Efeitos da exposição neonatal ao bisfenol A e ao 17-β estradiol sobre a glândula mamária de fêmeas adultas de gerbilo da Mongólia
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2019-03-15
Autores
Leonel, Ellen Cristina Rivas
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Universidade Estadual Paulista (Unesp)
Resumo
A incidência de câncer de mama tem aumentado consideravelmente ao longo dos anos. Frente a esta alta taxa epidemiológica a atenção às causas desta doença tem sido significativa em meio a grupos de pesquisa. Fatores genéticos e algumas situações de risco, como a exposição a componentes químicos disruptores endócrinos, podem estimular o seu desenvolvimento. O bisfenol A (BPA), utilizado na manufatura de plásticos e resinas, pode ser liberado destes componentes e exercer efeitos estrogênicos, causando distúrbios na função endócrina e aumentando a predisposição à carcinogênese. Alguns estudos têm demonstrado os efeitos do BPA em longo prazo, de modo que sua exposição durante o período de desenvolvimento embrionário inicial e perinatal pode predispor a glândula mamária (GM) ao desenvolvimento de câncer em indivíduos já adultos. Seu mecanismo de ação, assim como o do estradiol endógeno, baseia-se principalmente na ligação a receptores celulares hormonais, podendo estimular a proliferação, promovendo um desbalanço nos ciclos de renovação celular mamária. Para o estudo de carcinogênese o gerbilo da Mongólia (Meriones unguiculatus) é um modelo experimental interessante, já que possui capacidade de desenvolver tumores espontâneos em órgãos hormônio-responsivos, mimetizando, naturalmente, o ambiente de um indivíduo predisposto à tumorigênese. Assim, os objetivos deste trabalho foram (1) caracterizar morfologicamente a GM de fêmeas de gerbilo da Mongólia em diferentes estágios funcionais, (2) descrever as alterações morfológicas encontradas na GM de fêmeas adultas expostas ao BPA e a 17-β estradiol durante o período de desenvolvimento perinatal avaliando a presença de lesões histopatológicas, índice de proliferação celular e expressão do marcador de alteração epigenética, EZH2, bem como (3) descrever as variações na expressão de receptores levando em consideração níveis séricos hormonais, com o intuito de esclarecer os possíveis efeitos do BPA administrado durante o desenvolvimento embrionário na GM adulta. Nossos resultados demonstraram que aos 6 meses de idade houve um aumento significativo no índice proliferativo, na incidência de hiperplasia e considerável alteração na deposição de fibras colágenas no compartimento estromal da glândula. Verificou-se aumento na expressão de EZH2 nas células epiteliais mamárias dos animais do grupo tratado apenas com o óleo de milho (veículo), revelando uma ação inesperada do mesmo na GM. As análises de receptores hormonais mostraram que diferenças significativas nas taxas de expressão ocorreram nas GMs dos grupos tratados tanto com BPA quanto com 17-β estradiol em comparação ao grupo controle intacto. Com isso, pôde-se concluir que a exposição neonatal ao BPA causa alterações morfológicas e moleculares na GM de gerbilos da Mongólia refletidas após 6 meses de idade, que podem indicar sinais de pré-malignidade, confirmando o efeito carcinogênico deste composto.
The incidence of breast cancer has increased considerably over the years. Facing this high epidemiological rate, attention to the causes of this disease has been significant among research groups. Genetic factors and some risk situations, such as exposure to chemical endocrine disrupting components may stimulate its development. Bisphenol A (BPA), a compound used in the manufacture of plastics and resins, can be released from these components and exert estrogenic effects, causing disturbances of endocrine function and increasing the predisposition to carcinogenesis. Some studies have demonstrated the long-term effects of BPA, in a way that exposure during embryonic development (perinatal phase) may predispose the mammary gland (MG) to development of cancer in adults. Its mechanism of action, as that of endogenous estradiol, is mainly based on cellular hormonal receptors binding, which can stimulate the proliferation, promoting an imbalance of breast cell cycles and renewal. For these carcinogenesis studies, the Mongolian gerbil (Meriones unguiculatus) is an interesting experimental model, since it has the ability to develop spontaneous tumors in hormone-responsive organs, naturally mimicking the environment of an individual predisposed to tumorigenesis. Thus, the aims of this study were to (1) characterize morphologically the mammary gland of Mongolian gerbil females at different stages of functionality, (2) describe morphological changes found in the MG of adult females exposed to BPA or 17-β estradiol during the perinatal development evaluating the presence of histopathological lesions, cell proliferation index and expression of the epigenetic alteration marker, EZH2, as well as (3) to describe the variations in hormone receptors expression taking into account hormonal serum levels, with the purpose of clarifying the possible effects of BPA administered during embryonic development in adult MG. Our results demonstrated that at 6 months age there was a significant increase in proliferative index, incidence of hyperplasia and considerable alteration in the deposition of collagen fibers in the stromal compartment of the gland. There was an increase in EZH2 expression in the mammary epithelial cells of animals treated with corn oil (vehicle), revealing an unexpected action of it in MG. Hormone receptor analsis showed that significant differences in expression rates occurred in the mammary glands of the groups treated with both, BPA and 17β-estradiol compared to the intact control group. Thus, we observed that neonatal exposure to BPA causes morphological and molecular changes in the MG of Mongolian gerbils reflected after 6 months age, which may indicate signs of pre-malignancy, confirming the carcinogenic effect of this compound.
The incidence of breast cancer has increased considerably over the years. Facing this high epidemiological rate, attention to the causes of this disease has been significant among research groups. Genetic factors and some risk situations, such as exposure to chemical endocrine disrupting components may stimulate its development. Bisphenol A (BPA), a compound used in the manufacture of plastics and resins, can be released from these components and exert estrogenic effects, causing disturbances of endocrine function and increasing the predisposition to carcinogenesis. Some studies have demonstrated the long-term effects of BPA, in a way that exposure during embryonic development (perinatal phase) may predispose the mammary gland (MG) to development of cancer in adults. Its mechanism of action, as that of endogenous estradiol, is mainly based on cellular hormonal receptors binding, which can stimulate the proliferation, promoting an imbalance of breast cell cycles and renewal. For these carcinogenesis studies, the Mongolian gerbil (Meriones unguiculatus) is an interesting experimental model, since it has the ability to develop spontaneous tumors in hormone-responsive organs, naturally mimicking the environment of an individual predisposed to tumorigenesis. Thus, the aims of this study were to (1) characterize morphologically the mammary gland of Mongolian gerbil females at different stages of functionality, (2) describe morphological changes found in the MG of adult females exposed to BPA or 17-β estradiol during the perinatal development evaluating the presence of histopathological lesions, cell proliferation index and expression of the epigenetic alteration marker, EZH2, as well as (3) to describe the variations in hormone receptors expression taking into account hormonal serum levels, with the purpose of clarifying the possible effects of BPA administered during embryonic development in adult MG. Our results demonstrated that at 6 months age there was a significant increase in proliferative index, incidence of hyperplasia and considerable alteration in the deposition of collagen fibers in the stromal compartment of the gland. There was an increase in EZH2 expression in the mammary epithelial cells of animals treated with corn oil (vehicle), revealing an unexpected action of it in MG. Hormone receptor analsis showed that significant differences in expression rates occurred in the mammary glands of the groups treated with both, BPA and 17β-estradiol compared to the intact control group. Thus, we observed that neonatal exposure to BPA causes morphological and molecular changes in the MG of Mongolian gerbils reflected after 6 months age, which may indicate signs of pre-malignancy, confirming the carcinogenic effect of this compound.
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Palavras-chave
Gerbilo da Mongólia, Receptor hormonal, Disruptor endócrino, Morfologia, Histopatologia, Mongolian gerbil, Hormonal receptor, Endocrine disruptor, Morphology, Histopathology