Dibutyltin Disrupts Glucocorticoid Receptor Function and Impairs Glucocorticoid-Induced Suppression of Cytokine Production

BACKGROUND: Organotins are highly toxic and widely distributed environmental chemicals. Dibutyltin (DBT) is used as stabilizer in the production of polyvinyl chloride plastics, and it is also the major metabolite formed from tributyltin (TBT) in vivo. DBT is immunotoxic, however, the responsible targets remain to be defined. Due to the importance of glucocorticoids in immune-modulation, we investigated whether DBT could interfere with glucocorticoid receptor (GR) function. METHODOLOGY: We used HEK-293 cells transiently transfected with human GR as well as rat H4IIE hepatoma cells and native human macrophages and human THP-1 macrophages expressing endogenous receptor to study organotin effects on GR function. Docking of organotins was used to investigate the binding mechanism. PRINCIPAL FINDINGS: We found that nanomolar concentrations of DBT, but not other organotins tested, inhibit ligand binding to GR and its transcriptional activity. Docking analysis indicated that DBT inhibits GR activation allosterically by inserting into a site close to the steroid-binding pocket, which disrupts a key interaction between the A-ring of the glucocorticoid and the GR. DBT inhibited glucocorticoid-induced expression of phosphoenolpyruvate carboxykinase (PEPCK) and tyrosine-aminotransferase (TAT) and abolished the glucocorticoid-mediated transrepression of TNF-alpha-induced NF-kappaB activity. Moreover, DBT abrogated the glucocorticoid-mediated suppression of interleukin-6 (IL-6) and TNF-alpha production in lipopolysaccharide (LPS)-stimulated native human macrophages and human THP-1 macrophages. CONCLUSIONS: DBT inhibits ligand binding to GR and subsequent activation of the receptor. By blocking GR activation, DBT may disturb metabolic functions and modulation of the immune system, providing an explanation for some of the toxic effects of this organotin

Disruption of glucocorticoid and mineralocorticoid receptor-mediated responses by environmental chemicals

Glucocorticoids and mineralocorticoids are key endocrine hormones modulating essential physiological processes such as energy metabolism, cell growth and differentiation, maintenance of blood pressure and immune responses. Despite their importance and the fact that their impaired function has been associated with various diseases, there are only few studies on the potential disruption of glucocorticoid and mineralocorticoid action by xenobiotics. To facilitate the identification and characterization of such chemicals, we established cell-based assays to determine the impact of xenobiotics on different steps of corticosteroid hormone action. Screening of a small library of chemicals led to the identification of several compounds inhibiting the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) prereceptor enzymes 11 beta-HSD1 and/or 11 beta-HSD2 and of chemicals blocking the function of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). These findings build a basis to extend the search for chemicals acting on additional targets of the corticosteroid hormone pathway and to apply in silico prediction tools in combination with biological testing to screen large numbers of chemicals. The identification of chemicals interfering with corticosteroid action and the elucidation of the underlying molecular mechanisms are relevant with respect to the potential contribution to common diseases such as metabolic syndrome, immune diseases, brain disorders and cancer

Les images des passions adolescentes

Les recherches en neurosciences utilisant des sets de photographies d’expression faciale afin de tester, à l’aide des techniques d’imageries, les réactions émotionnelles des adolescent-e-s ont participé à établir un modèle neurobiologique de l’adolescence. Ce modèle, qui postule que la configuration cérébrale particulière à cette période de la vie soumet les jeunes personnes à un déficit de contrôle émotionnel, tend à s’imposer dans le domaine des sciences de l’adolescence, particulièrement en lien avec la question des prises de risque. Cet article propose d’investiguer le processus par lequel les neurosciences cognitives ont produit, à partir de portraits photographiques d’acteurs mimant des émotions, des stimuli valides qui permettent de rendre visible par le biais de l’IRMf une différence cérébrale discriminant d’une part les adolescent-e-s et les adultes et d’autre part les jeunes filles et les jeunes garçons dans la gestion de l’information émotionnelle. En effet, le cerveau émotionnel adolescent est construit selon deux hiérarchies enchâssées : si la différence d’âge fait figure de hiérarchie fondatrice, celle de sexe constitue un élément tantôt moteur tantôt modérateur à l’intérieur de celle-ci.Neuroscience research using sets of pictures of facial affect to test the emotional reactions of teenagers with fMRI has participated to construct a neurobiological model of adolescence. This model postulates that the particular brain configuration of young people indicates a lack of emotional control. This model tends to prevail in the sciences of adolescence, particularly in connection with the issue of risk taking. This paper investigates the process by which cognitive neuroscience, by using photographic portraits of actors mimicking emotions in fMRI studies, has produced valid stimuli that help to make visible a cerebral difference between adolescents and adults, as well as between girls and boys, in the management of emotional information. In effect, the adolescent emotional brain is constructed along two embedded hierarchies: if the age difference is the founding hierarchy, within that, sex at times act as a driving factor and at times as a moderating one.Las investigaciones en neurociencias que utilizan sets de fotografías de expresión facial a fin de verificar, con la ayuda de técnicas de imaginología, las reacciones emocionales de adolescentes contribuyeron a establecer un modelo neurobiológico del adolescente. Ese modelo que postula que la configuración cerebral particular a ese período de vida somete a las personas jóvenes a un déficit de control emocional, tiende a imponerse en el ámbito de las ciencias del adolescente, particularmente en relación con el aspecto de tomas de riesgo. Este artículo propone investigar el proceso por el cual las neurociencias cognoscitivas elaboraron a partir de retratos fotográficos de actores imitando emociones, estímulos válidos que permitirán de hacer visible por intermedio de IRMs una diferencia del cerebro, discriminando de una parte los adolescentes de los adultos y de otra parte las chicas de los varones en la gestión de la información emocional. En consecuencia, el cerebro emocional adolescente se construye según dos jerarquías encastradas, si la diferencia de edad es la figura de jerarquía fundamental, la del sexo constituye un elemento a veces moderador dentro de la jerarquía fundamental

Glucocorticoid and mineralocorticoid action : Why should we consider influences by environmental chemicals?

Treatment of so-called civilization diseases, including some forms of cancer, immune-related diseases and metabolic disorders, represent a major challenge in the industrialized world. In addition to genetic predisposition, behavior and exposure to xenobiotics contribute to these diseases. Here, we review existing evidence for an association of environmental chemicals with disturbed glucocorticoid- and mineralocorticoid-regulated physiological processes. impaired activity of glucocorticoids and mineralocorticoids can contribute to several diseases, including neurological diseases, immune disorders and metabolic syndrome. Recent studies provide evidence for the existence of environmental chemicals that are able to disrupt the function of these hormones at different levels of their action. Therefore, potential interferences with these hormones should be considered for safety assessment of chemicals. Compared with the extensive knowledge on chemicals interfering with estrogen or androgen responses, the study of glucocorticoid and mineralocorticoid disruptors is an emerging field of research, and the identification of relevant xenobiotics and their underlying mechanisms of toxicity remains a major challenge. (C), 2008 Elsevier Inc. All rights reserved

Désirer : une histoire de la sexologie à Lausanne (1950-2000) = Desire : A History of Sexology in Lausanne (1950-2000)

Cet article se propose de retracer une histoire de la sexologie à Lausanne des années 1950 à 2000 sous l’angle du désir sexuel et de ses problèmes. Il s’intéresse tout particulièrement à la manière dont s’est construit localement un savoir expert sur le désir sexuel, des femmes en particulier, entre théories sexologiques, pratiques cliniques, de conseil conjugal et de planning familial, dans le contexte politique et social de la Suisse romande de la deuxième moitié du 20ème siècle. A partir de cette étude de cas, basée sur l’analyse des archives du Centre médico-social Pro Familia de Lausanne et diverses autres sources produites par les acteur/trices les plus impliqué-e-s dans le domaine de la sexologie en Suisse romande, il s’agira d’intégrer les « troubles » du désir sexuel dans une histoire plus large du désir et de la sexualité. Par l’identification des termes qui régissent la question du désir sexuel (sauvegarde de l’union conjugale, régulation des naissances, lutte contre l’avortement, épanouissement personnel, etc.), nous mettrons ainsi en évidence les diverses modalités sur lesquelles la question du désir sexuel cristallise, pendant la période considérée, des normes de sexe, de genre et de sexualité, mais aussi des enjeux disciplinaires et professionnels (en particulier, entre sexologie médicale, conseil conjugal et planning familial) dans l’établissement d’une approche médico-sociale de la sexualité). ENGLISH ABTRACT: This article retraces the history of sexology in Lausanne from 1950 to 2000, with a thematic focus on the issue of sexual desire. It seeks to analyze the singular ways in which expert knowledge about sexual desire, female sexual desire in particular, was produced at the intersection of sexological theories, clinical practice, couple counseling, and family planning in the social and political context of the second half of the 20th century in French-speaking Switzerland. Based on archival research in the social medical Centre «Pro Familia» in Lausanne and on various other sources produced by the main actors involved in the field of sexology in French-speaking Switzerland, this case study makes it possible to appreciate sexual desire «problems» within a broader history of desire and sexuality.This article iden- tifies the terms governing the issue of sexual desire (saving marriages, birth control, fighting abortion, personal development, etc.) to better highlight the va- rious ways in which, at the time, normative ideals for sex, gender, and sexuality crystallized in the issue of female sexual desire, but also disciplinary and professional tensions (especially between medical sexology, couple counseling, and family planning), in the process of establishing a medical social approach to sexuality

Disruption of glucocorticoid action by environmental chemicals: potential mechanisms and relevance

Glucocorticoids play an essential role in the regulation of key physiological processes, including immunomodulation, brain function, energy metabolism, electrolyte balance and blood pressure. Exposure to naturally occurring compounds or industrial chemicals that impair glucocorticoid action may contribute to the increasing incidence of cognitive deficits, immune disorders and metabolic diseases. Potentially, "glucocorticoid disruptors" can interfere with various steps of hormone action, e.g. hormone synthesis, binding to plasma proteins, delivery to target cells, pre-receptor regulation of the ratio of active versus inactive hormones, glucocorticoid receptor (GR) function, or export and degradation of glucocorticoids. Several recent studies indicate that such chemicals exist and that some of them can cause multiple toxic effects by interfering with different steps of hormone action. For example, increasing evidence suggests that organotins disturb glucocorticoid action by altering the function of factors that regulate the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) pre-receptor enzymes, by direct inhibition of 11beta-HSD2-dependent inactivation of glucocorticoids, and by blocking GR activation. These observations emphasize on the complexity of the toxic effects caused by such compounds and on the need of suitable test systems to assess their effects on each relevant step

Des lois d'exception? Légitimation et délégitimation de l'internement administratif = Sondergesetze? Legitimierung und Delegitimierung der administrativen Versorgung

En Suisse, jusqu'en 1981, un arsenal légal permettait d'enfermer des personnes dont les comportements étaient jugés déviants des normes dominantes en matière de travail, de famille ou de sexualité. Sous prétexte de réguler les coûts de l'assistance comme de protéger l'ordre et la morale publics, l'internement administratif excluait ces individus du droit commun. Cet ouvrage explicite les conditions politiques, sociales et scientifiques qui ont permis l'édiction, la perduration, puis l'abrogation de bases légales matérialisant des tensions et des contradictions entre État de droit, justice et liberté personnelle. In der Schweiz ermöglichte es bis 1981 ein rechtliches Instrumentarium, Personen wegzusperren, deren Verhalten als von den vorherrschenden Normen hinsichtlich Arbeit, Familie oder Sexualität abweichend angesehen wurde. Unter dem Vorwand, die Kosten der Fürsorge zu regeln und die öffentliche Ordnung und Moral zu schützen, schloss die administrative Versorgung diese Personen vom gemeinen Recht aus. Dieses Buch beleuchtet die politischen, sozialen und wissenschaftlichen Bedingungen, die es ermöglicht haben, solche Rechtsgrundlagen zu schaffen, zu erhalten und letztlich aufzuheben. Dabei werden Spannungen und Widersprüche zwischen Rechtsstaatlichkeit, Gerechtigkeit und persönlicher Freiheit sichtbar