Efeitos tardios da exposição ao bisfenol A na mama de fêmeas de gerbilos durante o período gestacional e lactacional
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Data
2022-02-25
Autores
Ruiz, Thalles Fernando Rocha [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
As glândulas mamárias apresentam grande plasticidade morfológica devido ao seu remodelamento associado à modulação por hormônios durante as fases da vida. O estabelecimento do câncer de mama vem sendo relacionado com compostos chamados desreguladores endócrinos. O bisfenol A (BPA), um xenoestrógeno disseminado nos ambientes, é alvo de estudos aprofundados sobre seu potencial cancerígeno devido à sua atuação em diversos níveis dos sistemas biológicos. Ainda, a exposição à este desregulador endócrino causa efeitos persistentes nos organismos observados tardiamente. Assim, o objetivo do presente estudo foi avaliar o potencial desregulador do BPA nas glândulas mamárias de fêmeas senis expostas durante duas janelas de remodelamento mamário, a gestação e lactação. Foram utilizados gerbilos da Mongólia (Meriones unguiculatus) como modelo experimental devido seu potencial para o desenvolvimento espontâneo de neoplasias. Vinte fêmeas foram divididas em 4 grupos experimentais: controle (gavadas com água); veículo (gavadas com óleo de milho); BPA (50 µg/kg/dia); e BPA (5000 µg/kg/dia). As fêmeas foram expostas durante 39 dias (gestação e lactação) e eutanasiadas aos 18 meses de idade (senis). Análises histopatológicas demonstraram o início do desenvolvimento tumoral, associados à transição epitélio-mesenquimal (EMT) das células epiteliais. Ainda, a exposição ao BPA apresentou um aumento na expressão de TGF-β1, indicado como marcador do processo de EMT. Um perfil microinvasivo foi observado pela expressão de metaloproteases (MMP-2, MMP-3, MMP-9) pelas células tumorais. O BPA promoveu um microambiente estromal com aumento de fibroblastos associados ao câncer e remodelamento das fibras colágenas e elásticas. Em relação aos receptores, no carcinoma induzido pelo BPA apresentou um aumento expressivo no receptor de estrógeno ERα, e uma perda da expressão dos receptores ERβ, de progesterona e de prolactina. Nas células que expressaram ERα foi co-localizado o marcador epigenético EZH2, relacionado à instalação tumoral ERα-positivo. Ainda, o BPA modulou a localização dos receptores de andrógeno (AR) e HER2/ErbB2 nas células do epitélio mamário. Por fim, a exposição ao BPA promove um microambiente tumoral (TME) que corrobora com o desenvolvimento neoplásico mamário. O recrutamento de elementos como perfis de macrófagos e mastócitos associados ao câncer expressando meidadores inflamatórios foi observado no estroma. Ainda, a expressão de COX-2 e fosfo-STAT3 nas células neoplásicas contribuem com a sinalização epitélio-estroma para o desenvolvimento do TME. Em conclusão, o BPA apresenta-se como um indutor carcinogênico do câncer de mama durante a senilidade após a exposição na janela gestacional/lactacional.
Mammary glands present a great morphological plasticity due to their remodeling associated to hormonal modulation during the phases of life. The establishment of breast cancer has been related to compounds called endocrine disruptors. Bisphenol A (BPA), a xenoestrogen widespread in environments, is the target of in-depth studies on its carcinogenic potential due to its action on several levels of biological systems. Furthermore, exposure to this endocrine disruptor causes persistent effects in organisms observed in long term. Thus, the aim of the present study was to evaluate the deregulatory potential of BPA in the mammary glands of aged females exposed during two windows of mammary remodeling, pregnancy and lactation. Mongolian gerbils (Meriones unguiculatus) were used as an experimental model due to their potential for the spontaneous development of neoplasias. Twenty females were divided into 4 experimental groups: control (gavaged with water); vehicle (gavaged with corn oil); BPA (50 µg/kg/day); and BPA (5000 µg/kg/day). Females were exposed for 39 days (pregnancy and lactation) and euthanized at 18 months of age (aging). Histopathological analyses demonstrated the onset of tumor development, associated with epithelial-mesenchymal transition (EMT) of epithelial cells. Also, exposure to BPA showed an increase in the expression of TGF-β1, indicated as a marker of the EMT process. A microinvasive profile was observed by the expression of metalloproteases (MMP-2, MMP-3, MMP-9) by the tumor cells. BPA promoted a stromal microenvironment with increased cancer-associated fibroblasts and remodeling of collagen and elastic fibers. Regarding receptors, BPA-induced carcinoma showed an expressive increase in the estrogen receptor ERα, and a loss of expression of ERβ, progesterone and prolactin receptors. In cells expressing ERα, was observe co-localization of the epigenetic marker EZH2, related to ERα-positive tumor establishment. Also, BPA modulated androgen receptor (AR) and HER2/ErbB2 localization in the mammary epithelial cells. Finally, BPA exposure promotes a tumor microenvironment (TME) that corroborates with mammary neoplastic development. Recruitment of elements, such as cancer-associated phenotypes of macrophage and mast cells, that express inflammatory mediators was observed in the stroma. Also, COX-2 and phospho-STAT3 expression in neoplastic cells contribute to epithelium-stroma signaling for TME development. In conclusion, BPA presents as a carcinogenic inducer of mammary cancer during aging, especially when exposure occurs in the gestational/lactational window
Mammary glands present a great morphological plasticity due to their remodeling associated to hormonal modulation during the phases of life. The establishment of breast cancer has been related to compounds called endocrine disruptors. Bisphenol A (BPA), a xenoestrogen widespread in environments, is the target of in-depth studies on its carcinogenic potential due to its action on several levels of biological systems. Furthermore, exposure to this endocrine disruptor causes persistent effects in organisms observed in long term. Thus, the aim of the present study was to evaluate the deregulatory potential of BPA in the mammary glands of aged females exposed during two windows of mammary remodeling, pregnancy and lactation. Mongolian gerbils (Meriones unguiculatus) were used as an experimental model due to their potential for the spontaneous development of neoplasias. Twenty females were divided into 4 experimental groups: control (gavaged with water); vehicle (gavaged with corn oil); BPA (50 µg/kg/day); and BPA (5000 µg/kg/day). Females were exposed for 39 days (pregnancy and lactation) and euthanized at 18 months of age (aging). Histopathological analyses demonstrated the onset of tumor development, associated with epithelial-mesenchymal transition (EMT) of epithelial cells. Also, exposure to BPA showed an increase in the expression of TGF-β1, indicated as a marker of the EMT process. A microinvasive profile was observed by the expression of metalloproteases (MMP-2, MMP-3, MMP-9) by the tumor cells. BPA promoted a stromal microenvironment with increased cancer-associated fibroblasts and remodeling of collagen and elastic fibers. Regarding receptors, BPA-induced carcinoma showed an expressive increase in the estrogen receptor ERα, and a loss of expression of ERβ, progesterone and prolactin receptors. In cells expressing ERα, was observe co-localization of the epigenetic marker EZH2, related to ERα-positive tumor establishment. Also, BPA modulated androgen receptor (AR) and HER2/ErbB2 localization in the mammary epithelial cells. Finally, BPA exposure promotes a tumor microenvironment (TME) that corroborates with mammary neoplastic development. Recruitment of elements, such as cancer-associated phenotypes of macrophage and mast cells, that express inflammatory mediators was observed in the stroma. Also, COX-2 and phospho-STAT3 expression in neoplastic cells contribute to epithelium-stroma signaling for TME development. In conclusion, BPA presents as a carcinogenic inducer of mammary cancer during aging, especially when exposure occurs in the gestational/lactational window
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Palavras-chave
Morfologia, Histologia, Glândula Mamária, Endocrinologia, Biologia da Reprodução, Epithelial-mesenchymal transition, Microenvironment, Inflammation, Receptors