Disruptores endócrinos: interações com o meio ambiente e puberdade / Endocrine disruptors: interactions with the environment and puberty

Este estudo tem como objetivo apresentar substâncias conhecidas como disruptores endócrinos e suas possíveis interferências no desenvolvimento puberal das meninas. Trata-se de uma revisão da literatura feita a partir do levantamento e análise de 37 referências bibliográficas nas quais os autores chamam a atenção para as diversas formas de absorção de produtos ricos em componentes desequilibradores hormonais que, por ação conjunta e prolongada, interferem no sistema endócrino, promovendo antecipação no desenvolvimento dos caracteres sexuais secundários. Concluiu-se que a exposição a inúmeros agentes disruptores presentes no dia a dia das meninas, por ação prolongada e acumulativa, pode promover uma antecipação na maturação dos caracteres sexuais secundários.(AU)

This study aims to present substances known as endocrine disruptors and theirpossible interference in girls puberal development. This is a systematic review of the literaturebased on the survey and analysis of 37 bibliographical references in which the authors drawattention to the multiple ways of absorption of products rich in hormonal imbalancecomponents that by combined and prolonged action, interfere in the endocrine system, promoting anticipation in the development of secondary sexual characteristics. In conclusion, the exposure to numerous disrupting agents present in the daily lives of girls, by prolonged andcumulative action, can promote an anticipation in the maturation of secondary sexual characteristics.(AU)

Contaminación, disruptores endocrinos y cáncer / Contamination, endocrine disruptors and cancer

Desde mediados del siglo XX numerosas especies, muy diferentes entre sí y ubicadas en todas las áreas y rincones del planeta, comenzaron a presentar diversas alteraciones, muchas de las cuales sugerían estar relacionadas con trastornos del sistema endocrino. Las investigaciones demostraron que tales alteraciones eran producidas por la exposición a diferentes sustancias químicas contaminantes, las cuales podían alterar la salud y producir graves enfermedades. Dentro de ellas destacó un grupo heterogéneo de compuestos con estructuras químicas muy diferentes, capaces de actuar a dosis muy bajas, mostrar distintos mecanismos de acción y ser capaces de alterar el equilibrio hormonal, por lo que se les denominó “disruptores endocrinos químicos”. Estas sustancias, al ser liberadas al medioambiente o formar parte de objetos, alimentos o medicinas, constituyen un gran riesgo para los seres humanos y toda la vida del planeta, produciendo no solo disfunciones endocrinas sino también diferentes tipos de cáncer, destacando los más frecuentes. A pesar de la trascendencia y significado del impacto de estos compuestos, ellos no son suficientemente conocidos ni entendidos, por lo que el objetivo de esta revisión es mostrar su origen e impacto en la salud humana, resaltando su papel como inductores de cáncer, lo cual ha motivado múltiples investigaciones clínicas y biológicas.

Since the mid-twentieth century, many species, very different from each other and located in all areas and corners of the planet, began presenting various alterations, many of which suggested to be related to endocrine disorders. Research has shown that such alterations were caused by exposure to various chemical contaminants that could affect the health and cause serious illnesses. Among them stands a diverse and large group of compounds, with very different chemical structures, capable of altering the hormonal balance, act at very low doses and with different mechanisms of action, that are called “endocrine disrupting chemicals”. When released into the environment or as part of objects, food or medicines, constitute a major risk to animals and humans, which produces not only endocrine dysfunctions but also different cancers, which include the most common types. Despite the importance and significance of the impact of these compounds, they are not sufficiently known or understood, so the aim of this review is to show their origin and impact in the field of human health, highlighting their role as inducers of cancer, which has led to multiple clinical and biological investigations.

Regulamentação do estrogênio sintético 17-etinilestradiol em matrizes aquáticas na Europa, Estados Unidos e Brasil / Regulación del estrógeno sintético 17-etinilestradiol en matrices acuáticas en Europa, Estados Unidos y Brasil / Regulation of the synthetic estrogen 17-ethinylestradiol in water bodies in Europe, the United States, and Brazil

O estrogênio sintético 17α-etinilestradiol, principal componente utilizado em formulações de contraceptivos orais, tem sido apontado como um dos principais compostos responsáveis por provocar efeitos adversos no sistema endócrino de várias espécies. O objetivo deste estudo foi analisar o estado da arte dos dispositivos legais e normativos referentes ao controle desse estrogênio sintético nas águas da Europa e dos Estados Unidos, e traçar um paralelo com a realidade brasileira. No geral, os países têm buscado ampliar a regulamentação e monitoramento de alguns micropoluentes emergentes que antes não eram objeto de atenção por parte dos dispositivos legais. A Europa está mais avançada no que tange à qualidade dos corpos hídricos, enquanto que nos Estados Unidos esta substância é alvo de regulamentação apenas para a água destinada ao consumo humano. No Brasil, ainda não há nenhum dispositivo legal ou normativo que aborde esse estrogênio, o que pode ser associado a uma baixa maturidade do sistema brasileiro quanto ao controle de poluentes hídricos.

El estrógeno sintético 17α-etinilestradiol, principal componente utilizado en fórmulas de contraceptivos orales, ha sido apuntado como uno de los principales compuestos responsables por provocar efectos adversos en el sistema endócrino de varias especies. El objetivo de este estudio fue analizar el estado de la cuestión de los dispositivos legales y normativos referentes al control de este estrógeno sintético en las aguas de Europa y de los Estados Unidos, y trazar un paralelo con la realidad brasileña. En general, los países han buscado ampliar la regulación y el monitoreo de algunos microcontaminantes emergentes que antes no eran objeto de atención por parte de los dispositivos legales. Europa está más avanzada en lo que se refiere a la calidad de los cuerpos hídricos, mientras que en los Estados Unidos esta substancia es objeto de regulación solamente para el agua destinada al consumo humano. En Brasil todavía no existe ningún dispositivo legal o normativo que aborde este estrógeno, lo que puede ser asociado a una inmadurez del sistema brasileño respecto al control de contaminantes hídricos.

The synthetic estrogen 17α-ethinylestradiol, the principal component of oral contraceptives, has been identified as one of the main compounds accounting for adverse effects on the endocrine system in various species. This study aimed to analyze the state-of-the-art in legislation and guidelines for the control of this synthetic estrogen in water bodies in Europe and the United States and to draw a parallel with the Brazilian reality. Countries have generally attempted to expand the regulation and monitoring of certain emerging micropollutants not previously covered by legislation. Europe is more advanced in terms of water quality, while in the United States this estrogen is only regulated in water for human consumption. Brazil still lacks legal provisions or standards for this estrogen, which can be explained by the relatively limited maturity of the country's system for controlling water pollutants.

Telarquia precoz en la niñez: causas y estudio / Premature thelarche in childhood: causes and study

Se define Telarquía Precoz como la aparición del botón mamario antes de los ocho años en ausencia de otros signos de pubertad. En los primeros años de vida puede ser secundaria al fenómeno de la minipubertad, mientras que en la etapa escolar podría ocurrir debido a la interacción entre disruptores endocrinológicos y la obesidad. Una parte importante se mantiene estacionaria o revierte, mientras que un pequeño porcentaje puede evolucionar hacia la pubertad precoz. Se debe realizar una anamnesis y examen físico adecuado buscando otros signos puberales, una buena curva de crecimiento y puede complementarse con imágenes y con un seguimiento para intentar determinar aquellas pacientes que evolucionarán hacia la pubertad precoz.

Premature thelarche is defined as the breast bud appearance before eight years, without other signs of puberty development. During the first years of life it can be secondary to the minipuberty phenomenon, while during school period it's usually secondary to the interaction between endocrine disruptors and obesity. Although most of cases remain stable or regresses, a small percentage can evolve to precocious puberty. An appropriate clinical history and physical exam looking for other signs of precocious puberty must be held, complemented with the correspondent follow up and images studies, in order to diagnose patients that will evolve to precocious puberty.

Testicular toxic changes induced by bisphenol A in adult albino rats: a histological, biochemical, and immunohistochemical study

Bisphenol A [BPA] is an endocrine disruptor that is incorporated in many plastic industries worldwide. The exposure of humans to such substances starts from the fetal life to the postnatal life and extends throughout the life of the individual. Many agencies have raised warnings against the excessive use of such substances. The present study was designed to evaluate the biochemical and histological changes induced by BPA in the testis of adult male albino rats and to detect the ability of self-regeneration after stoppage. Thirty-two adult male albino rats were used. The rats were divided equally into four groups [eight animals each]. Groups I and II were used as negative and positive control groups, respectively. Rats of group III were given an oral dose of 50 mg/kg of BPA per day for 8 weeks. In group IV, the rats were treated in the same manner as in group III and then left without treatment for 4 weeks for recovery. At the time of sacrifice, all rats were anesthetized with ether, and blood samples were collected for estimation of testosterone. The testes were dissected out and processed for testicular malondialdehyde and glutathione measurement and light and electron microscopic examination. The diameter and epithelial height of the seminiferous tubules were estimated morphometrically and statistically analyzed. Biochemical results of the BPA-treated group [group III] revealed testicular affection with oxidative stress. Testes of this group showed many distorted seminiferous tubules lined by disorganized epithelium and separated with wide interstitium containing congested blood vessels. Apoptotic nuclei of some spermatids and intercellular spaces were also seen. There was a decrease in estrogen receptors. Statistical analysis of epithelial height and tubular diameter confirmed the results. However, in the recovery group [group IV], the histological and the biochemical changes were reduced but did not return to normal. These results demonstrated that BPA had deleterious effects on the testis with some sort of self-recovery after stoppage

Contribution of environmental pollutants to male infertily: A working model of germ cell apoptosis induced by plasticizers

Bisphenol A [2,2-bis(4-hydroxyphenyl)propane] (BPA), 4-nonylphenol (NP) and di(2-ethylhexyl)phthalate (DEHP), and its metabolite mono-2-ethylhexyl phthalate (MEHP) are chemicals found in plastics, which act as endocrine disruptors (EDs) in animals, including human. EDs act like hormones in the endocrine system, and disrupt the physiologic function of endogenous hormones. Most people are exposed to different endocrine disruptors and concern has been raised about their true effect on reproductive organs. In the testis, they seem to preferentially attack developing testis during puberty rather than adult organs. However, the lack of information about the molecular mechanism, and the apparently controversial effect observed in different models has hampered the understanding of their effects on mammalian spermatogenesis. In this review, we critically discuss the available information regarding the effect of BPA, NP and DEHP/ MEHP upon mammalian spermatogenesis, a major target of EDs. Germ cell sloughing, disruption of the blood-testis-barrier and germ cell apoptosis are the most common effects reported in the available literature. We propose a model at the molecular level to explain the effects at the cellular level, mainly focused on germ cell apoptosis.

A exposição ao glifosato-roundup causa atraso no início da puberdade em ratos machos / Glyphosate-roundup exposure delays puberty onset in male rats

Os efeitos causados pelas substâncias contidas nos pesticidas e adjuvantes podem ser responsáveis por inúmeras alterações no sistema reprodutivo de machos e de fêmeas. A partir do momento que o glifosato-Roundup penetra na célula ele reduz a atividade da proteína StAR e da enzima aromatase. Este trabalho avaliou a possível correlação entre o desenvolvimento das características puberais em animais expostos diariamente ao herbicida glifosato, pela observação do crescimento e desenvolvimento e do início do período púbere. Utilizou-se 32 ratos machos divididos em 4 grupos de tratamentos (0, 5, 50 e 250 mg/kgPV), dos 23 aos 53 dias de idade. Utilizou-se análise de MANCOVA para a comparação dos pesos corporais, Kruskall-Wallis para o dia e ANOVA para o peso ao descolamento do prepúcio. Não houve interferências do tratamento sobre o crescimento dos animais em nenhum grupo. A idade à puberdade foi significativamente diferente entre os grupos 50 mg/kg e 0 mg/kg (36,6±0,5; 36 dias; p<0,05), 250 mg/kg e 0 mg/kg (37,2±0,4; 36 dias; p<0,001) e 5 mg/kg e 250 mg/kg (36,5±0,53; 36 dias; p<0,05). O peso à puberdade foi maior no grupo de 250 mg/kg em relação aos grupos de 0 mg/kg e 5 mg/kg (142,7 ± 9,3; 128,9 ± 5,4; 126,1 ± 8,8 g, respectivamente; p<0,001). O peso do grupo de 50 mg/kg (134,1 ± 9,2g) não foi diferente dos outros grupos. É provável que a exposição crônica ao herbicida glifosato-Roundup cause a disrupção endócrina no eixo hipotalâmico-hipofisário-gonadal durante a maturação sexual, pela evidenciação do atraso no início da puberdade.

The effects of herbicides and it's adjuvants can be responsible for several alterations in reproductive organs of male and female. Since glyphosate-Roundup penetrates in the cell, it reduces the activity of StAR protein and aromatase enzime. This study evaluated the development of pubertal characteristics in animals receiving oral dosages of glyphosate-Roundup by gavage, by daily body weight measurement and verification of preputial separation (PPS). 32 male rats were allocated in 4 groups of treatments (0, 5, 50 e 250 mg/kg) from 23 to 53 days of age. The body weight from 23 to 53 days was compared using analysis of MANCOVA, Kruskall-Wallis was used to compare the day at PPS and ANOVA was used to compare the body weight at PPS. Age at PPS was different between groups 50 mg/kg and 0 mg/kg (36,6±0,5; 36 days; p<0,05), 250 mg/kg and 0 mg/kg (37,2±0,4; 36 days; p<0,001) and 5 mg/kg and 250 mg/kg (36,5±0,5; 36 days; p<0,05). The body weight at PPS was higher in group of 250 mg/kg n comparison to groups of 0 mg/kg and 5 mg/kg (142,7 ± 9,3; 128,9 ± 5,4; 126,1 ± 8,8 g, respectively; p<0,001). The body weight of group 50 mg/kg (134,1 ± 9,2g) wasn't differ from another groups. Probably, the daily exposure to glyphosate-Roundup causes endocrine disruption in hypothalamic-pituitary-gonad axis during sexual maturation, because it delayed the onset of puberty.

Exposição ambiental a interferentes endócrinos com atividade estrogênica e sua associação com distúrbios puberais em crianças / Environmental exposure to endocrine disruptors with estrogenic activity and the association with pubertal disorders in children

A substância exógena que causa efeitos adversos na saúde de um organismo ou sua descendência, como resultado de distúrbios na função hormonal, é denominada interferente endócrino. Nos últimos anos, produtos ambientais com atividades hormonais têm sido documentados como causadores de anormalidades puberais ou reprodutivas em animais. Os poucos casos comprovados em humanos foram aqueles relacionados a exposições acidentais. Apesar disso, pediatras e pais recomendam a suspensão de todos os alimentos potencialmente contaminados, em especial carne (aves, gado) e derivados da soja quando a criança apresenta alguma alteração puberal. Estas recomendações, se não embasadas cientificamente, podem ter conseqüências deletérias, não apenas pela eliminação de fontes protéicas da dieta, como também por retardar a investigação de causas tratáveis. Por outro lado, a não investigação dos efeitos adversos destes produtos é da mesma forma danosa. Esta revisão descreve os principais interferentes endócrinos responsáveis por alterações puberais em humanos e conclui que, excetuando exposições acidentais a altas quantidades destes produtos, mais estudos são necessários para responsabilizar a ação crônica e em baixas doses destas substâncias na alteração do tempo de desenvolvimento puberal em nossa espécie.

Endocrine disruptors are exogenous substances with adverse health effects in intact organisms or their progeny, secondary to changes in endocrine function. Recent years have witnessed constant reports of environmental factors with hormone-like effects causing pubertal or reproductive abnormalities in animals. The few cases proven to be associated with pubertal disorders in humans have been related to accidental exposure. Nevertheless, pediatricians and parents recommend suspending all possible estrogen-contaminated food, especially meat (poultry, beef) and soy products, when the child presents with a pubertal disorder. These recommendations, if not scientifically sound, may have deleterious consequences by eliminating sources of dietary protein and possibly delaying the investigation of other potential and treatable causes. On the other hand, not investigating potential side effects of these products could have similar harmful effects. The current article describes the main endocrine disruptors associated with pubertal disorders in humans and concludes that except for accidental exposure to high doses, more research is needed on the effects of chronic and low-dose exposures in altering human pubertal development.

Ingestão excessiva de fitoestrógenos e telarca precoce: relato de caso com possível correlação / High intake of phytoestrogens and precocious thelarche: case report with a possible correlation

Telarca precoce, desenvolvimento mamário antes dos 8 anos de idade, apresenta dois picos de incidência, nos dois primeiros anos de vida e após os 6 anos de idade. Uma menina de 4,75 anos apresentou-se com telarca associada à ingestão excessiva de fitoestrógenos. O desenvolvimento puberal M2P1-2, os níveis hormonais e o US pélvico eram compatíveis com puberdade precoce periférica. Durante o seguimento, observou-se ingestão diária de alimentos baseados em soja (> 40 mg fitoestrógenos/dia). Soja contém fitoestrógenos, principalmente genisteína e daidzeína. Embora menos potentes do que o estradiol, sua concentração pode ser 13.000 a 22.000 vezes maior em crianças alimentadas somente com fórmulas baseadas em soja. Os pais foram aconselhados a reduzir para uma vez na semana o seu fornecimento na dieta. O desenvolvimento puberal cessou em M2-3P1 e a paciente, com 8,66 anos, continua a desenvolver-se com idades óssea e cronológica equivalentes. Questões relacionadas à segurança alimentar, principalmente de alimentos baseados em soja, permanecem sem respostas precisas. Embora sejam conhecidas as etiologias da puberdade precoce não progressiva e da telarca prematura, neste caso esteve fortemente relacionada à ingestão excessiva de soja e de outros alimentos ricos em fitoestrógenos que poderiam ter desencadeado a telarca atuando como desreguladores endócrinos.

Precocious thelarche is the breast development before 8 years of age with two peaks of incidence during the first two years of life and after 6 years of age. A 4.75-year-old girl presented with thelarche associated to an excessive intake of phytoestrogens (phye). Tanner development B2P1-2, hormonal levels and pelvic US were compatible with peripheral precocious puberty. During follow-up, a daily intake of soy-based foods was observed (> 40 mg phye/day). Soy is rich in phytoestrogens, mainly genistein and daidzein. Although phye are less strong than estradiol, its concentration could be from 13,000 to 22,000 times stronger in children fed only by soy-based formulas. Parents were advised and soy intake was reduced to once a week. Progression of pubertal development ceased at B2-3P1. The patient, now 8.66 years old, keeps growing with similar bone and chronological ages. Some questions related to industrial food security, mainly the soy-based food, remain without precise answer. Although it is well known the entity of non-progressive precocious puberty and premature thelarche, pubertal development in this case was strongly related to excessive daily intake of soy and other phye-rich food that could trigger puberty as endocrine disruptor.

Compuestos disruptores endocrinos y su participación en la programación del eje reproductivo / Endocrine disruptor compounds and their role on the developmental programming of the reproductive axis

Different perturbations during fetal and post natal development unleash endocrine adaptations that permanently alter metabolism, increasing the susceptibility to develop later disease, process known as "developmental programming"'. Endocrine disruptor compounds (EDC) are widely spread on the environment and display estrogenic, anti-estrogenic or anti-androgenic activity; they are lypophilyc and stored for long periods on the adipose tissue. Maternal exposure to EDC during pregnancy and lactation produces the exposure of the fetus and neonate through placenta and breast milk. Epidemiological and experimental studies have demonstrated reproductive alterations as a consequence of intrauterine and/or neonatal exposure to EDC. Diethystilbestrol (DES) is the best documented compound, this synthetic estrogen was administered to pregnant women at the BO and 60 to prevent miscarriage. It was implicated in urogenital abnormalities in children exposed in utero and withdrawn from the market. The "DES daughters" are women with high incidence of vaginal hypoplasia, spontaneous abortion, premature delivery, uterine malformation, menstrual abnormalities and low fertility. The "DES sons" show testicular dysgenesis syndrome, which is characterized by hypospadias, cryptorchidism and low semen quality. This entity is also associated to the fetal exposure to anti-androgens as flutamide. The effects on the reproductive axis depend on the stage of development and the window of exposure, as well as the dose and the compound. The wide distribution of EDC into the environment affects both human health and ecosystems in general, the study of their mechanisms of action is extremely important currently.

Diversas perturbaciones durante el desarrollo fetal y posnatal desencadenan adaptaciones endocrinas que modifican permanentemente el metabolismo, incrementando la susceptibilidad para el desarrollo de enfermedades, proceso conocido como "programación durante el desarrollo". Los compuestos disruptores endocrinos (CDE) se encuentran en el medio ambiente y presentan actividad estrogénica, antiestrogénica o antiandrogénica; son altamente lipofílicos y se almacenan por periodos prolongados en el tejido adiposo. La exposición materna a CDE durante el embarazo y la lactancia permite su paso al producto a través de la placenta y la leche materna. Estudios epidemiológicos y experimentales han demostrado alteraciones en el eje reproductivo como consecuencia de la exposición intrauterina y/o neonatal a CDE. El compuesto mejor documentado es el dietilestilbestrol (DES), este estrógeno sintético fue administrado a mujeres embarazadas durante los 50s y 60s y retirado del mercado por su implicación en anormalidades urogenitales de los bebés expuestos in útero. Las denominadas "hijas del DES" son mujeres con alta incidencia de hipoplasia vaginal, malformaciones uterinas, irregularidades menstruales, baja fertilidad y alta prevalencia de aborto espontáneo y parto prematuro. Por su parte, "los hijos del DES" presentan una entidad clínica conocida como síndrome de disgenesia testicular caracterizado por hipospadias, criptorquidia y baja calidad del semen. Este síndrome también se asocia a la exposición fetal a compuestos antiandrogénicos como la ñutamida. Los efectos en el eje reproductivo dependen del estadio de desarrollo y del tiempo de exposición, así como de la dosis y el compuesto del que se trate. La extensa presencia de CDE en el ambiente afecta la salud humana e impacta al ecosistema en general por lo cual es de suma importancia el estudio de los mecanismos involucrados en su acción.