O estudo de poluentes com características orgânicas e inorgânicas nas águas subterrâneas e superficiais de uma dada região é uma ferramenta importante na avaliação da poluição. Os interferentes endócrinos são produtos químicos sintéticos ou naturais que têm a capacidade de atuar no sistema endócrino de seres humanos e animais mimetizando hormônios naturais estimulando respostas diferentes das que originalmente seriam geradas e podem produzir efeitos adversos sobre os organismos, mesmo em concentrações de μg e ng L-1. As atividades antrópicas são a principal fonte de entrada de interferentes endócrinos no meio ambiente. O objetivo desta pesquisa foi determinar 13 compostos orgânicos (dietilftalato, dibutilftalato, nonilfenol, bisfenol A, cafeína, androstano, estrona, estradiol, etinilestradiol, progesterona, coprostanol, colesterol e colestanol) que podem estar presentes nas águas subterrâneas e superficiais da área de instalação do Reator Multipropósito Brasileiro (RMB). Este é um estudo sem precedentes e de grande importância para a região avaliada, uma vez que fornecerá orientação sobre o grau de contaminação das águas locais antes do início do projeto de construção. O estudo também permitirá verificar se o projeto de construção do reator oferecerá algum prejuízo ambiental para a área em seu entorno. Para a determinação dos compostos de interesse, foi utilizado um método analítico desenvolvido e validado para determinação dos compostos de interesse em amostras de água e particulado da coluna d\'água, consistindo na concentração das amostras por extração em fase sólida (SPE) e/ou extração ultrassônica, seguido de quantificação por cromatografia gasosa acoplada a detector de espectrometria de massa (GC/MS). Os resultados revelaram baixas concentrações de alguns dos compostos orgânicos estudados, derivados de atividades antrópicas nas proximidades do local. Os rios que atravessam a área do projeto de instalação apresentam a maioria dos valores abaixo de 0,05 μg L-1, normalmente em estação seca, exceto para cafeína, em outubro de 2016 (0,80±0,03 μg L-1 a jusante do empreendimento) e outubro de 2017 (0,22±0,01 μg L-1 a jusante do empreendimento) e para colesterol em outubro de 2017 a montante do empreendimento (6,6±0,3 μg L-1). / The study of pollutants with organic and inorganic characteristics in groundwater and surface waters of a region is an important tool in the assessment of pollution. Endocrine disrupters are synthetic or natural chemicals that have ability to act in endocrine system of humans and animals mimicking natural hormones stimulating responses different from those originally generated, and can produce adverse effects on organisms even at concentrations of μg and ng L-1. Anthropogenic activities are the main source of input of endocrine disrupters into the environment. The objective of this research was to determine 13 organic compounds (diethyl phthalate, dibutyl phthalate, nonylphenol, bisphenol A, caffeine, androstane, estrone, estradiol, ethinyl estradiol, progesterone, coprostanol, cholesterol and cholestanol) that may be present in the groundwater and surface Brazilian Multipurpose Reactor (RMB). This is an unprecedented and important study for the evaluated region, as it will provide guidance on the local water degree contamination prior to the start of the construction project. The study will also allow verifying if the construction project of the reactor will offer some environmental damage to the area in its surroundings. For the determination of the compounds of interest, an analytical method developed and validated for the determination of the compounds of interest in samples of water and particulate of the water column, consisting of the concentration of the samples by solid phase extraction (SPE) followed by quantification by gas chromatography coupled to mass spectrometry detector (GC/MS). By the results were observed low concentrations of some of the organic compounds studied, derived from anthropic activities near the site. The rivers that cross the installation project area show values below 0.05 μg L-1, usually in the dry season, except for caffeine, in October 2016 (0.80±0.03 μg L-1 downstream of the project) and October 2017 (0.22±0.01 μg L-1 downstream of the enterprise) and for cholesterol in October 2017 (6.6±0.3 μg L-1 upstream).

While diet and sedentary lifestyle remain important factors in the development of obesity, recent findings have shown the possible involvement of environmental obesogens, chemicals that can disrupt homeostatic energy balance and increase adiposity. Bisphenol A (BPA) is a compound used in the manufacturing of plastics as a hardening agent and is ubiquitous in the environment due to its widespread use. BPA has been shown to be an endocrine disruptor through its ability to mimic estrogen, which is now known to play important roles in adipose tissue growth and metabolism. In fact, a small but compelling number of studies have shown that mice exposed to BPA in utero or postnatally are fatter as adults. We hypothesized that BPA exposure exerts effects on adipose tissue, promoting adipogenesis and inflammation, and altering energy homeostasis in a manner that promotes obesity. We tested our hypothesis using both in vitro and in vivo models. First, we found that low concentrations of BPA increased the expression of the inflammatory genes, Il-6 and Tnfa, approximately 1.5-3.0 fold in mouse adipose tissue explants. We also found a 3-fold increase in the expression of the lipogenic gene, Fasn. BPA also altered the adipose tissue metabolism, increasing the levels of a number of glycolytic and TCA cycle metabolites, suggesting that BPA may disrupt energy homeostasis. We also found that BPA exposure increased proliferation of mesenchymal stem cells approximately 1.2-fold, which are potential adipocyteprecursors. The study was expanded using two different strains of mice, C57BL/6 and DBA/2J, chronically exposing them to BPA through drinking water for six weeks. A moderate concentration of BPA increased the perigonadal fat pad mass in males. This increase in adiposity was associated with adipocyte hypertrophy and decreased serum adiponectin levels. There were also changes in the expression of some genes with BPA treatment, including a 1.4-fold increase in Leptin and decreases in some Cytochrome P450 genes; however the genes differentially expressed were different between the two strains. Our results suggest that childhood exposure to low doses of BPA, in lieu of any developmental exposure, may contribute to childhood obesity.

Understanding how anthropogenic activity impacts the health and viability of wildlife populations is one of the most important tasks of environmental biology. A key concern related to bi-products of human activity is the accumulation of environmental pollutants within aquatic environments. Pollutants such as endocrine disruptors and heavy metals have the potential to impact both human and wildlife populations in contaminated areas. While much research has focused on how these compounds impact natural selection processes, such as viability and reproduction, their effect on sexual selection processes is not as clear. The goal of this dissertation was to address how environmental contaminants impact sexual selection processes in a sex-role reversed pipefish and evaluate how these effects may impact long-term population viability. Here we show that short periods of exposure to environmentally relevant concentrations of a synthetic estrogen result in male pipefish with female-like secondary sexual traits. While these males are capable of reproduction, exposed males are discriminated against by females in mate choice tests. In natural populations, this type of discrimination could reduce male mating opportunities, potentially reducing their reproductive success. In an additional component of this dissertation, it was discovered that pipefish populations around Mobile Bay, specifically Weeks Bay, are currently being exposed to significantly elevated levels of mercury. These populations are genetically distinct from coastal populations but moderate levels of gene flow occur among sites, and gene flow between contaminated and non-contaminated population may be influencing how environmental contaminants are impacting genetic diversity and population viability. In the case of endocrine disruptors, migration between contaminated and non-contaminated sites may negatively impact population viability. Morphological traits induced with exposure to contaminants may be maintained for extended periods of time, therefore, the effect the exposed phenotype has on mating dynamics and sexual selection could be carried to non-contaminated sites if exposed individuals move to new populations. On the other hand, immigration of individuals from non-contaminated sites into contaminated areas may help maintain genetic diversity within exposed populations. In conclusion, the work presented in this dissertation shows that the presence of environmental toxins can significantly impact sexual selection processes, which in turn can have profound effects on the viability and future evolutionary trajectory of populations. Future work in this area should not only address how these toxins impact individual fitness, but should also address how population structure may be influencing the severity of these compounds on natural populations.

Ecological impacts of natural estrogens and xenoestrogens in treated wastewater include altered sexual development and sex ratios among continuously exposed organisms. The primary sources of estrogenic activity in wastewater are natural estrogens such as estrone, 17β-estradiol and estriol and synthetic compounds like 17α- ethinylestradiol, alkylphenols and alklphenol ethoxylates. Precursors in raw wastewater can yield estrogenic intermediates during wastewater treatment. All these compounds can be destroyed by biochemical processes conventional wastewater treatment processes, suggesting that conventional processes can be optimized for removal of estrogenic activity from wastewater. Sorption to sludges derived from wastewater treatment affects the fates of hydrophobic xenoestrogens such as nonylphenol, in part because the biodegradability of sorbed contaminants is limited. It may also be possible to tailor sludge stabilization processes to remove trace contaminants, including estrogens. For example, there are significant differences in the efficiencies of aerobic and anaerobic digestion for destruction of alkylphenols and probably other estrogenic compounds with aromatic moieties. Because advanced wastewater treatment is not economically feasible for most communities, there is ample incentive to develop accurate relationships between operational parameters and removal of estrogenic compounds during secondary wastewater treatment. Large quantities of polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in clothing and plastic products since the 1970s. A small fraction of the PBDEs in manufactured products subsequently enters municipal wastewater. The resistance of these compounds to chemical and biochemical transformations provides opportunities for accumulation in sediments. Balances developed for PBDE congeners indicate that conventional wastewater treatment processes and soil infiltration of treated wastewater in recharge operations do not discriminate significantly among the major congeners in commercially available PBDE products. Accumulation of PBDEs at near part-per-million levels was measured in the sediments at the Sweetwater Recharge Facility in Tucson, Arizona, during 10-15 years of operation. Half times for loss of major PBDE congeners from sediments were decades or longer. Local agricultural soils amended with biosolids over a 20-year period showed similar accumulation of PBDEs. The widespread use of PBDEs in commercial products, compound persistence and toxicity indicate that additional effort is warranted to better understand fate-determining processes for PBDEs in the environment.

Polycystic ovary syndrome (PCOS) is one of the most common and complex endocrinopathies among reproductive-aged women. Symptom heterogeneity among clinical cases and in sibling studies suggests that PCOS is a multifactorial disease with environmental components. Investigators hypothesize that endocrine disruptors may contribute to the pathophysiological origins of PCOS in utero. The goal of this literature review is to present and compare the available research investigating the developmental origins of PCOS deriving from prenatal exposure to three major classes of endocrine disruptors: bisphenol A (BPA), phthalates, and androgenic endocrine disruptors. Considerable evidence has been found to suggest links between fetal exposure to endocrine disruptors and PCOS. Rodent studies reported that maternal BPA exposure dysregulates postnatal development and sexual maturation. In rats, gestational exposure to dibutyl phthalate (DBP) and di(2-ethylhexyl)phthalate (DEHP) resulted in polycystic ovaries among first and third generation offspring. Additionally, serum DBP concentrations are higher among women with PCOS. Regarding DEHP, animal studies have shown that prenatal exposure results in an endocrinological profile similar to PCOS. Nicotine and 3,4,4'-trichlorocarbanilide (TCC) are known androgenic endocrine disruptors. Inducing prenatal exposure to excess androgens in animal models has successfully recreated a PCOS-like phenotype that includes abnormal ovarian function, anovulatory cycling, impaired fertility, and increased visceral fat distribution. Based on the literature, endocrine disruptors appear to have an etiological role in PCOS development through prenatal exposure and thus may pose one of the greatest hazards to fetal health and development.

Os disruptores endócrinos são substâncias químicas, sintéticas ou naturais, capazes de interferir no sistema endócrino de seres humanos e animais. Pertencem à classe dos micro poluentes, pois mesmo em concentrações de μg e ng.L-1 causam efeitos adversos aos organismos a eles expostos. Os hormônios destacam-se dentre os disruptores endócrinos por serem compostos potencialmente ativos no sistema biológico e estão relacionados à origem de diversos tipos de cânceres. Esta dissertação teve por objetivo desenvolver e validar metodologia para determinar hormônios, considerados disruptores endócrinos, em amostras de água bruta e tratada da região da Bacia Hidrográfica do Rio Paraíba do Sul utilizando a técnica de cromatografia gasosa com detecção por espectrometria de massas. A população atendida pelas unidades da SABESP dessa região é de aproximadamente 11 milhões de habitantes. Através do processo de validação, a metodologia desenvolvida pode ser considerada seletiva, robusta, exata, linear e precisa para a análise proposta. Aplicando o procedimento analítico validado nas amostras coletadas, alguns dos compostos estudados puderam ser detectados tanto em água bruta como em água tratada permanecendo abaixo do limite de quantificação, exceto a cafeína que apresentou concentração média de 0,45 μg.L-1 em água bruta e 0,17 μg.L-1 em água tratada, observando-se indícios de contaminação principalmente nas épocas secas. Este projeto de pesquisa está vinculado a uma parceria entre o Instituo de Pesquisas Energéticas e Nucleares (IPEN) e a Companhia de Saneamento Básico do Estado de São Paulo (SABESP). / The endocrine disruptors are chemicals substances, synthetic or natural, which can interfere in endocrine system from humans and animals. They belong to the class of micro pollutants, because even at concentrations of μg e ng.L-1 can cause adverse effects to organisms to them exposed. The hormones stand out as endocrine disruptors because they are potentially active compounds in biological systems and are related to the origin of several types of cancers. This work aimed to develop and validate analytical methodology to determine hormones, considered endocrine disruptors, in drinking water and raw water at region of Paraíba do Sul River, using gas chromatography with mass spectrometry detector. The population served by the units of SABESP is around 11 million inhabitants. By the validation process, the developed methodology can be considered selective, robust, accurate and linear for the proposed analysis. Applying the validated analytical procedure for the samples, some compounds could be detected at drinking water and raw water remaining below limit of quantization, except caffeine that was detected in mean concentration of 0,45 μg.L-1 in raw water and 0,17 μg.L-1 in drinking water, principally due to drought season. This Project is linked to a partnership between Instituto de Pesquisas Energéticas e Nucleares (IPEN) and Companhia de Saneamento Básico do Estado de São Paulo (SABESP).

Orientador: Sebastião Roberto Taboga / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-16T00:12:46Z (GMT). No. of bitstreams: 1 Biancardi_ManoelFrancisco_M.pdf: 6869231 bytes, checksum: 32275d5e0c79d81cecdc898bc5e42bb9 (MD5) Previous issue date: 2010 / Resumo: A próstata é uma glândula encontrada não somente em machos de mamíferos, podendo estar presente em fêmeas de alguns roedores e também em mulheres. Os andrógenos são essenciais durante o desenvolvimento e também para a manutenção da homeostasia prostática ao longo da vida. No entanto, sensíveis interferências, principalmente em momentos críticos do desenvolvimento, podem predispor este órgão a desenvolver lesões durante a vida adulta e senil. Pesquisas tem demonstrado que o programa de expressão gênica controlado pelo receptor de andrógeno durante a organogênese prostática é muito semelhante ao que é ativado durante a instalação do câncer de próstata. Aliado a isso, um grande número de estudos tem demonstrado que a predisposição às desordens prostáticas tem sua origem nos momentos iniciais da vida. Desta forma, o objetivo deste trabalho foi avaliar se a exposição androgênica intra-uterina e pós-natal pode interferir na morfofisiologia da próstata de roedores, podendo levar ao surgimento de desordens prostáticas durante a vida adulta. Para isto, este trabalho foi dividido em duas etapas. Primeiro, grupos de ratos Wistar jovens e adultos não tratados e de ratas adultas tratadas com testosterona (1 mg/Kg/48 horas) durante 7, 14 e 21 dias foram analisadas. As próstatas destes animais foram submetidas a análises morfométrico-estereológicas, imunohistoquímicas e ultra-estruturais. Em uma segunda etapa, grupos de gerbilos machos e fêmeas expostos à testosterona durante a vida embrionária (100 ?g ou 1 mg) e pós-natal (100 ?g) foram avaliados na vida adulta. As glândulas prostáticas destes animais foram submetidas a análises morfométrico-estereológicas, imunohistoquímicas, além da reconstrução tridimensional. Os resultados mostraram que as próstatas das ratas sujeitas a terapias androgênicas durante a vida adulta apresentaram um intenso desenvolvimento, tornando-se mais ativas nos processos de síntese e secreção. Além de sofrer um intenso desenvolvimento, a glândula prostática destes animais tornou-se, morfologicamente e fisiologicamente, muito semelhante à próstata ventral dos ratos. Entretanto, apesar das próstatas das ratas tratadas sofrerem um expressivo desenvolvimento induzido pela ação androgênica, não foram observadas a presença de lesões nestas glândulas. Já os machos e as fêmeas de gerbilos que sofreram exposição androgênica anormal durante o período embrionário, apresentaram uma alta incidência de lesões prostáticas na vida adulta, podendo-se evidenciar a presença frequente de focos inflamatórios e de neoplasias intra-epiteliais. Os resultados mostraram que o excesso de andrógeno interfere significantemente na homeostasia prostática, levando a um intenso desenvolvimento glandular ou mesmo predispondo esta glândula a desenvolver lesões durante a vida adulta. Estes aspectos são de grande interesse, pois é cada vez maior o número de relatos na literatura mostrando que a desbalanço hormonal durante os momentos iniciais do desenvolvimento prostático podem predispor este órgão a manifestar doenças durante a vida adulta e senil. / Abstract The prostate is a gland found not exclusively in male mammals, may also be present in female of some rodents and also in women. The androgens are essential for the development and maintenance of prostatic homeostasis throughout life. However, sensible interferences, especially during critical stages of development, can predispose this organ to develop lesions in adult and senile life. Researches have shown that the gene expression program controlled by androgen receptor during prostatic organogenesis is very similar to that activated during the installation of prostate cancer. Moreover, a large number of studies have demonstrated that the predisposition to prostate disorders has its origin in the early stages of life. Thus, the objective of this study was to evaluate whether intrauterine and postnatal androgen exposure alters the morphophysiology of rodents prostate leading to the development of prostatic disorders in adulthood. For this, the work was divided into two stages. At first, groups of untreated young and adult male Wistar rats and adult female rats treated with testosterone (1mg/Kg/48 hours) for 7, 14 and 21 were analyzed. The prostates of these animals were subjected to morphometric-stereological, immunohistochemical and ultrastructural analyses. In a second step, groups of male and female gerbils exposed to testosterone (100 ?g or 1 mg) during embryonic and postnatal (100 ?g) life were analyzed at adulthood. The prostatic glands of these animals were subjected to morphometric-stereological, immunohistochemical and also to three-dimensional reconstruction analyses. The results showed that prostates of female rats subjected to androgen therapy during adulthood had an intense development, presenting a more active synthesis and secretion status. In addition to this intense development, the prostate gland of these animals became morphologically and physiologically very similar to the ventral prostate of adult male rats. However, despite the prostates of treated rats suffered a significant development caused by the androgenic action, it was not observed the presence of lesions in these glands. In other hand, males and females gerbils submitted to abnormal androgen exposure during the embryonic period exhibited a high incidence of prostatic lesions in adulthood, being frequent the presence of inflammatory foci and intraepithelial neoplasia. The results showed that androgen excess interfere significantly in the prostate homeostasis, leading to an intense glandular development or even predisposes this gland to develop lesions during adulthood. These aspects are of great interest because a growing number of reports in the literature has shown that the hormonal imbalance during the early stages of prostate development may predispose this organ to manifest disease during adulthood and senescence. / Mestrado / Mestre em Biologia Celular e Estrutural

Os metais podem causar efeitos adversos de grande amplitude na função reprodutiva de animais, principalmente em organismos aquáticos. Eles podem alterar o sistema endócrino, atuando na esteroidogênese, afetando o processo reprodutivo dos peixes. Nosso objetivo foi investigar os efeitos dos metais alumínio (Al) e manganês (Mn) em pH ácido sobre a esteroidogênese de machos de Astyanax bimaculatus, sexualmente maduros, após uma exposição aguda de 96 horas e avaliar se os animais foram capazes de recuperar dos possíveis efeitos destes metais em água livre de metais. Esses animais foram expostos a uma concentração nominal de 0,5 mg.L-1 de Al e Mn (isolados ou combinados), e os grupos experimentais foram mantidos em pH ácido (5,5) para manter os metais biodisponíveis. Foi realizada uma exposição aguda de 96 horas, com amostragens em 24h e 96h, e depois também um período de 96h em água livre de metais, com amostragens em 120h e 192h, a partir do o início do experimento. Foram determinadas as concentrações plasmáticas de testosterona (T), 11-cetotestosterona (11-KT), 17β-estradiol (E2) e cortisol (C) por ELISA. Além disso, foram realizadas análises histológicas dos testículos e avaliação da concentração espermática. Os metais estudados, além do pH ácido, foram capazes de aumentar as concentrações plasmáticas dos androgénos T e 11-KT. Também foi observado um aumento transitório de E2 em 24h, mas apenas em animais expostos ao Mn e depois uma diminuição em 96h. A exposição ao pH ácido e metais, sozinhos ou combinados não provocou alterações nos níveis de C. Sendo assim, Al e Mn , assim como a acidez da água podem atuar como desregulador endócrino em machos de A. bimaculatus, principalmente por estimulação da síntese de androgénos, causando alterações no sistema fisiológico. No entanto, 96 horas não foram suficientes para que os animais se recuperassem. Os testículos encontravam-se em estágio avançado de maturação, enquanto que a concentração espermática não apresentou alterações significativas que indicassem a atuação dos metais em conjunto ao pH ácido. Táticas reprodutivas podem ter sido utilizadas pela espécie para desencadear alterações na esteroidogênese testicular, principalmente acelerando o processo de espermatogênese e espermiogênese, o que pode interferir com a dinâmica reprodutiva / Metals can cause adverse wide range effects on reproductive function of animals, mostly in aquatic organisms. They can alter the endocrine system, acting on gonadal steroidogenesis, affecting the reproductive process of fish. We aimed to investigate the effects of the metals aluminum (Al) and manganese (Mn) in acidic pH on the steroidogenesis of Astyanax bimaculatus males, sexually mature, after an acute exposure of 96 hours and evaluate if the animals were able to recover of the possible effects of these metals in the water free of metals. Mature males were exposed to a concentration of 0.5 mg.l-1 of Al and Mn (isolated or combined) and the experimental groups were maintained at acidic pH (5.5) to keep the metals bioavailable. We performed an acute exposure of 96 hours, with samplings at 24h and 96h, and then also a period of 96h in water free of metals, with samplings at 120h and 192h from the beginning of the experiment. We measured the plasma levels of testosterone (T), 11-ketotestosterone (11-KT), 17?-estradiol (E2) and cortisol (C) by elisaimmunoassay. Furthermore, histological analysis of testes and evaluation of the sperm concentration were performed. The metals studied, in addition to acidic pH, were able to alter the plasma concentration of the androgens T and 11KT. A transitory increase (24h) of E2 levels was also observed, but only in animals exposed to Mn and then a decrease in 96h occurred. Exposure to acidic pH and metals, alone or combined did not trigger changes in C plasma levels. Generally, Al and Mn as well as the acidity of water can act as endocrine disruptor in A. Bimaculatus males, mainly by stimulating the androgens synthesis, causing changes on physiological system. However, 96 hours in water free of metals were not enough for the animals to recover from the effects of the metals. The testes were in the advanced stage of maturation, while sperm concentration was not significantly changed to suggest any influence of metals together with acidic pH in altering this variable. Reproductive tactic could be used by the species to trigger changes in testicular steroidogenesis, mainly accelerating the process of spermatogenesis and spermiogenesis, what may interfere with the reproductive dynamics

Orientador: Wilma De Grava Kempinas / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-22T22:18:22Z (GMT). No. of bitstreams: 1 Guerra_MarinaTrevizan_D.pdf: 6009222 bytes, checksum: 1ca90ae1ef82035a0e6930b277dac172 (MD5) Previous issue date: 2013 / Resumo: Os desreguladores endócrinos são substâncias químicas que podem mimetizar ou antagonizar os hormônios endógenos, alterando o equilíbrio hormonal necessário para o desenvolvimento correto. Sabe-se que a exposição de organismos a agentes hormonalmente ativos durante períodos críticos do desenvolvimento pode levar a alterações permanentes detectadas somente na vida adulta. Em várias espécies animais estes compostos podem atingir o feto via placenta ou a prole, pelo leite materno. Embora pesquisas iniciais tenham focado em estrógenos e antiandrógenos ambientais, a presença de compostos com atividade androgênica tem sido descrita como contaminante em rios e animais destinados a alimentação. Vários estudos demonstraram que a exposição de animais a altos níveis de andrógenos durante o período perinatal pode causar alterações morfológicas, bioquímicas e funcionais permanentes em vários órgãos e sistemas. A exposição perinatal a andrógenos exógenos pode causar masculinização fisiológica e comportamental em fêmeas e levar a alterações reprodutivas em machos. O objetivo deste trabalho foi avaliar os possíveis efeitos da exposição a um agente androgênico sobre o sistema genital e a função reprodutiva de animais expostos durante períodos críticos de desenvolvimento. Para tanto, ratas prenhes foram alocadas em quatro grupos experimentais: controle, que recebeu somente óleo de milho (veículo), e tratados com propionato de testosterona nas doses de 0,05mg/kg, 0,1mg/kg, ou 0,2mg/kg. Os tratamentos foram realizados por via subcutânea, do dia gestacional 12 ao final da lactação. A prole feminina foi avaliada quanto ao número de células germinativas fetais, peso corpóreo e distância anogenital no dia pós-natal 1, número de mamilos, idade de instalação da puberdade, histologia uterina e ovariana, dosagens hormonais, comportamento sexual, fertilidade, níveis de receptores esteroides uterinos através de imunohistoquímica, assim como taxa de proliferação/morte celular uterina e testes uterotróficos. Nos filhotes do sexo masculino foram avaliados, na idade adulta e meia idade, a histologia testicular e epididimária, contagens, morfologia e motilidade espermáticas, dosagens hormonais, comportamento sexual e fertilidade. Os resultados demonstraram que em fêmeas, a exposição perinatal ao propionato de testosterona ocasionou alteração na intensidade de marcação dos receptores esteroides uterinos em todas as doses testadas, diminuição nos índices de proliferação e morte celular no tecido uterino nas doses de 0,1 e 0,2mg/kg e aumentou a predisposição uterina a responder a estímulos estrogênicos na dose de 0,1mg/kg e 0,2mg/kg. Entretanto, estas alterações não foram capazes de prejudicar a diferenciação sexual feminina e a fisiologia normal do sistema genital feminino. Em relação aos filhotes do sexo masculino, a exposição perinatal a andrógenos provocou redução na produção e nas reservas espermáticas na idade adulta, sem, contudo, alterar a fertilidade destes animais após acasalamentos naturais. Podemos concluir que a exposição perinatal a andrógenos, nas doses utilizadas neste experimento, provocou o aparecimento de alterações tardias no sistema genital feminino como modificações nos receptores esteroides uterinos e anormalidade na resposta a estímulos estrogênicos e, no sistema genital masculino, alterações na produção espermática. Estas repercussões, entretanto, não foram capazes de alterar o desempenho geral de fertilidade em ambos os sexos / Abstract: Endocrine disruptors are chemicals that may mimic or antagonize endogenous hormones, altering the critical hormonal balance required for proper health and development. It is well known that exposure of organisms to some hormonally active agents during critical periods of development imprints permanent changes that can be detected later in adulthood. In many animal species these substances reach the fetus via placenta and/or the offspring via the mother's milk. Although first researches have focused on environmental estrogens and antiandrogens, androgenic activity has been described as contaminant in rivers and beef cattle. Previous studies demonstrated that exposure of experimental animals to high levels of androgens during perinatal age causes permanent morphological, biochemical, and functional alterations in several organs and systems. Perinatal exposure of female rodents to exogenous androgens results in both physiological and behavioral masculinization and causes reproductive disruption in male rodents. The aim of this study was to assess the possible effects of an androgenic compound on genital system and reproductive function of animals exposed during critical periods of development. Pregnant female rats were allocated into four experimental groups: control, which received corn oil (vehicle), and treated with testosterone propionate at doses of 0.05mg/kg, 0.1mg/kg and 0.2mg/kg. Treatments were performed subcutaneously, from gestational day 12 until the end of lactation. The female offspring was evaluated for fetal germ cell number, body weight and anogenital distance at post-natal day 1, number of nipples, puberty onset, histology of reproductive organs, hormonal levels, sexual behavior, fertility test, immunohistochemistry of steroid receptors, proliferation/apoptotic index, uterotrophic test and uterine stimulation with estrogens. On male offspring, at adult age and middle-age, histology of testis and epididymis, sperm counts, morphology and motility, hormonal levels, sexual behavior and fertility test were evaluated. Results demonstrated that, in females, the perinatal testosterone propionate exposure caused an alteration in the pattern of uterine steroidal receptors imunostaining in all tested doses, a decreased proliferation/apoptotic index in the uterine tissue at 0.1 and 0.2mg/kg and a greater predisposition from uterus in responding to estrogens stimulation at dose of 0.2mg/kg. However, these alterations were not capable of impairing female sexual differentiation and normal physiology of female genital tract. On male offspring, the perinatal androgenization provoked a reduction in sperm production and reserves at adult age, without altering fertility after natural mating. We can conclude that perinatal exposure to androgens, at doses used in this experiment, provoked the appearance of late alterations in the female genital system as modifications in the uterine steroidal receptors and abnormalities in uterine response to estrogenic stimulation, and in male genital system, as spermatic production impairment. These repercussions, however, were not capable to alter the general fertility performance in both sexes / Doutorado / Biologia Celular / Doutora em Biologia Celular e Estrutural

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