifepristona/farmacologia , Progesterona/administração & dosagem , Progesterona/metabolismo , Progesterona/farmacologia , Domínios Proteicos , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Tubarões , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/fisiologia
8.
PLoS One ; 16(3): e0248771, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33735311

RESUMO

Since 2012, studies in mice, rats, and humans have suggested that abnormalities in purinergic signaling may be a final common pathway for many genetic and environmental causes of autism spectrum disorder (ASD). The current study in mice was conducted to characterize the bioenergetic, metabolomic, breathomic, and behavioral features of acute hyperpurinergia triggered by systemic injection of the purinergic agonist and danger signal, extracellular ATP (eATP). Responses were studied in C57BL/6J mice in the maternal immune activation (MIA) model and controls. Basal metabolic rates and locomotor activity were measured in CLAMS cages. Plasma metabolomics measured 401 metabolites. Breathomics measured 98 volatile organic compounds. Intraperitoneal eATP dropped basal metabolic rate measured by whole body oxygen consumption by 74% ± 6% (mean ± SEM) and rectal temperature by 6.2˚ ± 0.3˚C in 30 minutes. Over 200 metabolites from 37 different biochemical pathways where changed. Breathomics showed an increase in exhaled carbon monoxide, dimethylsulfide, and isoprene. Metabolomics revealed an acute increase in lactate, citrate, purines, urea, dopamine, eicosanoids, microbiome metabolites, oxidized glutathione, thiamine, niacinamide, and pyridoxic acid, and decreased folate-methylation-1-carbon intermediates, amino acids, short and medium chain acyl-carnitines, phospholipids, ceramides, sphingomyelins, cholesterol, bile acids, and vitamin D similar to some children with ASD. MIA animals were hypersensitive to postnatal exposure to eATP or poly(IC), which produced a rebound increase in body temperature that lasted several weeks before returning to baseline. Acute hyperpurinergia produced metabolic and behavioral changes in mice. The behaviors and metabolic changes produced by ATP injection were associated with mitochondrial functional changes that were profound but reversible.


Assuntos
Transtorno do Espectro Autista/metabolismo , Comportamento Animal , Metabolômica , Purinas/metabolismo , Doença Aguda , Trifosfato de Adenosina/metabolismo , Animais , Temperatura Corporal , Quimiocinas/metabolismo , Corticosterona/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo
9.
Psychopharmacology (Berl) ; 238(6): 1687-1701, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33649967

RESUMO

RATIONALE: Over the past decade, adolescent cigarette smoking has been declining. However, adolescent nicotine consumption via electronic cigarettes is rapidly gaining popularity. Earlier onset nicotine use is associated with increased risk of dependence. A bidirectional relationship between nicotine and stress exists; perceived stress is a predictor for nicotine use, and stress reduction is a commonly reported reason for using nicotine. OBJECTIVES: We assessed the prolonged impact of adolescent high-dose nicotine and/or footshock exposure on adult nicotine self-administration, anxiety-like behaviour, and hormonal responsivity. METHODS: During adolescence (postnatal day [P]28-56) male Sprague-Dawley rats were assigned to one of five groups: saline (SALPRE: 1 ml/kg, SC, every day), nicotine (NICPRE: 1 mg/kg, SC, alternating daily with saline; 14 total nicotine injections), footshock (SHOCKPRE: 8 of 0.5 s, 0.8 mA alternating sessions; saline every day), or combination nicotine and footshock (NIC+SHOCK: concurrent and alternating daily with saline, or NIC-SHOCK: alternating with saline on shock sessions). On P70, one cohort underwent spontaneous intravenous nicotine self-administration (0.03 mg/kg/infusion); another cohort was assessed for open-field behaviour (P71), then corticosterone (CORT) response to nicotine or footshock in adulthood (P72-73). RESULTS: Intermittent adolescent nicotine or footshock alone (NICPRE and SHOCKPRE) did not potentiate adult spontaneous nicotine intake compared to SALPRE. However, both combination groups (NIC+SHOCK, NIC-SHOCK) showed increased adult nicotine consumption without associated differences in baseline anxiety-like behaviour or CORT response. CONCLUSIONS: Adolescent nicotine and footshock stressors have a synergistic effect on adult nicotine consumption, enhancing nicotine intake. Avenues toward reducing stress in adolescent nicotine users may provide opportunities to reduce vulnerability to adult nicotine consumption.


Assuntos
Ansiedade/psicologia , Comportamento de Procura de Droga/fisiologia , Nicotina/administração & dosagem , Animais , Corticosterona/metabolismo , Sistemas Eletrônicos de Liberação de Nicotina , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração
10.
Hum Cell ; 34(2): 400-418, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33532907

RESUMO

This study aimed to investigate the changes associated with acute systemic hypoxia in the endocrine system, particularly in pancreatic tissues. The investigation was based on macroscopic, pathohistological, biochemical, and molecular biological findings in cell lines and human cadavers. The results showed that cases of death due to asphyxia more frequently showed severe subcapsular/interstitial hemorrhage versus the other causes of death. Histological examination showed that asphyxia cases were associated with severe morphological changes. Although measured insulin levels in the asphyxia were higher compared to other causes of death, no differences were noted for the glucagon and amylase levels with regard to the cause of death. Increased blood insulin levels were not associated with macro- and micromorphological changes, and did not show any association with glucose or cortisol levels. The experiment conducted under hypoxic conditions in cultured cells demonstrated that insulin mRNA expression and insulin protein levels peaked at 10 min after hypoxia exposure. However, there were no changes in either the amylase mRNA or protein levels. Corticosterone level peaked at 120 min after exposure to hypoxic conditions. Overall, acute systemic hypoxic conditions can directly affect the mechanisms involved in pancreatic insulin secretion.


Assuntos
Asfixia/patologia , Hipóxia/patologia , Pâncreas/metabolismo , Pâncreas/patologia , Doença Aguda , Asfixia/metabolismo , Cadáver , Linhagem Celular , Corticosterona/metabolismo , Feminino , Humanos , Hipóxia/metabolismo , Insulina/metabolismo , Masculino
11.
Aging (Albany NY) ; 13(5): 6681-6701, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33621199

RESUMO

Chronic Kidney Disease (CKD) and neurodegenerative diseases are aging-related diseases. CKD with declined renal function is associated with an elevation of circulating indoxyl sulfate, a metabolite synthesized by gut microbes. We explored the roles of gut microbial metabolites in linking with Central Nervous System (CNS) diseases by administrating indoxyl sulfate intraperitoneally to male C57BL/6 mice with unilateral nephrectomy. Upon exposure, the accumulation of indoxyl sulfate was noted in the blood, prefrontal cortical tissues, and cerebrospinal fluid. Mice showed behavioral signs of mood disorders and neurodegeneration such as anxiety, depression, and cognitive impairment. Those behavioral changes were accompanied by disturbed neuronal survival, neural stem cell activity, expression of Brain-Derived Neurotrophic Factor, serotonin, corticosterone, and Repressor Element-1 Silencing Transcription Factor, and post-receptor intracellular signaling, as well as upregulated oxidative stress and neuroinflammation. Uremic toxin adsorbent AST-120 improved the above mentioned changes. Intriguingly, intracerebroventricular indoxyl sulfate administration only caused limited alterations in the normal mice and the alterations were reversed by aryl hydrocarbon receptor antagonism. The findings suggest pathogenic roles of indoxyl sulfate in the development of CNS diseases, and highlight gut microbiota as alternative targets for intervention with the aim of slowing down the progression of CKD and decreasing CNS complications.


Assuntos
Comportamento Animal/efeitos dos fármacos , Indicã/farmacologia , Nefrectomia , Afeto/efeitos dos fármacos , Animais , Ansiedade/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carbono/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Corticosterona/metabolismo , Depressão/induzido quimicamente , Indicã/análise , Injeções Intraperitoneais , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Oxidativo , Óxidos/farmacologia , Córtex Pré-Frontal/química , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/metabolismo , Insuficiência Renal Crônica , Proteínas Repressoras/metabolismo , Serotonina/metabolismo
12.
J Pharmacol Exp Ther ; 377(1): 108-120, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33526603

RESUMO

Aldosterone, which regulates renal salt retention, is synthesized in adrenocortical mitochondria in response to angiotensin II. Excess aldosterone causes myocardial injury and heart failure, but potential intracardiac aldosterone synthesis has been controversial. We hypothesized that the stressed heart might produce aldosterone. We used blue native gel electrophoresis, immunoblotting, protein crosslinking, coimmunoprecipitations, and mass spectrometry to assess rat cardiac aldosterone synthesis. Chronic infusion of angiotensin II increased circulating corticosterone levels 350-fold and induced cardiac fibrosis. Angiotensin II doubled and telmisartan inhibited aldosterone synthesis by heart mitochondria and cardiac production of aldosterone synthase (P450c11AS). Heart aldosterone synthesis required P450c11AS, Tom22 (a mitochondrial translocase receptor), and the intramitochondrial form of the steroidogenic acute regulatory protein (StAR); protein crosslinking and coimmunoprecipitation studies showed that these three proteins form a 110-kDa complex. In steroidogenic cells, extramitochondrial (37-kDa) StAR promotes cholesterol movement from the outer to inner mitochondrial membrane where cholesterol side-chain cleavage enzyme (P450scc) converts cholesterol to pregnenolone, thus initiating steroidogenesis, but no function has previously been ascribed to intramitochondrial (30-kDa) StAR; our data indicate that intramitochondrial 30-kDa StAR is required for aldosterone synthesis in the heart, forming a trimolecular complex with Tom22 and P450c11AS. This is the first activity ascribed to intramitochondrial StAR, but how this promotes P450c11AS activity is unclear. The stressed heart did not express P450scc, suggesting that circulating corticosterone (rather than intracellular cholesterol) is the substrate for cardiac aldosterone synthesis. Thus, the stressed heart produced aldosterone using a previously undescribed intramitochondrial mechanism that involves P450c11AS, Tom22, and 30-kDa StAR. SIGNIFICANCE STATEMENT: Prior studies of potential cardiac aldosterone synthesis have been inconsistent. This study shows that the stressed rat heart produces aldosterone by a novel mechanism involving aldosterone synthase, Tom22, and intramitochondrial steroidogenic acute regulatory protein (StAR) apparently using circulating corticosterone as substrate. This study establishes that the stressed rat heart produces aldosterone and for the first time identifies a biological role for intramitochondrial 30-kDa StAR.


Assuntos
Aldosterona/biossíntese , Citocromo P-450 CYP11B2/metabolismo , Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Fosfoproteínas/metabolismo , Animais , Linhagem Celular , Corticosterona/metabolismo , Masculino , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley
13.
J Exp Zool A Ecol Integr Physiol ; 335(3): 301-310, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33411403

RESUMO

Environmental sex determination (ESD) is common among ectothermic vertebrates. The stress axis and production of stress hormones (corticosteroids) regulates ESD in fish, but evidence of a similar influence in reptiles is sparse and conflicting. The central bearded dragon (Pogona vitticeps) has a system of sex determination involving the interplay between sex chromosomes (ZZ/ZW female heterogamety) and the thermal environment. High egg incubation temperatures induce sex reversal of the ZZ genotype, feminizing chromosomally male individuals. Here we show that corticosterone elevation is not associated with sex reversal in the central bearded dragon, either during embryonic development or adulthood. We also demonstrate experimentally that sex determination is not affected by corticosterone injection into the yolk. This strongly suggests that stress axis upregulation by high temperature during incubation does not cause sex reversal in P. vitticeps. Our work is in general agreement with other research in reptiles, which suggests that the stress axis does not mediate sex in reptiles with ESD. Alternative biological systems may be responsible for capturing environmental conditions during reptile development, such as cellular calcium and redox regulation or the action of temperature-sensitive splicing factors.


Assuntos
Corticosterona/metabolismo , Lagartos/metabolismo , Processos de Determinação Sexual , Temperatura , Animais , Embrião não Mamífero/fisiologia , Desenvolvimento Embrionário , Estresse Fisiológico
14.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445547

RESUMO

The present study explored the hypothesis that an adverse intrauterine environment caused by maternal undernutrition (MUN) acted through corticosteroid-dependent and -independent mechanisms to program lasting functional changes in the neonatal cerebrovasculature and vulnerability to mild hypoxic-ischemic (HI) injury. From day 10 of gestation until term, MUN and MUN-metyrapone (MUN-MET) group rats consumed a diet restricted to 50% of calories consumed by a pair-fed control; and on gestational day 11 through term, MUN-MET groups received drinking water containing MET (0.5 mg/mL), a corticosteroid synthesis inhibitor. P9/P10 pups underwent unilateral carotid ligation followed 24 h later by 1.5 h exposure to 8% oxygen (HI treatment). An ELISA quantified MUN-, MET-, and HI-induced changes in circulating levels of corticosterone. In P11/P12 pups, MUN programming promoted contractile differentiation in cerebrovascular smooth muscle as determined by confocal microscopy, modulated calcium-dependent contractility as revealed by cerebral artery myography, enhanced vasogenic edema formation as indicated by T2 MRI, and worsened neurobehavior MUN unmasked HI-induced improvements in open-field locomotion and in edema resolution, alterations in calcium-dependent contractility and promotion of contractile differentiation. Overall, MUN imposed multiple interdependent effects on cerebrovascular smooth muscle differentiation, contractility, edema formation, flow-metabolism coupling and neurobehavior through pathways that both required, and were independent of, gestational corticosteroids. In light of growing global patterns of food insecurity, the present study emphasizes that infants born from undernourished mothers may experience greater risk for developing neonatal cerebral edema and sensorimotor impairments possibly through programmed changes in neonatal cerebrovascular function.


Assuntos
Córtex Cerebral/irrigação sanguínea , Corticosterona/metabolismo , Transtornos da Nutrição Fetal/etiologia , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/metabolismo , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Animais , Biomarcadores , Corticosterona/sangue , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/patologia , Imageamento por Ressonância Magnética , Microscopia Confocal , Gravidez , Ratos
15.
Neurosci Lett ; 746: 135618, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33429002

RESUMO

Stress is a common seizure trigger in persons with epilepsy. The body's physiological response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and involves a hormonal cascade that includes corticotropin releasing hormone (CRH), adrenocorticotropin releasing hormone (ACTH) and the release of cortisol (in humans and primates) or corticosterone (in rodents). The prolonged exposure to stress hormones may not only exacerbate pre-existing medical conditions including epilepsy, but may also increase the predisposition to psychiatric comorbidities. Hyperactivity of the HPA axis negatively impacts the structure and function of the temporal lobe of the brain, a region that is heavily involved in epilepsy and mood disorders like anxiety and depression. Seizures themselves damage temporal lobe structures, further disinhibiting the HPA axis, setting off a vicious cycle of neuronal damage and increasing susceptibility for subsequent seizures and psychiatric comorbidity. Treatments targeting the HPA axis may be beneficial both for epilepsy and for associated stress-related comorbidities such as anxiety or depression. This paper will highlight the evidence demonstrating dysfunction in the HPA axis associated with epilepsy which may contribute to the comorbidity of psychiatric disorders and epilepsy, and propose treatment strategies that may dually improve seizure control as well as alleviate stress related psychiatric comorbidities.


Assuntos
Epilepsia/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Transtornos Mentais/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/antagonistas & inibidores , Hormônio Adrenocorticotrópico/metabolismo , Animais , Anticonvulsivantes/administração & dosagem , Corticosterona/antagonistas & inibidores , Corticosterona/metabolismo , Desoxicorticosterona/antagonistas & inibidores , Desoxicorticosterona/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Resultado do Tratamento
16.
Horm Behav ; 127: 104884, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33171133

RESUMO

Corticosterone affects physiology and behavior both during normal daily processes but also in response to environmental challenges and is known to mediate life history trade-offs. Many studies have investigated patterns of corticosterone production at targeted times of year, while ignoring underlying annual profiles. We aimed to understand the annual regulation of hypothalamic-pituitary-adrenal (HPA) axis function of both migrant (Zonotrichia leucophrys gambelii; n = 926) and resident (Z. l. nutalli; n = 688) subspecies of white-crowned sparrow and how it is influenced by environmental conditions - wind, precipitation, and temperature. We predicted that more dramatic seasonal changes in baseline and stress-induced corticosterone would occur in migrants to precisely time the onset of breeding and cope with environmental extremes on their arctic breeding grounds, while changes in residents would be muted as they experience a more forgiving breeding schedule and comparatively benign environmental conditions in coastal California. During the course of a year, the harshest conditions were experienced the summer breeding grounds for migrants, at which point they had higher corticosterone levels compared to residents. For residents, the winter months coincided with harshest conditions at which point they had higher corticosterone levels than migrants. For both subspecies, corticosterone tended to rise as environmental conditions became colder and windier. We found that the annual maxima in stress-induced corticosterone occurred prior to egg lay for all birds except resident females. Migrants had much higher baseline and acute stress-induced corticosterone during breeding compared to residents; where in a harsher environment the timing of the onset of reproduction is more critical because the breeding season is shorter. Interestingly, molt was the only stage within the annual cycle in which subspecies differences were absent suggesting that a requisite reduction in corticosterone may have to be met for feather growth. These data suggest that modulation of the HPA axis is largely driven by environmental factors, social cues, and their potential interactions with a genetic program.


Assuntos
Córtex Suprarrenal/fisiologia , Migração Animal/fisiologia , Estações do Ano , Pardais/fisiologia , Animais , Regiões Árticas , Corticosterona/metabolismo , Feminino , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Muda/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Reprodução/fisiologia , Estresse Fisiológico/fisiologia , Temperatura
17.
Horm Behav ; 127: 104874, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33191199

RESUMO

Current food supply is a major driver of timing of breeding in income-breeding animals, likely because increased net energy balance directly increases reproductive hormones and advances breeding. In capital breeders, increased net energy balance increases energy reserves, which eventually leads to improved reproductive readiness and earlier breeding. To test the hypothesis that phenology of income-breeding birds is independent of energy reserves, we conducted an experiment on food-supplemented ("fed") and control female black-legged kittiwakes (Rissa tridactyla). We temporarily increased energy costs (via weight handicap) in a 2 × 2 design (fed/unfed; handicapped/unhandicapped) during the pre-laying period and observed movement via GPS-accelerometry. We measured body mass, baseline hormones (corticosterone; luteinising hormone) before and after handicap manipulation, and conducted a gonadotropin-releasing hormone challenge. Females from all treatment groups foraged in similar areas, implying that individuals could adjust time spent foraging, but had low flexibility to adjust foraging distance. Consistent with the idea that income breeders do not accumulate reserves in response to increased food supply, fed birds remained within an energy ceiling by reducing time foraging instead of increasing energy reserves. Moreover, body mass remained constant until the onset of follicle development 20 days prior to laying regardless of feeding or handicap, implying that females were using a 'lean and fit' approach to body mass rather than accumulating lipid reserves for breeding. Increased food supply advanced endocrine and laying phenology and altered interactions between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, but higher energy costs (handicap) had little effect. Consistent with our hypothesis, increased food supply (but not net energy balance) advanced endocrine and laying phenology in income-breeding birds without any impact on energy reserves.


Assuntos
Charadriiformes/fisiologia , Abastecimento de Alimentos , Hormônios Gonadais/metabolismo , Comportamento Sexual Animal/fisiologia , Animais , Aves/fisiologia , Composição Corporal , Corticosterona/metabolismo , Metabolismo Energético/fisiologia , Comportamento Exploratório/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Alimentos , Hormônio Liberador de Gonadotropina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hormônio Luteinizante/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Reprodução/fisiologia , Fatores de Tempo
18.
Gen Comp Endocrinol ; 300: 113640, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017585

RESUMO

A common response to parasite infestations is increased production of glucocorticoid hormones that regulate immune function. We examined relationships between ectoparasite infestations and fecal corticosterone metabolites (FCM) in deer mice (Peromyscus maniculatus). Furthermore, we experimentally removed fleas to determine if reductions in ectoparasites affected FCM production. Individuals were assigned to control (no flea removal) or treatment (anti-flea application, physical combing) groups and individuals were recaptured to assess changes in FCM concentrations. There was a significant and negative effect of number of anti-flea treatment applications on FCM concentrations of deer mice. However, models including host biology traits and environmental predictors had a better model fit compared to models containing ectoparasite predictors. In particular, there was a significant relationship of deer mouse FCM with date and host age, where glucocorticoid production decreased towards the end of the breeding season and increased with age. Overall, adverse events associated with reproduction and age class, rather than ectoparasites, may be more important to variation in glucocorticoids of deer mice.


Assuntos
Envelhecimento/fisiologia , Corticosterona/metabolismo , Parasitos/fisiologia , Peromyscus/parasitologia , Reprodução/fisiologia , Estações do Ano , Animais , Fezes/química , Feminino , Modelos Lineares , Masculino , Metaboloma , Sifonápteros/fisiologia
19.
Gen Comp Endocrinol ; 300: 113639, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33017588

RESUMO

When vertebrates are exposed to stressors, the subsequent acute increase in glucocorticoids by the hypothalamic-pituitaryadrenal (HPA) axis triggers a suite of adaptive responses, including mobilization of stored energy and repression of non-essential processes. However, chronic exposure to high concentrations of glucocorticoids can lead to metabolic dysregulation, impaired immune function, and cognitive decline. In developing young, this hormonal stress response shows considerable variation. Generally, the physiological stress response of young of precocial species is comparable to that of adults, whereas offspring of altricial species exhibit an attenuated response compared to adults. The developmental hypothesis of the HPA axis proposes that the dampened stress response in dependent offspring is an adaptive response to avoid the negative effects of elevated glucocorticoids, particularly in altricial species where young lack the ability to mitigate stressful stimuli.We aimed to test the developmental hypothesis in a tropical avian species, the lance-tailed manakin (Chiroxiphia lanceolata). We predicted that nestlings of this altricial species should have a dampened corticosterone response, in both magnitude and duration, compared to that of adults. We also predicted that recently fledged hatch-year birds would display a response intermediate to that of adults and nestlings. We quantified circulating corticosterone levels in adults, recently fledged hatch-year birds, and 11-day-old nestlings using a standardized capture and restraint protocol. Nestlings showed a lower maximal corticosterone response and faster negative feedback compared to adults. Further, five post-fledging hatch-year birds showed a feedback response intermediate to those of nestlings and adults. However, we caution against generalizing about fledgling responses beyond this study due to the small sample (n = 5). Interestingly, lance-tailed manakin nestlings appear to return to baseline concentrations faster than nestlings of temperate species. These results support the developmental hypothesis of the HPA axis explaining variation in stress response. This study is the first to assess the development of the hormonal stress response in nestlings of a tropical bird, which is of interest because of our still-developing understanding of how tropical and temperate species differ physiologically. Finally, findings here underscore the importance of validating and adjusting sampling protocols that quantify nestling stress responses, as sampling timelines identified for adults may underestimate the magnitude of the nestling stress response.


Assuntos
Corticosterona/metabolismo , Retroalimentação , Sistema Hipotálamo-Hipofisário/metabolismo , Passeriformes/crescimento & desenvolvimento , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Corticosterona/sangue , Modelos Lineares , Masculino , Passeriformes/sangue , Reprodutibilidade dos Testes , Estresse Fisiológico
20.
Neurosci Lett ; 740: 135362, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166635

RESUMO

Nitric oxide (NO) has been implicated as an important neurotransmitter in stress responses and sleep regulatory processes. However, the role of NO in the relationship between stress and sleep remains unclear. The medial septum (MS) and vertical diagonal band (VDB), regions of the basal forebrain involved in sleep regulation, contain nitric oxide synthase (NOS) producing neurons. Additionally, NOS neurons in the dorsal raphe nucleus (DRN) encode information about stress duration. The role of nitrergic neurons in these regions in subserving sex-specific responses to stress and sleep loss has yet to be elucidated. In this study, NADPH-d, an index of NOS activity, was used to examine the effects of acute restraint stress and sleep loss on NOS activity in the MS, VDB, and DRN. We show that NOS activity in response to restraint stress, total sleep deprivation (TSD), and partial sleep restriction (PSR) differs based on sex and region. Initial analysis showed no effect of restraint stress or TSD on NOS activity in the basal forebrain. However, investigation of each sex separately revealed that restraint stress and TSD significantly decrease NOS activity in the MS of females, but not males. Interestingly, the difference in NOS activity between restraint stress and TSD in females was not significant. Furthermore, PSR was not sufficient to affect NOS activity in males or females. These data suggest that restraint stress and sleep loss regulate NOS activation in a sex-dependent manner, and that the NOS stress response in females may be mediated by sleep loss.


Assuntos
Óxido Nítrico , Transdução de Sinais , Privação do Sono/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Corticosterona/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADP/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Prosencéfalo/enzimologia , Núcleos da Rafe/enzimologia , Restrição Física , Caracteres Sexuais
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