No description available.

No / Human aging involves a gradual decrease in cellular integrity that contributes to multiple complex disorders such as neurodegenerative disorders, cancer, diabetes, and cardiovascular diseases. Genome-wide association studies (GWAS) play a key role in discovering genetic variations that may contribute towards disease vulnerability. However, mostly disease-associated SNPs lie within non-coding part of the genome; majority of the variants are also present in linkage disequilibrium (LD) with the genome-wide significant SNPs (GWAS lead SNPs). Overall 600 SNPs were analyzed, out of which 291 returned RegulomeDB scores of 1-6. It was observed that just 4 out of those 291 SNPs show strong evidence of regulatory effects (RegulomeDB score < 3), while none of them includes any GWAS lead SNP. Nevertheless, this study demonstrates that by combining ENCODE project data along with GWAS reported information will provide important insights on the impact of a genetic variant-moving from GWAS towards understanding disease pathways. It is noteworthy that both genome-wide significant SNPs as well as the SNPs in LD must be considered for future studies; this may prove to be crucial in deciphering the potential regulatory elements involved in complex disorders and aging in particular.

Abstract Glucocorticoids are the most important and widely used treatment modality in dermatology. A large variety of topical as well as systemic preparations is available. Most patients treated with glucocorticoids respond quickly to the treatment, but some are considered insensitive or even resistant to glucocorticoid therapy. Currently, there is no known measurable variable, through which the response can be predicted. Glucocorticoids mediate their actions through glucocorticoid receptors (GR). Several isoforms of GR exist, but the α (GRα) and β (GRβ) isoforms are clinically the most important. Based on previous studies, it has been proposed that the abundance of GR isoforms or the GRβ: GRα –ratio could affect individual responsiveness to corticosteroid treatment. In particular, up-regulation of GRβ expression has been shown to be linked to resistance to corticosteroid treatment. This thesis comprises three sub-studies. Firstly, we wanted to determine whether GRα and GRβ are expressed in inflammatory skin diseases. Secondly, we examined if the expression is altered by corticosteroid treatment in eczema atopicum, bullous pemphigoid and psoriasis. Finally, we measured the effects of a topical vitamin D3 analogue (calcipotriol) combined with betamethasone compared with betamethasone monotherapy on inflammatory biomarkers of psoriasis. Our studies provide detailed novel data about the expression of GRα and GRβ. GRα and GRβ were shown to be expressed in the blood lymphocytes and lesional skin of patients with eczema atopicum, bullous pemphigoid and psoriasis, as well as in the skin of patients with eczema nummulare, lichen simplex chronicus and lichen ruber planus. Systemic corticosteroid treatment was shown to affect the expression of GRα and GRβ in eczema atopicum and bullous pemphigoid, but the inconsistent variation in their expression between patients prevented us from drawing firm conclusions. Neither GRα nor GRβ as a single marker were found to be a suitable predictor of corticosteroid responsiveness. Clinical and laboratory analyses showed that topical treatment of psoriasis with calcipotriol/betamethasone combination ointment is more beneficial measured by both than betamethasone monotherapy. / Tiivistelmä Glukokortikoideja (”kortisoni”) käytetään tulehduksellisten ihotautien hoidossa paikallisesti tai systeemisenä lääkkeenä. Suurin osa potilaista reagoi hoitoon nopeasti, mutta osalla hoitovaste on heikompi tai ilmenee hitaasti. Tällä hetkellä ei tunneta keinoja ennustaa luotettavasti kortisonihoidon vastetta. Glukokortikoidit vaikuttavat elimistössä glukokortikoidireseptorien (GR) kautta. Glukokortikoidireseptorista tunnetaan useita alatyyppejä, joista tärkeimmät ovat α (GRα) ja β (GRβ). Aiemman tiedon pohjalta on pidetty mahdollisena, että GR-alatyyppien suhteella tai määrällä on merkitystä kortisonivasteen syntymisessä. Erityisesti on arveltu, että ylimäärä GRβ:aa voisi estää kortisonihoidon vaikutusta. Tässä väitöskirjassa tavoitteena on ollut selvittää, tapahtuuko GR-alatyyppien ilmenemisessä muutoksia tulehduksellisia ihosairauksia sairastavilla potilailla sekä tutkia, miten kortisonihoito vaikuttaa GR-tasoihin atooppista ihottumaa, pemfigoidia ja psoriaasia sairastavilla potilailla. Lisäksi olemme verranneet paikallishoitoa pelkällä kortisonivoiteella D-vitamiinijohdos kalsipotriolin ja kortisonin yhdistelmähoitoon psoriaatikoilla. Tutkimus on antanut uutta yksityiskohtaista tietoa GRα:n ja GRβ:n esiintymisestä ihossa ja tulehdussoluissa ihosairauksia sairastavilla potilailla. Tutkimustulosten perusteella voidaan todeta, että GRα ja GRβ esiintyvät atooppista ihottumaa, pemfigoidia ja psoriaasia sairastavien potilaiden ihossa ja veren tulehdussoluissa sekä nummulaari-ihottumaa, neurodermatiittia ja punajäkälää sairastavien potilaiden ihossa. Suun kautta annettu kortisonihoito vaikuttaa GRα- ja GRβ–lähetti-RNA:n ilmenemiseen, mutta potilaskohtaiset erot ovat suuret, eikä kumpikaan, GRα tai GRβ, sovellu yksinään ennustamaan kortisonihoidon vastetta. Paikallisella kortisonihoidolla D-vitamiinijohdos kalsipotrioliin yhdistettynä on suotuisampi vaikutus psoriaasin tulehduksellisiin välittäjäaineisiin ja tulehdussoluihin kuin pelkällä paikallisella kortisonihoidolla.

Les neutrophiles sont généralement considérés résistants aux glucocorticoïdes. Cependant, peu d’études comparant l’effet de ces drogues sur les neutrophiles et les autres leucocytes sanguins (monocytes, lymphocytes et éosinophiles) ont été rapportées. Dans notre étude, nous avons évalué la réponse aux glucocorticoïdes de ces deux populations cellulaires chez le cheval et l’homme. Les cellules, préalablement isolées du sang de 6 chevaux et 4 sujets humains sains, ont été incubées pendant 5 h en présence de lipopolysaccharide (LPS; 100 ng/mL) seul ou combiné avec de l’hydrocortisone, de la prednisolone ou de la dexaméthasone (10-8M et 10-6M). L’expression d’ARNm pour l’IL-1β, le TNF-α, l’IL-8, la glutamine synthétase et le récepteur α des glucocorticoïdes (GR-α) a été quantifiée par qPCR. Les neutrophiles équins ont également été incubés pendant 20 h en présence de ces 3 glucocorticoïdes et la survie cellulaire a été évaluée par cytométrie de flux et microscopie optique. Nous avons démontré que les glucocorticoïdes inhibaient l’expression des gènes pro-inflammatoires induite par le LPS pour les deux populations cellulaires chez les deux espèces étudiées. L’expression de la glutamine synthétase était également significativement augmentée par les glucocorticoïdes chez les neutrophiles et les autres leucocytes sanguins équins. De manière générale, l’intensité de la réponse aux glucocorticoïdes s’est avérée similaire dans les 2 populations leucocytaires et chez les deux espèces. Les glucocorticoïdes augmentaient également la survie des neutrophiles équins, phénomène également rapporté dans d’autres espèces. Ainsi, les glucococorticoïdes exercent des effets d’intensité comparable sur les neutrophiles et les autres leucocytes sanguins. Nous spéculons que la faible réponse à la corticothérapie observée lors de maladies inflammatoires chroniques neutrophiliques comme l’asthme sévère ou la Maladie Pulmonaire Obstructive Chronique (MPOC) ne s’explique pas par une corticorésistance intrinsèque des neutrophiles. / Neutrophils are generally considered resistant to glucocorticoids compared to other inflammatory cells. However, there are few studies comparing the effects of glucocorticoids in neutrophils and those of other blood leukocytes (monocytes, lymphocytes and eosinophils). In our study, we assessed glucocorticoid-responsiveness in equine and human peripheral blood neutrophils and in neutrophil-depleted leukocytes. Cells were isolated from 6 healthy horses and 4 human healthy subjects. They were incubated for 5 h with or without lipopolysaccharide (LPS; 100 ng/mL) alone or combined with hydrocortisone, prednisolone or dexamethasone (10-8M and 10-6M). IL-1β, TNF-α, IL-8, glutamine synthetase and Glucocorticoid Receptor α (GR-α) mRNA expression was quantified by qPCR. Equine neutrophils were also incubated for 20 h with or without the three glucocorticoids and cell survival was assessed by flow cytometry and light microscopy. We found that glucocorticoids down-regulated LPS-induced pro-inflammatory mRNA expression in both cell populations and species. These drugs also significantly increased glutamine synthetase gene expression in both equine cell populations. The magnitude of glucocorticoid response was generally similar in both cell populations and species. As reported in other species, glucocorticoids significantly increase the survival in equine neutrophils. Based on these results, it appears that glucocorticoids exert effects of similar magnitude on neutrophils and on other blood leukocytes. We speculate that the poor response to glucocorticoids observed in some chronic neutrophilic human diseases such as severe asthma or Chronic Obstructive Pulmonary Disease (COPD) is not explained by an inherent attenuated response of neutrophils to these drugs.

La NAFLD (non alcoholic fatty liver disease) ou stéatopathie dysmétabolique est la manifestation hépatique du syndrome métabolique. Elle regroupe l’ensemble des lésions hépatiques liées à l’obésité en dehors de toute consommation d’alcool : la stéatose, la NASH (non alcoholic steatohepatitis), la fibrose, la cirrhose et le carcinome hépatocellulaire. Les systèmes immunitaires inné et adaptatif participent activement à la pathologie. J’ai étudié deux axes : l’axe du récepteur des glucocorticoïdes-GILZ dans les cellules de Kupffer et CXCR4-CXCL12 dans les lymphocytes T CD4+.Les cellules de Kupffer (CK) jouent un rôle clé dans la pathologie de la NASH. GILZ (glucocorticoid induced leucine zipper) est exprimé par les monocytes/macrophages et est sous le contrôle du récepteur aux glucocorticoïdes (GR). De plus, GILZ intervient dans l’inhibition des processus inflammatoires. J’ai montré que l’obésité entraîne une diminution de l’expression du GR et de GILZ dans les CK. En utilisant du RU486, un antagoniste spécifique du GR, j’ai prouvé que la diminution de l’expression du GR entraîne la diminution de l’expression de GILZ et sensibilise les CK au LPS. Ce mécanisme joue un rôle déterminant dans le développement de l’inflammation hépatique au cours de l’obésité, en modulant la réponse inflammatoire des CK. Le recrutement de cellules inflammatoires dans le foie est un élément clé de la progression de la NASH. Les lymphocytes T CD4+ issus de souris obèses ont des propriétés chimiotactiques accrues dépendantes de CXCR4. J’ai montré que la NASH augmente les propriétés migratoires dépendantes de CXCR4 des lymphocytes T CD4+ chez l’homme et la souris dans trois modèles murins de NASH. Le traitement de souris obèses par de l’AMD3100, un antagoniste de CXCR4, permet de diminuer le recrutement hépatique de lymphocytes. L’augmentation du chimiotactisme des lymphocytes T CD4+ n’était pas dû, ni à une augmentation de l’expression de CXCR4 et CXCR7, ni même de CXCL12 au niveau du foie. J’ai montré que ce mécanisme dépendait de l’augmentation de l’affinité de CXCR4 pour CXCL12.Ainsi, j’ai mis en évidence deux axes participant à l’inflammation hépatique au cours de l’obésité. Ces axes représentent de nouvelles cibles thérapeutiques potentielles. / NAFLD (non alcoholic fatty liver disease) is the hepatic manifestation of metabolic syndrome. It encompasses the entire spectrum of obesity-related liver lesions : steatosis, NASH (non alcoholic steatohepatitis), fibrosis, cirrhosis and hepatocellular carcinoma. Innate and adaptative immune systems participate actively to the pathophysiology.I studied two axis : the glucocorticoid receptor-GILZ axis in Kupffer cells and CXCR4-CXCL12 in CD4+ T lymphocytes.Kupffer cells (KC) play a key role in pathophysiology of NASH. GILZ (glucocorticoid induced leucine zipper) is expressed by monocytes/macrophages and is under the control of glucocorticoid receptor (GR). Moreover, GILZ takes part in inhibition of inflammatory processes. I showed that obesity induces a decreased expression of GR and GILZ in KC. Using RU486, a GR antagonist, I proved that decreased expression of GR induces the decreased expression of GILZ and sensitize KC to LPS. This mechanism plays a decisive role in initiation of liver inflammation in obesity, modulating inflammatory response of KC. In obese mice, recruitment of inflammatory cells into the liver is a key element in the progression of NASH. CD4+ T lymphocytes from obese mice have enhanced CXCR4-dependent chemotactic properties. I showed that NASH enhances CXCR4-dependent chemotactic properties of CD4+ T lymphocytes in patients and in three mouse models of NASH. Obese mice treatment with AMD3100, a CXCR4 antagonist, decreases lymphocytes recruitement into the liver. Enhanced chemotactic properties of CD4+ T lymphocytes were not due to increased expressions of nor CXCR4 and CXCR7, neither CXCL12 in the liver. I showed that this mechanism was dependent of an increased affinity of CXCR4 to CXCL12.Therefore, I highlighted two axis participating to obesity-related liver inflammation. These axis represent new potential therapeutic targets.

Introdução: A deficiência da 21-hidroxilase (21-OHD) é um frequente erro herdado do metabolismo que resulta no comprometimento da síntese do cortisol e/ou aldosterona e aumento da produção de andrógenos. A doença é caracterizada por uma diversidade fenotípica, variando desde virilização pré-natal da genitália externa de fetos femininos e pós-natal em ambos os sexos, com ou sem perda de sal, até quadros assintomáticos. Em seu tratamento é necessária reposição com glicocorticoide para se evitar a insuficiência adrenocortical e os sinais de virilização. Um fino ajuste na dose diária do glicocorticoide é essencial para se evitar sub ou supertratamento, com o objetivo de preservar o potencial de estatura final e fertilidade. Entretanto, tem sido observada maior frequência de obesidade e outras comorbidades metabólicas nestes pacientes; porém, a prevalência destas complicações ainda não é conhecida, bem como se estariam associadas à exposição ao glicocorticoide e/ou com fatores genéticos. Objetivos: avaliar a frequência de obesidade e de síndrome metabólica (SM) em pacientes com 21OHD; caracterizar a distribuição alélica dos polimorfismos dos genes do receptor de glicocorticoide (NR3C1) e da enzima 11beta-hidroxiesteróide desidrogenase tipo I (HSD11B1), e correlacionar a distribuição destes polimorfismos com a presença das complicações metabólicas. Métodos: Foram selecionados 109 pacientes (60 PS/49 VS), sendo 41 crianças e adolescentes (idade média 11,4 ± 3,9 anos) e 68 adultos (idade média 28,4 ± 9 anos) em tratamento com glicocorticoide e com adequado controle hormonal. Pacientes com a forma PS também receberam fludrocortisona. Adequado controle foi caracterizado por concentração normal de atividade plasmática de renina e de andrógenos de acordo com o sexo e idade nos últimos 2 anos. A obesidade nos adultos foi definida pelo IMC >= 30 kg/m² e em crianças e adolescentes pelo IMC acima do percentil 95. Síndrome metabólica foi definida segundo o critério do National Cholesterol Education Program em adultos e crianças. História familiar de hipertensão arterial, diabetes, dislipidemia, obesidade e/ou doença cardiovascular também foi avaliada. Foram mensuradas glicemia, lipoproteínas, triglicérides, colesterol total e insulina. Os alelos BclI, A3669G, ER22/23EK e N363S do gene NR3C1 e o alelo 4436InsA do gene HSD11B1 foram genotipados e as análises de associação com os fenótipos foram realizadas por meio dos testes Chi-quadrado, t-studant e análise de regressão. As análises de correlação foram feitas utilizando o teste de correlação de Pearson. Resultados: Obesidade foi observada em 31,7% das crianças e 23,5% dos adultos. Síndrome metabólica foi observada em 14,6% das crianças e 7,3% dos adultos. A prevalência dos componentes da SM foi maior no grupo dos obesos quando comparada a de pacientes não obesos (crianças e adultos). Não houve correlação significante entre o IMC, sexo, forma clínica da 21-OHD, duração da terapia e dose de GC. História familiar positiva para obesidade, hipertensão, dislipidemia e doença cardiovascular foi mais frequente nos pacientes obesos quando comparada a de pacientes não obesos, em adultos e crianças. Os polimorfismos BclI, A3669G e 4436InsA foram identificados em 23,2%, 9,7% e 14,6% dos alelos das crianças, respectivamente, e nos adultos em 26,4%, 9,6% e 18,4% dos alelos, respectivamente. A variante A3669G foi associada à maiores concentrações de LDL-c em crianças quando comparada aos carreadores do alelo selvagem. Os pacientes adultos carreadores do polimorfismo BclI apresentaram maior IMC, circunferência abdominal e PAS quando comparados aos carreadores do alelo selvagem. Não observamos diferenças estatisticamente significantes no perfil metabólico entre pacientes carreadores e não carreadores do polimorfismo 4436InsA (adultos e crianças). Conclusão: observamos que pacientes 21-OHD possuem maior prevalência de obesidade, e o grupo pediátrico maior prevalência de SM em relação à população de referência, sendo ambas independentes da dose de glicocorticoide e do tempo do tratamento. A presença de perfil metabólico adverso esteve associada à obesidade e à predisposição genética, tais como história familiar e variantes genéticas do receptor de glicocorticoide / Introduction: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is a common autosomal recessive disorder that leads to decreased glucocorticoid secretion, with or without mineralocorticoid deficiency, and increased androgen production. The disease is characterized by phenotypic variability, including a severe form with prenatal virilization of the external genitalia in female fetuses and postnatal virilization in both sexes, with or without salt loss. Current therapy aims to provide adequate glucocorticoid (GC) replacement and to suppress the abnormal androgen secretion; mineralocorticoid replacement aims to control the renal salt balance to avoid adrenal crisis. Nevertheless, these therapeutic goals are difficult to achieve in practice due to the complexity of replicating the physiologic cortisol circadian rhythm. Increased prevalence of obesity, insulin resistance, hypertension and adverse lipid profile have been observed among CAH patients under GC therapy; however, the extent of its prevalence and also whether it is associated with the GC dose or with genetic factors are not known. Objectives: to evaluate the obesity and metabolic syndrome (SM) frequencies in 21-OHD patients; to characterize the allelic distribution of the NR3C1 and HSD11B1 polymorphisms, and to correlate with the metabolic profile. Methods: One hundred and nine patients (60SW/49SV) were selected, 41 being children and adolescents (mean age 11.4 ± 3.9 yrs) and 68 adults (mean age 28.4 ± 9 yrs) all of whom received GC treatment and had adequate hormonal control. SW patients also received fludrocortisone. Adequate hormonal control was characterized by normal plasmatic rennin activity and androgen levels according to age and sex for at least two years. Blood fasting was used to obtain glucose, lipoproteins, triglycerides, total cholesterol and insulin levels. Obesity in the adult group was defined by BMI >= 30 kg/m², and in the young group by BMI > 95th percentile. Metabolic syndrome was defined by the NCEP ATPIII criteria. Family history of the hypertension, diabetes, dyslipidemia, obesity and/or cardiovascular disease was also evaluated. The BclI, A3669G, ER22/23EK and N363S alleles of the NR3C1 gene and 4436InsA of the HSD11B1 gene were genotyped and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis. Correlation analyses were performed by Pearson correlation test. Results: obesity was observed in 31.7% of children and 23.5% of adults. SM was observed in 14.6% of young and 7.3% of adult patients. SM prevalence was higher in the obese group than the nonobese group (children and adults). There was no significant correlation between GC dose and BMI, sex, clinical form or treatment duration. Prevalence of family history of obesity, hypertension, dyslipidemia and cardiovascular disease was higher in the obese than in non-obese patients (children and adults). The BclI, A3669G and 4436InsA polymorphisms were found in 23.2%, 9.7% and 14.6% of the alleles in children, respectively and in 26.4%, 9.6% and 18.4% of the alleles in adults. The A3669G variant was associated to increased LDL-c levels in comparison with noncarriers in the young group. The BclI adult carriers presented higher BMI, abdominal circumference and systolic blood pressure in comparison with noncarriers. Statistically significant differences were not observed in the metabolic profile between carriers and non-carriers of the 4436InsA polymorphism (children and adults). Conclusion: in the present study, which analyzed the clinical and metabolic profile of 21-OHD patients, high obesity prevalence, independent of GC dose and treatment duration, was observed. Adverse metabolic profile was mainly associated with obesity and genetic predisposition, such as family history and NR3C1 polymorphisms

No description available.

No description available.

Les neutrophiles sont généralement considérés résistants aux glucocorticoïdes. Cependant, peu d’études comparant l’effet de ces drogues sur les neutrophiles et les autres leucocytes sanguins (monocytes, lymphocytes et éosinophiles) ont été rapportées. Dans notre étude, nous avons évalué la réponse aux glucocorticoïdes de ces deux populations cellulaires chez le cheval et l’homme. Les cellules, préalablement isolées du sang de 6 chevaux et 4 sujets humains sains, ont été incubées pendant 5 h en présence de lipopolysaccharide (LPS; 100 ng/mL) seul ou combiné avec de l’hydrocortisone, de la prednisolone ou de la dexaméthasone (10-8M et 10-6M). L’expression d’ARNm pour l’IL-1β, le TNF-α, l’IL-8, la glutamine synthétase et le récepteur α des glucocorticoïdes (GR-α) a été quantifiée par qPCR. Les neutrophiles équins ont également été incubés pendant 20 h en présence de ces 3 glucocorticoïdes et la survie cellulaire a été évaluée par cytométrie de flux et microscopie optique. Nous avons démontré que les glucocorticoïdes inhibaient l’expression des gènes pro-inflammatoires induite par le LPS pour les deux populations cellulaires chez les deux espèces étudiées. L’expression de la glutamine synthétase était également significativement augmentée par les glucocorticoïdes chez les neutrophiles et les autres leucocytes sanguins équins. De manière générale, l’intensité de la réponse aux glucocorticoïdes s’est avérée similaire dans les 2 populations leucocytaires et chez les deux espèces. Les glucocorticoïdes augmentaient également la survie des neutrophiles équins, phénomène également rapporté dans d’autres espèces. Ainsi, les glucococorticoïdes exercent des effets d’intensité comparable sur les neutrophiles et les autres leucocytes sanguins. Nous spéculons que la faible réponse à la corticothérapie observée lors de maladies inflammatoires chroniques neutrophiliques comme l’asthme sévère ou la Maladie Pulmonaire Obstructive Chronique (MPOC) ne s’explique pas par une corticorésistance intrinsèque des neutrophiles. / Neutrophils are generally considered resistant to glucocorticoids compared to other inflammatory cells. However, there are few studies comparing the effects of glucocorticoids in neutrophils and those of other blood leukocytes (monocytes, lymphocytes and eosinophils). In our study, we assessed glucocorticoid-responsiveness in equine and human peripheral blood neutrophils and in neutrophil-depleted leukocytes. Cells were isolated from 6 healthy horses and 4 human healthy subjects. They were incubated for 5 h with or without lipopolysaccharide (LPS; 100 ng/mL) alone or combined with hydrocortisone, prednisolone or dexamethasone (10-8M and 10-6M). IL-1β, TNF-α, IL-8, glutamine synthetase and Glucocorticoid Receptor α (GR-α) mRNA expression was quantified by qPCR. Equine neutrophils were also incubated for 20 h with or without the three glucocorticoids and cell survival was assessed by flow cytometry and light microscopy. We found that glucocorticoids down-regulated LPS-induced pro-inflammatory mRNA expression in both cell populations and species. These drugs also significantly increased glutamine synthetase gene expression in both equine cell populations. The magnitude of glucocorticoid response was generally similar in both cell populations and species. As reported in other species, glucocorticoids significantly increase the survival in equine neutrophils. Based on these results, it appears that glucocorticoids exert effects of similar magnitude on neutrophils and on other blood leukocytes. We speculate that the poor response to glucocorticoids observed in some chronic neutrophilic human diseases such as severe asthma or Chronic Obstructive Pulmonary Disease (COPD) is not explained by an inherent attenuated response of neutrophils to these drugs.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Organophosphorus compounds such as methyl-parathion are used in the various stages of production to control pests both in agricultural activity as in aquaculture. The mechanism of action of this type of compound is the inhibition of the enzyme acetylcholinesterase. The zebrafish (Danio rerio) has been increasingly used as an experimental model in varied fields such as development, genetics and pharmacological research. The methyl-parathion has been characterized as endocrine disruptor of the hypothalamic-pituitary-interrenal axis (HHI). An experiment was carried out of 96 hours of exposure of adult fish to the substance tested, at the concentration of 5.2 mg/L. Was evaluated the whole-body cortisol level in order to measure the endocrine response to a stressful event. Were also investigated the gene expression of glucocorticoid receptor (GR), steroidogenic acute regulatory protein (StAR) and heat shock protein 70 (HSP 70). Fish exposed that have undergone a stressor event demonstrated low levels of cortisol. In addition, the fish stressed and exposed to agro-chemical showed a decreased expression of the StAR, HSP 70 and GR genes. The data indicate that exposure to methyl-parathion causes a decrease in the ability to respond appropriately to a stressor. Fish that have an inability to produce a satisfactory answer by the HHI axis are not able to make the necessary metabolic and ion adjustments for recovery the homeostasis, getting vulnerable to stress caused by aquaculture practices or environmental changes. / Compostos organofosforados como o parationato metílico são utilizados nas diversas etapas de produção para controlar pragas tanto na atividade agrícola como na aquicultura. O mecanismo de ação desse tipo de composto é a inibição da enzima acetilcolinesterase. O peixe-zebra (Danio rerio) vem sendo cada vez mais usado como modelo experimental em variados campos, como desenvolvimento, genética e pesquisa farmacológica. O parationato metílico já foi caracterizado como interruptor endócrino do eixo hipotálamo-hipófise-interrenal (HHI). Foi realizado um experimento de 96 horas de exposição de peixes adultos à substância testada, na concentração de 5,2 mg/L. Foi avaliado o nível de cortisol de corpo inteiro, visando medir a resposta endócrina a um evento estressor. Também foram investigadas a expressão dos genes do receptor de glicocorticoide (GR), da proteína regulatória de esteroidogenese aguda (StAR) e a proteína do choque térmico 70 (HSP 70). Os peixes expostos que foram submetidos a um evento estressor demonstraram baixos níveis de cortisol de corpo inteiro. Além disso, os peixes estressados e expostos ao agroquímico apresentaram uma diminuição da expressão dos genes GR, StAR e HSP 70. Os dados indicam que a exposição ao parationato metílico provoca uma diminuição da capacidade de responder adequadamente a um evento estressor. Peixes que possuem uma incapacidade em produzir uma resposta satisfatória do eixo HHI, não são capazes de realizar os ajustes iônicos e metabólicos necessários à recuperação da homeostase, ficando vulneráveis ao estresse causado pelas práticas aquícolas ou por alterações ambientais.