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Improved analytical methods using novel cleanup techniques and inexpensive instrumentation for the determination of residue estrogens in municipal wastewater and swine lagoon wastewater have been developed. Presented approaches are less expensive, less time consuming, yet produce comparable detection limits and extraction efficiencies to existing methods. Chapter I provides an overview on environmental estrogens. Chapter II describes a novel method to quantify five estrogens including estriol, estrone, 17alpha-estradiol, 17beta-estradiol, and 17alpha-ethynylestradiol in influent and effluent municipal wastewater. The method includes sample preparation using solid-phase extraction followed by a “QuEChERS” cleanup, dansylation and LC/MS/MS detection. Hydrophilic-lipophilic balance solid phase extraction (SPE) was used for sample preconcentration and the extract was cleaned up using a dispersive SPE method using MgSO4, PSA and C-18. The resulting extract was then derivatized with dansyl chloride. Separation was achieved on a C-18 column and quantification was accomplished in the positive ion mode using multiple reaction monitoring. The method is capable of detecting below 1 ng/L. Chapter III describes improved approaches to quantify five estrogens and two conjugates, Estrone 3-glucuronide and beta-Estradiol 3-sulfate, in swine lagoon wastewater and storm water runoff. A considerable residue was collected when lagoon wastewater samples were centrifuged therefore both resulting residues and aqueous portions were analyzed separately. Analysis of the aqueous portions was carried out using a similar approach to the method described in Chapter II. However, a simple test-tube liquid-liquid extraction was used as an additional sample clean-up step. A modified QuEChERS method was utilized to efficiently extract the target analytes in the residue. Methods have 0.9 – 2 ng/L detection limits. Chapter IV describes an approach to quantify residue estrogens in municipal wastewater using a comprehensive two-dimensional gas chromatograph (GCxGC). This method requires no further cleanups after SPE and has detection limits ranging from 1.4 – 22.2 ng/L. All presented methods use relatively small initial sample volumes and produce negligible matrix interferences. The developed methods were validated by performing mini surveys on the estrogen levels in environmental aqueous matrices in north Mississippi.

<p>Uvod. Ftalati su endokrini disruptori, &scaron;iroko se koriste kao plastifikatori, rastvarači i aditivi u mnogim potro&scaron;ačkim proizvodima. Eksperimentalni podaci i humane studije sugeri&scaron;u na povezanost ftalata sa gojazno&scaron;ću i dijabetesom. Cilj. Utvrditi da li su i koji urinami metaboliti ftalata prisutni i da li postoje razlike u njihovim nivoima između bolesnika s tipom 2 &scaron;ećeme bolesti, gojaznih i kontrolne grupe zdravih osoba; da li postoji povezanost između metabolita ftalata i gojaznosti, lipida i lipoproteina seruma, glikemije, insulinemije i insulinske rezistencije.<br />Metode. Istraživanje je obuhvatilo 305 ispitanika, podeljenih u 3 grupe: gojazni (n=104), dijabetesni bolesnici tip 2 (n=101) i zdrave osobe (n=100), oba pola. U svih ispitanika su izvr&scaron;ena antropometrijska merenja (BMI i obim struka), određivanje serumskih lipida (ukupni holesterol, trigliceidi, HDL i LDL holesterol), te glikemija, insulinemija i izračunat indeks insulinske rezistencije (HOMA IRI). U jutarnjem uzorku urina meren je nivo 10 ftalatnih metabolita: mono-metil ftalat (MMP), mono-etil ftalat (MEP), mono-n-butil ftalat (MnBP), mono- benzil ftalat (MBzP), mono-cikloheksil ftalat (MCHP), mono-n-propil ftalat (MPP), mono-n-amil ftalat (MnAP), mono-izo-amil ftalat (MiAP), mono- n-oktil ftalat (MOP), mono-2-etilheksil ftalat (MEHP). U odnosu na prisustvo ftalata u urinu svaka grupa je podeljena u podgrupe na one sa prisutnim ftalatima i one bez ftalata u urinu, odnosno na podgrupe MEP pozitivne, MEP negativne, MEHP pozitivne i MEHP negativne. Rezultati. Kod polovine ispitanika registrovali smo prisustvo u urinu pojedinih metabolita ftalata. Najče&scaron;ći su bili MEHP i MEP. Najveća sličnost u nivou MEP-a i MEHP-a je bila između gojaznih i dijabetesnih ispitanika. U odnosu na antropometrij ske parametre uočena je pozitivna korelacija MEP-a sa BMI i obimom struka, a negativna korelacija MEHP-a sa BMI i obimom struka, ali su bile nesignifikantne. Samo kod MEHP pozitivnih kontrolne grupe uočena je statistički značajna pozitivna korelacija MEHP-a i obima struka. Utvrđena je statistički značajna negativna korelaciju MEP-a i HDL holesterola, a pozitivna korelacija MEP-a i triglicerida samo kod gojaznih. Samo u kontrolnoj grupi MEHP pozitivnih postojala je statistički značajna negativna korelacija sa HDL holesterolom. Postojala je pozitivna korelacija MEP-a i HOMA-IRI, a pozitivna korelacija MEHP-a sa glikemijom samo kod MEHP pozitivnih DM tip 2. Zaključak. Potvrđeno je da je kontaminacija ftalatima prisutna u na&scaron;oj populaciji, a najče&scaron;će su prisutni MEHP i MEP, ukazujući na ekspoziciju DEHP i DEP. Indirektno smo stekli uvid da povećana izloženost DEP i DEHP može doprineti nastanku izvesnih poremećaja lipida i lipoproteina, insulinskoj rezistenciji kao i razvoju gojaznosti.</p> / <p>Introduction. Phthalates are endocrine disruptors, widely used as plasticizers, solvents and additives in a wide range of consumer products. Experimental data and human studies suggest that phthalate exposure is linked with obesity and diabetes. Aim. To determine whether urinary phthalate metabolites are present, which ones are present, whether there are differences between their levels among the patients with type 2 diabetes, obesity patients and a control group of healthy individuals; whether there is a link between phthalate metabolites and obesity, lipids, serum lipoproteins, glycemia, insulinemia and insulin resistance. Methods. The research included 305 participants divided into three groups: obesity patients (n=104), type 2 diabetes patients (n=101) and healthy individuals (n=100) in both sexes. Anthropometric measurements were taken from all participants (BMI and waist circumference), as well as measurement of serum lipids (total cholesterol, triglycerides, HDL and LDL cholesterol), glycemia, insulinemia and a calculation of insulin resistance index (HOMA IRI). The levels of ten phthalate metabolites were<br />measured in a morning sample of urine: Mono-methyl phthalate (MMP), Mono-ethyl phthalate (MEP), Mono-n-butyl phthalate (MnBP), Mono-benzyl phthalate (MBzP), Mono- cyclohexyl phthalate (MCHP), Mono-n-propyl phthalate (MPP), Mono-n-amyl phthalate (MnAP), Mono-iso-amyl phthalate (MiAP), Mono-n-octyl phthalate (MOP), Mono-2- ethylhexyl phthalate (MEHP). Regarding the presence of phthalates in urine, each group was divided into subgroups, containing phthalates and or not containing phthalates, i.e. subgroups MEP positive and MEP negative, MEHP positive and MEHP negative. Results. In a half of participants, we have registered the presence of certain phthalate metabolites in urine, most often MEHP and MEP. The highest similarity in the levels of MEHP and MEP was between obesity and diabetes participants. Regarding anthropometric measurements, positive correlation has been registered between MEP and BMI and waist circumference, while negative correlation has been registered between MEHP and BMI and waist circumference, but it was insignificant. Only in MEHP positive control group, statistically significant positive correlation between MEHP and waist circumference has been registered. Statistically significant negative correlation between MEP and HDL cholesterol has been registered, while positive correlation between MEP and triglycerides has been registered only in obesity patients group. Only in MEHP positive control group statistically significant negative correlation with HDL cholesterol has been registered. There has been a positive correlation between MEP and HOMA-IRI, while positive correlation between MEHP and glycemia has been registered only in MEHP positive DM type 2. Conclusion. It has been confirmed that our population is contaminated with phthalates, most commonly MEHP and MEP, indicating exposure to DEHP and DEP. Indirectly, we have realized that an increased exposure to DEHP and DEP can contribute to the development of certain lipid and lipoprotein disorders, insulin resistance, as well as the development of obesity.</p>

Background: The human secondary sex ratio has been the subject of long-standing medical, environmental and social scientific curiosity and research. A decline in male birth proportion in some industrialised countries is linked to endocrine disruption and is validated by some empirical studies. Increasing parental age and population stress and associated decreases in sex ratio have also been demonstrated. A thorough literature review of 123 relevant and diverse studies provides context for these assessments. Methods: A spatial-temporal investigation of birth sex ratio in Scotland and potential determinants of endocrine disruptor pollution, socio-economic factors including neighbourhood stress, deprivation, smoking, and maternal age, was conducted. This involved review of national and regional sex ratio time trends, and stratified/spatial analysis of such factors, including the use of GIS tools. Secondary data were sourced from Scottish Government web portals including Scottish Neighbourhood Statistics and the Scottish Environmental Protection Agency. Results: Regional differences in sex ratio between 1973 and 2010 are observed which likely lever the national male birth proportion downwards, with the region of poorest air quality from industrial emissions, the Forth Valley, displaying the greatest sex ratio reduction. Further analysis shows significant upwards skewing in sex ratio for the population cohort experiencing the least and 2nd most deprivation. Localised reductions in sex ratio for areas of high modelled endocrine disruptor pollution within the Central Region in Scotland are also displayed. Discussion: Limitations of the analyses include the danger of ecological fallacy in interpreting from area-based measurement and the simplified pollution modelling adopted. Despite this, and given elevated incidence of testicular cancer in Scottish regions mirrors the study’s results, tentative confirmation of the endocrine disruptor hypothesis can be substantiated. Further, elucidation on advanced parental age as a contributory factor to secondary sex ratio change is also given. Recommendations are made with respect to environmental monitoring and health protection, and preventative health strategies in Scotland.

Les alkylphénol-polyéthoxylés et les substances pharmaceutiques appartiennent à la classe des contaminants émergents qui sont depuis peu étudiés dans les milieux naturels. Ces composés d’usage très répandu (aussi bien en termes d’applications qu’en termes de quantité) sont introduits dans le milieu aquatique, via les stations d’épuration, principalement et sont susceptibles d’engendrer des effets toxiques sur les organismes vivants dans ces milieux. La première partie de ce travail de thèse a consisté en le développement et la validation de différentes méthodologies d’échantillonnage (ponctuel et intégratif (POCIS)), de différents protocoles d’extraction (SPE, extraction assistée par micro-ondes) et d’analyse (CL/SM, CL/SM/SM), nécessaires pour un dosage fiable des alkylphénol-polyéthoxylés et des substances pharmaceutiques dans les différents compartiments des systèmes aquatiques (phases dissoute, particulaire et sédimentaire, organismes biologiques). Ensuite, un bilan de la contamination de différents systèmes aquatiques (le bassin de d’estuaire de Seine, la Garonne et la Gironde, la baie de la Vilaine, la baie de l’Authie, l’Adour, la rade de Marseille) a été dressé. Une contamination généralisée par ces composés a été mise en évidence pour l’ensemble des sites étudiés. Les concentrations mesurées apparaissent extrêmement variables selon la classe de molécule considérée, les sites et le temps avec des concentrations comprises entre le ng.l-1 et la dizaine de µg.l-1 pour les phases dissoutes et de la dizaine de ng.g-1 et la dizaine de µg.g-1 pour les phases solides (plusieurs centaines de µg.g-1 dans les boues d’épuration). Ces études ont également permis de documenter la présence et le devenir des molécules ciblées dans les stations d’épuration et ont permis d’en évaluer l’efficacité quant l’abattement des substances incriminées. Enfin, ces travaux ont également permis de mettre en évidence des phénomènes de partition entre les phases dissoutes et les phases solides ainsi que des phénomènes de transferts vers les organismes du milieu. / Alkylphenol-polyethoxylates and pharmaceutical substances belong to the class of the emerging contaminants which have been recently studied in natural environments. These compounds of very widespread use (in terms of applications as well as in terms of quantity) are introduced into the aquatic environment, via the wastewater treatment plants, mainly, and are likely to generate toxic effects on the living organisms in these systems. The first part of this work consisted in the development and validation of various methodologies of sampling (grab sampling and integrative sampling (POCIS)), of various protocols of extraction (SPE, microwaves assisted extraction) and of analysis (LC/MS, LC/MS/MS), necessary for a reliable quantification of alkylphenol-polyethoxylates and pharmaceutical substances in the various compartments of aquatic systems (phases dissolved, particulate and sedimentary, biological organisms). Then, an assessment of the contamination of numerous aquatic systems (the catchment area of the Seine estuary, the Garonne and the Gironde, the bay of Vilaine, the bay of Authie, the Adour, the Mediterranean coast of Marseilles) was undertaken. A generalized contamination by these compounds was highlighted for all the studied sites. The measured concentrations appear to be extremely variable according to the class of molecule considered, the sites and time with concentrations ranging from the ng.l-1 to tens of µg.l-1 for the dissolved phases and from tens of ng.g-1 to tens of µg.g-1 for the solid phases (several hundreds of µg.g-1 in the clarification sludge). These studies also made it possible to document the presence and the fate of these molecules in the French wastewater treatment plant and made it possible to evaluate their effectiveness to remove the studied compounds. Lastly, this work also made it possible to highlight phenomena of partition between the dissolved phases and the solid phases as well as phenomena of transfers through the biological organisms.

Le poly(éthylène téréphtalate) (PET) est largement utilisé pour le conditionnement des eaux. L’évaluation de l’inertie des matières plastiques au contact de denrées alimentaires est régie par le règlement européen N°10/2011 qui permet d’assurer la sécurité sanitaire des matériaux. Cependant, plusieurs études ont rapporté des effets cyto/génotoxiques et/ou œstrogéniques des eaux embouteillées en PET. Ces réponses ont été attribuées à des mélanges de composés provenant du matériau polymère. L’objectif de ce travail de recherche a été d’apprécier les phénomènes de migration de monomères, catalyseurs, d’additifs et de néoformés du PET vers l’eau. Conformément aux formulations déclarées pour la fabrication des bouteilles en PET, aucune présence de phtalates, d’antioxydants et de stabilisants UV a été détectée dans l’eau. Cependant, la présence de formaldéhyde, d’acétaldéhyde, du 2,4-di-tert-butylphénol et d’antimoine dans l’eau embouteillée en PET a été confirmée. Il a été mis en évidence que la température influence la migration de ces molécules due à une perte d’orientation de la phase amorphe sur la partie semi-cristalline de la bouteille PET. Cela entraine une augmentation de la mobilité des chaînes polymériques. Ainsi, il a été montré que l’exposition solaire n’influence que la migration du formaldéhyde. En effet, aucune oxydation des chaînes polymériques n’a été détectée en surface de bouteilles après irradiation naturelle. L’étude toxicologique in vitro sur des modèles cellulaires humains (cellules HepG2 et MDA-MB453-kb2) n’a pas mis en évidence de cytotoxicité, de génotoxicité et d’activité de type œstrogénique et (anti)-androgénique dans l’eau embouteillée en PET / Polyethylene terephthalate (PET) is widely used for the manufacture of packaging for drinking water. The chemical safety of plastic materials intended to come into contact with food is strictly regulated by the European regulation No. 10/201, which establishes a positive list of authorized compounds for the production of plastic packaging. Despite this, cyto-/genotoxic and estrogenic activity of PET-bottled water has been reported. Chemical mixtures migrating from PET into bottled water may explain the reported positive results. The aim of this study was to assess the migration of monomers, catalysts, additives, and degradation byproducts from PET into bottled water. In accordance with the chemical formulations reported for PET, no phtalates, antioxidants, and UV stabilizers were detected into bottled water. However, formaldehyde, acetaldehyde, 2,4-di-tert-butylphenol and antimony were found in PET bottled water. It was shown that temperature influences the migration of these compounds, due to orientation loss of the amorphous phase of the semi-crystalline part of PET bottles. This phenomenon increases the mobility of polymer chains and consequently, the compounds’ diffusion. Thus, it was found that sunlight exposure influences only the migration of formaldehyde. Indeed, no oxidation of the polymer chains was detected on the surface of PET bottles after exposure. The in vitro toxicological bioassays with human cell models (HepG2 and MDA-MB453-KB2 cells) did not show any cytotoxicity, genotoxicity or estrogenic- and (anti)-androgenic-like activity for PET bottled water

Les Troubles du Spectre Autistique (TSA) sont caractérisés par deux principaux symptômes : des difficultés de communication sociale et des comportements stéréotypés et intérêts restreints. Les TSA touchent 5 fois plus les garçons que les filles et une augmentation de la prévalence exponentielle et continue a été observée aux États-Unis ces dernières décennies. Cette augmentation ne peut s’expliquer par les facteurs génétiques à eux seuls qui ne représentent que 5 à 15% des cas de TSA. Il est donc indispensable d’identifier de potentiels facteurs de risque environnementaux des TSA. Le but de ce travail est d’étudier différents facteurs environnementaux potentiellement modifiables dans le développement de phénotypes autistiques dans différents modèles précliniques des TSA. Les objectifs spécifiques sont : (i) caractériser les effets neurocomportementaux provoqués par une exposition périnatale simultanée à 5 perturbateurs endocriniens parmi les plus prévalent dans notre environnement quotidien (DEHP, DBP, DiNP, BDE-47, BDE-99) à de faibles doses pertinentes pour l’exposition humaine, (ii) identifier les effets neurocomportementaux associés à une altération périconceptionnelle du microbiote maternelle (iii) déterminer les effets neurocomportementaux associés à une altération périconceptionnelle du métabolisme monocarboné. Les résultats présentés dans cette thèse démontrent le potentiel de chacun de ces facteurs environnementaux d’altérer le développement cérébral fœtal. Chaque condition expérimentale a provoqué l’apparition de traits autistiques chez les rats, avec des spécificités comportementales pour chaque exposition développementale. Des déficits d’interactions sociales ont été observés dans chaque situation expérimentale, associés soit à de l’anxiété, de l’hyperactivité, des altérations d’intégration sensorimotrice, et/ou des stéréotypies. Cela nous force à considérer les TSA comme une pathologie aux multiples facettes où l’hétérogénéité des tableaux cliniques est représentative de l’hétérogénéité des causes possibles. La multitude des interactions environnementales courantes possibles avec l’épigénome pourrait être à la base de la grande diversité observée dans la sévérité des symptômes et / ou des comorbidités des TSA. Ce travail ouvre des perspectives futures de prévention ciblée des TSA fondées sur de potentielles modifications de l’environnement comme la réduction de l’exposition aux perturbateurs endocriniens, ou des supplémentations en donneurs monocarbonés (e.g. acide folique) et/ou probiotiques.

Um dos grandes problemas da engenharia ambiental é a contaminação dos corpos hídricos. Os sanitaristas têm se preocupado com os hormônios sexuais, notadamente os estrógenos, compostos extremamente ativos biologicamente, que têm sido referidos como agentes etiológicos de feminilização e de vários tipos de cânceres. Os estrógenos naturais 17 \'beta\'-estradiol (E2), estriol (E3), estrona (E1) e o sintético 17 \'alfa\'-etinilestradiol (EE2), desenvolvidos para uso médico em terapias de reposição hormonal feminina e métodos contraceptivos, são os que despertam maiores preocupações, pela contínua introdução ao ambiente; hormônios que possuem a melhor conformação reconhecida pelos receptores que resultam respostas máximas, por isso são considerados responsáveis pela maioria dos efeitos disruptores desencadeados pela disposição de efluentes. A mudança de padrões quanto à atividade sexual dos jovens e a preocupação com o planejamento familiar, levaram ao grande consumo de contraceptivos que, através da urina, são levados pela rede coletora aos corpos de água. O indiscriminado uso desses hormônios na bovinocultura, suinocultura, avicultura e aqüicultura são responsáveis por parte considerável desse contaminante nos mananciais. Os hormônios excretados através da urina e fezes e agentes provenientes das indústrias de processamento de alimentos preocupam os sanitaristas porque o lançamento de efluentes in natura ou tratados, são as principais vias de contaminação do ambiente aquático, quer pelo déficit de infra-estrutura em saneamento, quer pela ineficiência tecnológica e/ou operacional na remoção desses compostos nas estações de tratamento de água ou de efluentes. Apesar de possuírem meia-vida relativamente curta, quando comparados a outros compostos orgânicos como praguicidas, os estrógenos naturais são continuamente introduzidos no ambiente, o que lhes confere caráter cumulativo. A proposta desta pesquisa foi verificar a presença de estrógenos na água bruta que chega à Estação de Tratamento de Água, após seu tratamento, em água tratada por osmose reversa e por tecnologia Milli Q (marca registrada). Para verificar e quantificar presença desses hormônios estrógenos em água de abastecimento de São Carlos-SP, foram realizadas exames através de imunoensaio quimiluminescente e radioimunoensaios. Os resultados apontaram que a ETA não possui solução eficiente para a remoção dos analitos de interesse dessa pesquisa, uma vez que na água tratada foram encontrados valores semelhantes aos da água bruta. / One of the major problems of environmental engineering is the water contamination. The sanitary persons have been concerned with the gonadal hormones, notably the estrogen, biologically active compounds extremely, which have been referred to as etiologic agents of feminization and several types of cancers. The natural estrogen 17 \'beta\'-estradiol (E2), estriol (E3), estrone (E1) and synthetic 17 \'alpha\'-ethinylestradiol (EE2), developed for medical use of hormone replacement therapy in women and contraceptive methods, are those that attract larger concerns by the continuous introduction into the environment; hormones that have the best conformation recognized by receptors that result answers maximum, so they are considered responsible for most of the effects disruptors triggered by the wastewater disposal. The change in patterns on the sexual activity of young people and the concern with family planning, led to the large consumption of contraceptives that, in the urine, are led by the distribution net to water. The indiscriminate use of these hormones in cattle, pigs, poultry and aquaculture are responsible for part of this contaminant in the source. The hormones excreted in the urine and feces and agents from the food processing industries in the sanitary concern that the launch of effluents in nature or treated, are the main routes of contamination of the aquatic environment, either by lack of infrastructure, sanitation, or by inefficiency technological and/or operating in the removal of these compounds in the treatment plants, water or effluent. Despite having relatively short stocking-lige when compared to other organics such as pesticides, natural estrogens are continuously released into the environment, which gives them character cumulative. The proposal of this research was to verify the presence of estrogen in the gross water that arrives at the water treatment plant, after the treatment, in water treated by reverse osmosis and by Milli Q technology. To verify and quantify presence of these hormones estrogen in water supply of San Carlos-SP, examinations were conducted through immunoassay chemiluminescent and radioimunoassays. The results showed that the ETA has no efficient solution for removal of interest analytes of this research, because in the treated water were found values similar to crude water.

L’incidence des cancers testiculaires a fortement augmenté au cours des 50 dernières années. Des études épidémiologiques in vitro et in vivo, ont montré que l’exposition des hommes aux perturbateurs endocriniens est impliquée dans l’initiation et la progression du cancer du testicule (Beiki et al., 2010). L’exposition fœtale à ces produits pourrait provoquer des altérations de la différenciation des cellules germinales (CGs) au cours leur développement pendant la vie fœtale. Au cours de cette thèse, nous nous sommes intéressés à déterminer le rôle des perturbateurs endocriniens œstrogéno-mimétiques en mélange sur la prolifération des cellules séminomateuses TCam-2. Nous avons identifié les voies de signalisation impliquées dans la réponse à ces produits. Nous nous sommes focalisés sur les effets d’un mélange d’alkylphénols appelé M4 (4-tert-octylphénol et le 4-nonylphénol), in vitro sur la prolifération des cellules séminomateuses TCam-2, et in vivo sur la croissance de tumeurs obtenues à partir des cellules de carcinome embryonnaire NT2/D1 xénogreffées chez la souris Nude. Dans notre étude, nous avons mis en évidence l’implication d’ERα36, une isoforme tronquée du récepteur ERα, dans la réponse au mélange d’alkylphénols, M4. Ce mélange stimule la prolifération des cellules du cancer testiculaire et l’expression du récepteur ERα36. Ces effets sont médiés par la phosphorylation de CREB via la voie PI3K-ERα36-dépendante, et aboutissent à la diminution de l’expression des gènes de la famille Dnmt3, limitant le niveau de méthylation de l’ADN. ERα36 pourrait donc constituer une cible thérapeutique dans le traitement des cancers testiculaires / In vitro and in vivo epidemiological studies showed that the exposure of men to endocrine disruptors triggers the initiation and the progression of the testis cancer (Beiki et al., 2010). The fetal exposure to these products is able to alter the differentiation of germ cells in the timing of their development during the fetal life. The aim of our study was to determine the role of an endocrine disruptor mix on the proliferation of seminoma cells TCam-2. We also identified the pathways involved. In this study, we focused on the estrogen-like effects of an alkylphenol mixture called M4 (4-tert-octylphenol and 4-nonylphenol): in vitro we measured the proliferation of TCam-2 seminoma cells after M4 exposure and in vivo, we measured the tumor growth of NT2/D1 cells xenografted into Nude mice. The results highlighted the implication of ERα36 receptor, a truncated isoform of ERα, in the response to the alkylphenol mixture M4. This mixture stimulates the cell proliferation of testicular cancer cells and the expression of the ERα36 receptor. These effects are mediated by CREB phosphorylation via the PI3K-ERα36-dependant pathway, and end by downregulation of Dnmt3 genes, thus limiting the level of DNA methylation. Therefore ERα36 appears to be a promising therapeutic target for testis cancer treatment

Poly- and perfluoroalkyl substances (PFAS) are ubiquitous contaminants across the globe, can bioaccumulate in aquatic taxa, and potentially biomagnify in food webs. Consequently, research examining the influence of PFAS on wildlife is warranted. Amphibians are sensitive to contaminants such as PFAS because of their porous skin and associations with aquatic habitats where contaminants accumulate. Because PFAS tend to bioaccumulate and can adversely affect the endocrine system, there is a need to examine uptake rates to inform ecotoxicology studies, as well as a need to examine sublethal effects. To address these knowledge gaps I conducted two experiments. First, I exposed larval northern leopard frogs (<i>Rana pipiens</i>), American toads (<i>Anaxyrus americanus</i>), and eastern tiger salamanders (<i>Ambystoma tigrinum</i>) to PFAS chemicals perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) at concentrations of 10 or 1000 ppb for 10 days and sampled them every 48 hours during the exposure period. In the next experiment, I examined the effects of PFAS exposure via contaminated substrate on the survival and growth of post metamorphic amphibians of the same species. I found that, for all species, body burdens often reached steady state within 48 to 96 h of exposure. Steady-state body burdens of PFOA ranged from 3,819–16,481 ng/g dry weight among treatments and species (corresponding BCFs of 0.5 to 2.5), while PFOS body burdens ranged from 6,955–489,958 ng/g dry weight (corresponding BCFs of 47–259) among treatments and species. These data suggest that steady state is rapidly reached in larval amphibians exposed to PFAS, particularly regarding PFOS. This reflects a high potential for trophic transfer of PFAS within food webs because amphibians are often low in trophic position and are important prey for many aquatic and terrestrial species. In post-metamorphic amphibians, there was no influence of PFAS on survival or mass. However, significant effects on snout-vent length were observed in all species, and body condition differences were observed for two of my species. I found that all leopard frogs increased in scaled mass index (SMI) when exposed to a PFAS treatment, indicating an increased body condition. Toads exhibited a more variable SMI pattern across treatments, with no outstanding trends, and tiger salamanders did not differ significantly across treatments. These data suggest that sublethal effects vary greatly depending on the species, possibly due to life history traits. Future research examining biomagnification potential is warranted to determine the influence of PFAS on food webs. Additionally, there is a need to determine the physiological mechanisms underlying the observed effects of PFAS exposure.<br>