Neste estudo foi realizada a avaliação de seis substâncias sintéticas resultantes de processos industriais e de atividades antropogênicas dietilftalato, dibutilftalato, nonilfenol, pentaclorofenol, bisfenol A e benzo[a]pireno os quais possuem capacidade de interferir negativamente no funcionamento normal do sistema endócrino de animais e de seres humanos (xenoestrógenos), em águas tratada e bruta de quatro municípios do Vale do Paraíba paulista. Para tanto, utilizou-se um método analítico de alta seletividade e sensibilidade, sendo a determinação por cromatografia gasosa acoplada ao detector de espectrometria de massas (GC/MS), precedida da concentração das amostras pelo método SPE (extração em fase sólida). Como não são suficientes apenas boas técnicas analíticas para garantir a qualidade dos dados gerados e a confiabilidade dos resultados, a metodologia desenvolvida foi submetida ao processo de validação, onde foram avaliados os parâmetros: seletividade, especificidade, linearidade, faixa linear de trabalho, limites de detecção e quantificação, precisão, exatidão, recuperação e robustez, além da incerteza na medição. Os resultados demonstraram que o método proposto é adequado para quantificação das amostras do rio Paraíba do Sul, e pela sua aplicação foi constatada a presença de todos os poluentes estudados tanto na água bruta quanto na potável em pelo menos um dos três períodos de amostragem, sendo as maiores concentrações mensuradas nas águas brutas e no período seco. Estes resultados evidenciam que as atividades antrópicas na região influenciam a qualidade da água do recurso hídrico estudado, bem como a qualidade da água de distribuição. / The evaluation of six synthetics substances from industrials process and anthropogenic activities - diethyl phthalate, dibuthyl phthalate, nonylphenol, pentachlorophenol, bisphenol A and benzo[a]pyrene which one can interfer negatively in normal function of the endocrine system from animals and humans (xenoestrogens), was carried out in this study in drinking water and raw water on four cities at region of Paraíba do Sul River. An analytical method with high selectivity and sensitivity, with determination by gas chromatography coupled to mass spectrometry detector (GC/MS), preceded of samples concentration through the SPE technique was used. Good analytical techniques are not enough to ensure quality and reliability of the generated data results. For this, the methodology was submitted to the validation process, where parameters evaluated were: selectivity, specificity, linearity, work range, detection and quantification limits, precision, accuracy, robustness, percentage of recovery and uncertainty in measurement. The validation results showed that proposed method is suitable to quantify Paraíba do Sul river samples, and by its application could observe presence of all studied pollutants in drinking and raw water in one of the three sampling periods at least, and the highest measured concentrations were in raw water at dry periods. These results evidence that the anthropic activities at region are influencing the water quality of the studied water resource, as well as the quality of water for public supply.

Alguns compostos orgânicos como interferentes endócrinos e ativos farmacêuticos estão sendo encontrados em águas superficiais e vêm chamando a atenção de orgãos públicos e da comunidade científica. Dentre esses compostos, foram enfatizados nesse trabalho, o hormônio sintético 17α-etinilestradiol, o surfactante (4-nonilfenol), bisfenol A, o antibiótico β-lactâmico amoxicilina e a cafeína como traçador de atividade antrópica. Estes compostos são continuamente introduzidos em corpos d\'água pelo lançamento de esgoto in natura o que afeta a qualidade da água, a saúde dos ecossistemas e impacta o suprimento de água potável. Considerando a baixa taxa de remoção desses contaminantes pelo tratamento de água atualmente utilizado no Brasil e o estado de degradação dos mananciais de água para abastecimento público, esse trabalho apresenta o desenvolvimento de metodologia analítica para determinação dos compostos citados e a avaliação da eficiência de remoção quando o tratamento convencional de água é aplicado. A determinação foi baseada em métodos já estabelecidos e envolveram as etapas de limpeza e concentração de amostra usando extração em fase sólida (SPE) e análise por cromatografia a líquido de alta eficiência (HPLC) com detector de arranjo de diodos (DAD) e espectrometria de massas. As amostras do Reservatório do Guarapiranga foram utilizadas para ensaios em escala laboratorial que simulavam o tratamento convencional de água em planta real. Os resultados mostraram a adequação dos métodos utilizados para a separação e determinação desses compostos em amostras ambientais. Além disso, apontaram para a necessidade de se avaliar a utilização de metodologias não convencionais que otimizem a remoção pelo tratamento de água atualmente utilizado. / Some organic compounds, such as endocrine disruptors and pharmaceuticals, are being found in the surface water, and are concerning both the public organs and the scientific community. Among these compounds, the synthetic hormone 17α-ethinylestradiol, the surfactant (4-nonylphenol), bisphenol-A, the β-lactam antibiotic amoxicillin and the marker of human activity caffeine were highlighted in the present work. These compounds are continuously drained to the water bodies by sewers, affecting not only the water quality itself, but also the ecosystems, and impacting the drinking water availability. Currently in Brazil, the removal rate of these contaminants is low, whereas the water sources for public supply are highly degraded. In this context, the present work develops an analytical method to detect the aforementioned compounds, and to evaluate the efficiency of its removal by conventional water treatments. Detection was based on pre-established methods and steps involved clean up and samples concentration by solid phase extraction (SPE), high performance liquid chromatography with diode array detection (DAD), and mass spectrometry. Recovery tests were done using environmental samples from Guarapiranga Reservoir (São Paulo, SP). This samples were further used in laboratorial tests, simulating real scale water conventional treatments. Current results revealed the adequacy of the chosen methods in the separation and determination of the abovementioned compounds from natural samples. Also, they highlight the need for the evaluation of non-conventional methodologies that optimize removal by current water treatment.

Many exogenous and endogenous compounds are referred to as endocrine disruptors (EDCs), as they interfere with natural synthesis, signaling and metabolism of endogenous hormones. Common exogenous endocrine disruptors are benzo(a)pyrene (BaP) and 17α-ethinylestradiol (EE2). Endogenous endocrine disruptor 17β-estradiol (E2) is frequently present in the environment as well. In this thesis, the effect of the mentioned EDCs and their combinations on gene and protein expression of CYP1B1, 3A1 and 3A2 in rat liver, kidney and lung was determined. Protein expression was studied using Western blot method and specific antibodies; gene expression was assessed by quantitative PCR. Moreover, the effect of tested EDCs and their combinations on BaP metabolism and CYP3A specific activity (measured as testosterone 6β-hydroxylation) were studied in liver microsomal samples. It was confirmed, that BaP significantly increases CYP1B1 expression in rat liver and lung both alone and together with EE2 or E2. Pretreatment of rat with E2 and BaP increases the ability of BaP to induce CYP1B1 expression. On the contrary, EE2, E2 and their combination decrease the CYP1B1gene expression. The rate of BaP metabolites formed in liver microsomal samples increases in rats pretreated with BaP and its combinations. In liver, there was...

The overall objective of the research presented in this dissertation was to assess exposure to endocrine disrupting chemicals (EDCs), polychlorinated biphenyls (PCBs), phthalates, and bisphenol A (BPA) in the general population and evaluate their associations with adverse reproductive health effects, including cancers, in women. Given the proven contribution of unopposed estrogens to the risk for endometrial neoplasia or breast cancer, renewed health concerns have aroused about estrogen mimicking EDCs found in food, personal care products or as environmental contaminants. Our meta-analysis showed that exposure to estrogen mimicking PCBs increased summary risk of breast cancer and endometriosis. We further evaluated the relationship between endometriosis and breast cancer, and EDCs using a bioinformatics method. Our bioinformatics approach was able to identify genes with the potential to be involved in interaction with PCB, phthalates and BPA that may be important to the development of breast cancer and endometriosis. Therefore, we hypothesized that exposure to EDCs such as PCBs, phthalates, and BPA, results in adverse reproductive health effects in women. Using subject data and biomarkers available from the Center for Disease Controls National Health and Nutrition Examination Survey database we conducted a cross-sectional study of EDCs in relation to self-reported history of endometriosis, uterine leiomyomas, breast cancer, cervical cancer, ovarian cancer, and uterine cancer. Significantly higher body burdens of PCBs were found in women diagnosed with breast cancer, ovarian cancer, and uterine cancer compared to women without cancer. PCB 138 was significantly associated with breast cancer, cervical cancer, and uterine cancer, while PCBs 74 and 118 were significantly associated with ovarian cancer. The sum of dioxin-like PCBs were significantly associated with ovarian cancer (OR of 2.02, 95% CI: 1.06-3.85) and the sum of non-dioxin-like PCBs were significantly associated with uterine cancer (OR of 1.12, 95%CI: 1.03-1.23). Significantly higher body burdens of PCBs were also found in women diagnosed with endometriosis and uterine leiomyomas. Documenting the exposure to EDCs among the general U.S. population, and identifying agents associated with reproductive toxicity have the potential to fill research gaps and facilitate our understanding of the complex role environmental chemicals play in producing toxicity in reproductive organs.

Les perturbateurs endocriniens (PE) posent des risques pour la santé Humaine et pour la faune. L’utilisation de tests biologiques basés sur des mécanismes d’action spécifiques permet de caractériser le potentiel PE des substances chimiques dans le cadre de l'évaluation toxicologique, mais les capacités de biotransformation de ces modèles sont rarement prises en compte. Or, le métabolisme conditionne le devenir des xénobiotiques (détoxication vs. bioactivation) et donc in fine l'activité biologique mesurée. Dans ce travail, le devenir de deux contaminants œstrogéniques émergents (benzophénone-2, bisphénol S) a été comparé dans de nouveaux modèles in vitro et in vivo de poisson zèbre (cellules ZELH-zfERs, larve transgénique cyp19a1b-GFP) et des lignées humaines. Nos résultats démontrent que les modèles de poissons zèbres sont métaboliquement compétents et soulignent leur pertinence dans une approche intégrée in vivo/in vitro pour le criblage de l'activité PE des substances chimiques. / Endocrine disruptors (ED) are potentially harmful for Human beings and for wildlife species. Species-specific mechanism-based screening tests nowadays allow characterizing the ED potency of chemicals in the context of their toxicological assessment. However, the biotransformation capabilities of the biological models used are seldom taken into consideration, despite they ultimately condition the fate of the tested xenobiotics (detoxification vs. bioactivation), and, consequently, the biological response. In this work, we examined the fate of two emerging ED (benzophenone-2, bisphenol S) using novel in vitro and in vivo zebrafish models (ZELH-zfERs cells and cyp19a1b-GFP transgenic larvae) as well as human cell lines. Our results demonstrate that the zebrafish models are metabolically competent, and underline their relevance, accuracy and usefulness in an integrated in vivo/in vitro screening approach designed to assess ED's biological activity

Contexte et objectif : Plusieurs facteurs de risque de cancer ont été identifiés et il a été estimé que plus de 40% des cas dans les pays développés pourraient être évités en modifiant les facteurs de risque connus. L'objectif général de cette thèse était de démontrer que l’intégration de données génomiques et épigénomiques aux données détaillées sur les expositions environnementales et le mode de vie peut être utile pour identifier des biomarqueurs de ces facteurs et contribuer à augmenter notre connaissance de l'étiologie du cancer. Résultats : Dans un premier temps, nous décrivons comment les signatures génomiques et épigénomiques peuvent être utilisées pour identifier des marqueurs d’exposition et déchiffrer l’étiologie du cancer. Ensuite, nous contribuons au débat relatif à l’hypothèse de la chance dans le développement du cancer et démontrons que les mutations induites par le tabagisme sont plus prédictives du risque de cancer que les mutations aléatoires. Nous introduisons un modèle probabiliste pour la simulation de données mutationnelles et comparons la performance des outils d’identification de ces signatures avec des données réelles et simulées. De plus, nous introduisons une nouvelle méthode pour l’identification des signatures mutationnelles. Enfin, nous utilisons les données de méthylation de la cohorte E3N pour étudier le lien entre l'exposition aux retardateurs de flamme bromés et aux composés perfluorés, deux substances classées parmi les perturbateurs endocriniens, et la méthylation de l’ADN sanguin. Globalement, notre étude ne fournit aucune preuve d'altérations globales du méthylome ou d'altérations à l’échelle des CpGs. Cependant, certains résultats suggèrent l’existence d'altérations de la méthylation de gènes impliqués dans des voies biologiques (ex., la réponse aux androgènes) et nécessitent des recherches supplémentaires.Conclusion : Ce travail contribue à la recherche méthodologique portant sur les signatures mutationnelles en introduisant un protocole de mesure de performance et d’identification des signatures mutationnelles pouvant servir de référence à de futures études méthodologiques ou appliquées. Nos recherches sur les signatures mutationnelles et le méthylome démontrent l'utilité de tels outils pour évaluer les expositions et élucider leur rôle dans l'étiologie du cancer. / Context and aim: Several risks factors have been identified for cancer, and it has been estimated that more than 40% of cases in developed countries are preventable through the modulation of known modifiable risk factors. The overall objective of this thesis was to demonstrate that the analysis of genomic and epigenomic data integrated with well-characterised exposure and lifestyle data may be used to identify markers of environmental exposures and lifestyle and may contribute to increase our understanding of cancer aetiology.Results: We first describe how genomic and epigenomic signatures can be used to identify markers of exposure and decipher the aetiology of cancer. Then, we adopt the mutational signatures framework to contribute to the debate about the “bad luck” hypothesis for cancer and demonstrate that tobacco-related mutations are more strongly correlated with cancer risk than random mutations. We introduce a probabilistic model for the simulation of mutational signature data and compare the performance of the available methods for the identification of mutational signatures using both simulated and real data. Additionally, we introduce a new method for the identification of such signatures. Finally, we use methylation array data in an epidemiological study within the E3N cohort to investigate the association between exposure to Brominated Flame Retardants and Per- and polyfluoroalkyl substances, two organic pollutants that are known endocrine disrupting chemicals, and methylation in DNA from blood. Overall, our study does not provide evidence of methylation alterations at the level of the whole genome, in regions or in single CpGs. Suggestive evidence of alterations in the methylation of genes within plausible biological pathways (e.g. androgen response) warrants further investigations. Conclusion: Our work on the methodological aspects of mutational signature research introduces an original framework for measuring the performance of tools for the identification of mutational signatures that may serve as reference for future methodological or applied research. Our applications of both mutational signature and methylome research demonstrate the usefulness of such tools to assess exposures and elucidate their role in cancer aetiology.

Les bisphénols et les phtalates sont des contaminants environnementaux ubiquitaires du fait de leur utilisation massive dans la fabrication de divers produits de consommation. L’exposition à ces molécules est liée à de nombreuses pathologies, dont les cancers hormono-dépendants, mais les mécanismes moléculaires exacts par lesquels elles induisent leurs effets restent largement inconnus.Au cours de ce travail, nous avons étudié l’implication de la sérine thréonine kinase PKD1 dans l’effet de quatre bisphénols : bisphénol A (BPA), bisphénol AF (BPAF), bisphénol F (BPF) et bisphénol S (BPS) et deux phtalates (DEHP et MEHP) sur des cellules du cancer du sein et de la prostate.Nous avons ainsi montré que le BPAF, BPF, BPS, DEHP et MEHP stimulent de manière dose-dépendante la prolifération, la clonogénicité et la croissance indépendante de l’ancrage des cellules MCF-7 et que ces processus sont dépendants de l’expression de PKD1. En revanche, nous avons mis en évidence l’absence d’effet pro-prolifératif du BPA dans trois lignées de cancer de la prostate (LNCaP, PC3 et DU145). D’autre part, nous avons pu identifier que le BPA induit la phosphorylation de PKD1 dans les mitochondries. Enfin, nous avons démontré qu’il existe un effet cumulatif de certaines combinaisons de traitement de bisphénols et de phtalates et mis en évidence que le BPAF induit la transition épithélio mésenchymateuse des cellules MCF-7.Nos résultats permettent ainsi d’identifier PKD1 comme étant une cible moléculaire de certains bisphénols et phtalates dans les cellules MCF-7 fournissant de nouvelles connaissances sur les mécanismes d’action de ces molécules. / Bisphenols and phthalates are ubiquitous environmental contaminants due to their extensive use in the production of a variety of consumer products. Exposure to these molecules is linked to multiple pathologies including hormone-dependent cancers. However, the exact molecular mechanisms by which they exert their effects remain largely unknown.In our study, we analyzed the implication of the serine threonine kinase PKD1 in the effect of four bisphenols : bisphenol A (BPA), bisphenol AF (BPAF), bisphenol F (BPF) and bisphenol S (BPS) and two phthalates (DEHP and MEHP) on breast and prostate cancer cells.We thus showed that BPAF, BPF, BPS, DEHP and MEHP induce, in a dose-dependent manner, the proliferation, clonogenicity and anchorage independent growth of MCF-7 breast cancer cells, via a PKD1-dependent pathway. On the other hand, we showed that BPA does not have a pro-proliferative effect in three prostate cancer cell lines (LNCaP, PC3 and DU145). Furthermore, we determine that BPA induced the phosphorylation of PKD1 into the mitochondria. Finally, we demonstrated that BPAF stimulates epithelial to mesenchymal transition of MCF-7 cells and that co-exposure to combinations of bisphenols and phthalates induces cumulative proliferation effects in MCF-7 cells.Our results characterize PKD1 as a molecular target for bisphenols and phthalates in MCF-7 cells, providing new elements in the knowledge of the mechanisms of action of these molecules.

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.