The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.

The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of endocrine disrupting chemical interference with PPAR signaling. We thus performed structural and functional analyses that demonstrate how monoethyl-hexyl-phthalate (MEHP) directly activates PPARgamma and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARgamma target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARgamma coregulators that includes Med1 and PGC-1alpha, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.

Aluminum as an endocrine disruptor in female Nile tilapia (Oreochromis niloticus)

The effects of aluminum on plasma ion, lipid, protein and steroid hormone concentration were evaluated in Oreochromis niloticus broodstock females. Lipid and protein concentrations from the gonads and liver were also measured Experiments were performed at neutral and acidic water pH Four groups of fish were tested for 96 h. 1) control conditions at neutral water pH, 2) control conditions at acidic water pH (CTR-Ac). 3) aluminum at neutral water pH (Al-N), and 4) aluminum at acidic water pH (Al-Ac) Aluminum and acidic water pH exposure caused no ionoregulatory disturbances Total lipid concentration increased in the mature gonads and decreased in the liver, suggesting an acceleration of lipid mobilization to the ovaries in animals exposed to aluminum However, a decreased protein concentration in ovaries was also observed Exposure of control fish to acidic water pH caused an increased concentration of plasma 17 alpha-hydroxyprogesterone However, females exposed to aluminum at acidic water pH showed a decreased of plasma 17 alpha-hydroxyprogesterone and cortisol. No differences in plasma 17 beta-estradiol were observed The physiological mechanisms underlying the disturbances observed are discussed focusing on reproduction We suggest that aluminum can be considered an endocrine disrupting compound in mature O. mloticus females (C) 2010 Elsevier Inc. All rights reserved

Determination of endocrine disruptor pesticides in river waters by SPME-GC-MS

FCT - PEst-C/EGE/LA0006/2011

Interference of pollutants with PPARs: endocrine disruption meets metabolism.

The concept of endocrine disruption emerged over a decade ago with the observation that several natural or industrial compounds can interfere with estrogen and androgen signaling, and thereby affect both male and female reproductive functions. Since then, many endocrine-disrupting chemicals (EDCs) have been identified and the concept has been broadened to receptors regulating other aspects of endocrine pathways. In that context, interference of EDCs with receptors regulating metabolism has been proposed as a factor that could contribute to metabolic diseases such as obesity and diabetes. We review recent studies showing that several pollutants, including phthalates and organotins, interfere with PPAR (peroxisome proliferator-activated receptors) nuclear receptors and may thereby affect metabolic homeostasis. Particular emphasis is given on the mechanisms of action of these compounds. However, unlike what has been suspected, we provide evidence from mouse models suggesting that in utero exposure to the phthalate ester di-ethyl-hexyl-phthalate most likely does not predispose to obesity. Collectively, these studies define a subclass of EDCs that perturb metabolic signaling and that we propose to define as metabolic disruptors.

Endocrine Disruptors and Hypothalamic Sexual Differentiation

The so-called endocrine disruptors have been described as compounds which interfere with the estrogen action in their receptors and may exert a crucial role in the development of the reproductive tract and in the brain sexual differentiation. Thus, conducts and/or exposure to these drugs in the perinatal period that apparently do not endanger the neonate may cause side effects. During embrionary development, the gonads, through discharge of a small quantity of reproductive hormones, will guarantee the phenotype of male or female at birth, as well as actuate in specific areas sexual differentiation of the central nervous system. Several experimental models have shown an interference of drugs acting as endocrine disruptors in hypothalamic sexual differentiation. Thus, reproductive function is impaired by exposure to estrogen in the perinatal life of rats and the mechanisms involved in this effect are distinct for males and females. Perinatal exposure to drugs which may be considered endocrine disrupters may induce an incomplete masculinization and defeminization of the central nervous system. Alterations in these processes, if present, generally are perceived only at puberty or adult reproductive life. These later alterations may include anomalies in the process of fertility or in sexual behavior.

Persistence of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the androgen 17β-trenbolone.

The aim of the present study was to investigate the effects of the androgenic endocrine disruptor 17β-trenbolone on the sexual development of zebrafish (Danio rerio) with special emphasis on the question of whether adverse outcomes of developmental exposure are reversible or persistent. An exposure scenario including a recovery phase was chosen to assess the potential reversibility of androgenic effects. Zebrafish were exposed to environmentally relevant concentrations of 17β-trenbolone (1 ng/L-30 ng/L) from fertilization until completion of gonad sexual differentiation (60 d posthatch). Thereafter, exposure was either followed by 40 d of recovery in clean water or continued until 100 d posthatch, the age when zebrafish start being able to reproduce. Fish exposed for 100 d to 10 ng/L or 30 ng/L 17β-trenbolone were masculinized at different biological effect levels, as evidenced from a concentration-dependent shift of the sex ratio toward males as well as a significantly increased maturity of testes. Gonad morphological masculinization occurred in parallel with decreased vitellogenin concentrations in both sexes. Changes of brain aromatase (cyp19b) mRNA expression showed no consistent trend with respect to either exposure duration or concentration. Gonad morphological masculinization as well as the decrease of vitellogenin persisted after depuration over 40 d in clean water. This lack of recovery suggests that androgenic effects on sexual development of zebrafish are irreversible.

Caffeine As An Indicator Of Estrogenic Activity In Source Water.

Caffeine has already been used as an indicator of anthropogenic impacts, especially the ones related to the disposal of sewage in water bodies. In this work, the presence of caffeine has been correlated with the estrogenic activity of water samples measured using the BLYES assay. After testing 96 surface water samples, it was concluded that caffeine can be used to prioritize samples to be tested for estrogenic activity in water quality programs evaluating emerging contaminants with endocrine disruptor activity.

Fotodegradación heterogénea de bisfenol A en agua con dióxido de titanio

Bisphenol A (BPA) is a monomer used in epoxy resin and polycarbonate manufacture. This molecule is considered as an endocrine disruptor that causes different diseases. The human exposition to this non biodegrable substance is increasing in the time; in particular, water is contaminated by industrial remainder flow. In this article heterogeneous photo degradation of a solution of BPA in water solution using a catalytic photo reactor with UV light and titanium dioxide (TiO2) was evaluated. High performance liquid chromatography (HPLC) was used to analyze the photo degradation of BPA solutions. The influence of titanium dioxide amount, BPA concentration, reaction temperature and the catalyst state like suspension and immobilized were also determinated. The highest elimination of BPA was 83.2%, in 240 min, beginning with 0.05 mM of BPA and 100 mg/L of TiO2 in suspension.

Estrogênios em águas naturais e tratadas da região de Jaboticabal - São Paulo

The aim of this work was to analyze 17 β estradiol and estrone, natural estrogenic hormones present in domestic effluents and animal excreta, in the public water supply system of Jaboticabal, SP. The results have shown the presence of estrogens in 22% of the samples in concentrations from 6,8 ng L-1 (treated water) to 30,6 ng L-1 (riverhead) for 17 β estradiol and 600 ng L-1 of estrone (stream), respectively. We concluded that animal wastes, discharges from the wastewater treatment station, and discharges of domestic effluent without treatment from rural proprieties were probably the cause of this contamination.

Triorganotin as a compound with potential reproductive toxicity in mammals

Organotin compounds are typical environmental contaminants and suspected endocrine-disrupting substances, which cause irreversible sexual abnormality in female mollusks, called "imposex". However, little is known about the capability of triorganotin compounds, such as tributyltin and triphenyltin, to cause disorders in the sexual development and reproductive functions of mammals, including humans and rodents. Moreover, these compounds can act as potential competitive inhibitors of aromatase enzyme and other steroidogenic enzymes, affecting the reproductive capacity of male and female mammals. In this review, we discuss the cellular, biochemical, and molecular mechanisms by which triorganotin compounds induce adverse effects in the mammalian reproductive function.

Caractérisation de la toxicocinétique de l’octylphénol chez le rat en vue d’une meilleure analyse de risque toxicologique des perturbateurs endocriniens

Le p-tert-octylphénol est un produit présent dans l’environnement et issu de la dégradation des alkylphénols éthoxylés. Ce composé a la capacité de se lier au récepteur œstrogénique et d’exercer ainsi un léger effet œstrogénique. Les objectifs de cette étude étaient de 1) développer une méthode d'identification de l'octylphénol dans le sang et les tissus à l'aide de la chromatographie en phase gazeuse jumelée à la spectrométrie de masse, 2) caractériser la toxicocinétique sanguine et tissulaire de l’octylphénol chez le rat Sprague-Dawley mâle et femelle et 3) développer un modèle toxicocinétique à base physiologique permettant de décrire la cinétique sanguine et tissulaire de l’octylphénol inchangé. Pour ce faire, des rats mâle et femelle Sprague-Dawley ont reçu des doses uniques d’octylphénol par les voies intraveineuse, orale et sous-cutanée. Deux autres groupes ont reçu des doses répétées d'octylphénol par voie orale pour une durée de 35 jours consécutifs pour les femelles ou 60 jours pour les mâles. Les concentrations sanguines et tissulaires d’octylphénol ont été mesurées à différents moments après administration à partir d’une méthode d’analyse développée dans nos laboratoires dans le cadre de ce projet. Les expériences impliquant des administrations uniques ont montré que les concentrations sanguines et tissulaires d'octylphénol étaient en général plus élevées chez les femelles que chez les mâles. Des expériences réalisées avec des microsomes hépatiques ont confirmé que ces différences étaient vraisemblablement reliées au métabolisme de l'octylphénol. Les expériences impliquant des administrations répétées ont montré qu'il n'y avait pas d'accumulation d'octylphénol dans l'organisme aux doses étudiées. Les résultats obtenus expérimentalement ont servi à développer et valider un modèle toxicocinétique à base physiologique. Ce modèle a permis de simuler adéquatement les concentrations sanguines et tissulaires d'octylphénol suite à des expositions intraveineuses, orales et sous-cutanées. En conclusion, cette étude a fourni des données essentielles sur la toxicocinétique de l'octylphénol. Ces données sont nécessaires pour établir la relation entre la dose externe et la dose interne et vont contribuer à une meilleure évaluation des risques liés à l'octylphénol.

Étude de la cinétique des pesticides pyréthrinoïdes en conditions contrôlées et en milieu de travail dans un objectif de biosurveillance

Les pyréthrinoïdes sont des insecticides largement utilisés. La population générale y est exposée par l’alimentation tandis que les travailleurs agricoles y sont exposés lors de tâches diverses en champs. Leurs effets neurotoxiques, immunitaires et endocriniens potentiels en font des composés à surveiller pour assurer la santé de la population. La mesure de biomarqueurs d’exposition, qui consiste à quantifier la concentration dans l’organisme d’une substance ou de ses métabolites, permet d’estimer les doses absorbées. Les biomarqueurs peuvent également être des molécules répondant à un stress physiologique, identifiées comme des biomarqueurs d’effets. Pour raffiner les stratégies de biosurveillance de l’exposition, on se doit de bien connaître la toxicocinétique d’un xénobiotique; actuellement, les études de biosurveillance considèrent rarement la variabilité temporelle, intra-invidivuelle et inter-individuelle, qui pourrait influencer l’estimation de l’exposition. L’objectif de la thèse est donc d’appliquer une approche cinétique pour l’évaluation de l’exposition aux pyréthrinoïdes en conditions contrôlées et en milieu de travail. Dans un volet exploratoire, l’effet de cette exposition sur des changements métaboliques précoces a également évalué. Trois métabolites finaux (cis-DCCA, trans-DCCA et 3-PBA) de deux pyréthrinoïdes les plus utilisés, soient la perméthrine et la cyperméthrine, ont été mesurés dans le plasma et l’urine de six volontaires oralement exposés à une dose équivalente à la dose de référence. Une demi-vie moyenne (t½) d’élimination apparente du trans-DCCA, cis-DCCA et 3-PBA dans le plasma de 5,1, 6,9 et 9,2 h, respectivement, a été obtenue après exposition orale à la cyperméthrine, comparativement à 7,1, 6,2 et 6,5 h après exposition à la perméthrine. Dans l’urine, la demi-vie d'élimination apparente (t½) était de 6,3, 6,4 et 6,4 h pour le trans-DCCA, cis-DCCA et 3-PBA, respectivement, après administration de la cyperméthrine comparé à 5,4, 4,5 et 5,7 h après administration de la perméthrine. Les profils temporels étaient semblables suite à l’exposition à la cyperméthrine et perméthrine. Ensuite, une étude en milieu agricole a été réalisée avec la participation de travailleurs pour évaluer leur exposition et raffiner les stratégies de biosurveillance. La variabilité intra-individuelle dans les niveaux de biomarqueurs d’exposition chez plusieurs travailleurs était plus importante que la variabilité inter-individuelle. Les échantillons urinaires ont également été utilisés pour identifier des modifications du métabolome pouvant fournir de nouveaux biomarqueurs d’effets précoces. Chez les travailleurs, une augmentation de l'hippurate urinaire (p <0,0001) a été observée après exposition aux pyréthrinoïdes, un biomarqueur de la conjugaison de l’acide benzoïque. En conclusion, cette étude a permis de mieux documenter la cinétique de biomarqueurs d’exposition aux pyréthrinoïdes dans des conditions contrôlées et réelles afin de raffiner les stratégies de biosurveillance. Elle a aussi contribué à renseigner sur les niveaux d’exposition agricole québécois et sur les paramètres professionnels associés à une plus forte exposition. Ce projet s’insère dans une démarche d’analyse de risque en santé au travail.

Degradation and plant uptake of nonylphenol (NP) and nonylphenol-12-ethoxylate (NP12EO) in four contrasting agricultural soils

Nonylphenol polyethoxylates (NPEOs) are surfactants found ubiquitously in the environment due to widespread industrial and domestic use. Biodegradation of NPEOs produces nonylphenol (NP), an endocrine disruptor. Sewage sludge application introduces NPEOs and NP into soils, potentially leading to accumulation in soils and crops. We examined degradation of NP and nonyl phenol-12-ethoxylate (NP12EO) in four soils. NP12EO degraded rapidly (initial half time 0.3-5 days). Concentrations became undetectable within 70-90 days, with a small increase in NP concentrations after 30 days. NP initially degraded quickly (mean half time 11.5 days), but in three soils a recalcitrant fraction of 26-35% remained: the non-degrading fraction may consist of branched isomers, resistant to biodegradation. Uptake of NP by bean plants was also examined. Mean bioconcentration factors for shoots and seeds were 0.71 and 0.58, respectively. Removal of NP from the soil by plant uptake was negligible (0.01-0.02% of initial NP). Root concentrations were substantially higher than shoot and seed concentrations. (C) 2008 Elsevier Ltd. All rights reserved.

Early Changes Induced by Short-Term Low-Dose Cadmium Exposure in Rat Ventral and Dorsolateral Prostates

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Estrogênios em águas naturais e tratadas da região de Jaboticabal - São Paulo

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)