Influência do praguicida diclorvós sobre o desenvolvimento de lesões prostáticas induzidas por MNU em ratos: avaliação de marcadores moleculares de inflamação
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Data
2019-03-13
Autores
Santos, Fernanda Oliveira dos
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Universidade Estadual Paulista (Unesp)
Resumo
O Brasil é o maior consumidor de produtos agrotóxicos no mundo. Os organofosforados, como o Diclorvós (DDVP), são um dos mais utilizados devido à sua eficiência e relativa baixa toxicidade. O DDVP pode atuar como desregulador endócrino, contribuindo para o desenvolvimento de lesões na próstata. O câncer de próstata assumiu, nestes últimos anos, o primeiro lugar em incidência de neoplasias nos Estados Unidos, e no Brasil estima-se 66,12 casos novos a cada 100 mil homens, sendo o câncer mais comum entre os homens. O processo inflamatório predispõe os indivíduos a vários tipos de câncer, pois induz a produção de citocinas como o TNFα que está envolvida no desenvolvimento do câncer de próstata. A inflamação pode ser ativada pelos receptores Toll-Like que pode resultar na ativação de duas vias, NFκB e a JNK. A via de sinalização do NFκB desempenha papel importante nas respostas ao câncer, inflamação, estresse e diferenciação celular. Assim, o presente estudo teve como objetivo avaliar a influência do praguicida Diclorvós em concentrações permitidas na próstata ventral de ratos em situação controle e após indução química por MNU (N-metil-N-nitrosureia), sobre a inflamação mediada por TLR4. Foram utilizados 40 ratos da linhagem Fischer 344, com idade de 90 dias. Os ratos foram separados em quatro grupos experimentais: Sham (G1), Sham+DDVP (G2), MNU (G3), MNU+DDVP (G4). Foram feitas análises histopatológica e imunohistoquímica da próstata ventral dos ratos. Foram encontrados três tipos de lesões na próstata ventral de ratos: Displasia, Neoplasia Intraepitelial Prostática (PIN) e Neoplasia intraepitelial de alto grau (HGPIN).O TLR4 esteve presente nas células epiteliais luminais da próstata ventral de todos os grupos experimentais. Nos grupos G1, G2 e G3 houve marcação em todo citoplasma, sendo a marcação mais intensa na região do aparelho de Golgi e no grupo G4 essa marcação foi moderada na região do aparelho de Golgi e intensa na membrana apical das células. O TNFα foi detectado em todo citoplasma das células epiteliais luminais da próstata ventral de todos os grupos experimentais destacando-se intensamente na região apical e moderadamente na região do aparelho de Golgi. O NFkB foi imunolocalizado em todo citoplasma das células epiteliais luminais da próstata ventral em todos os grupos experimentais, sendo mais intenso na região apical. Os grupos G1 e G2 apresentaram imunorreatividade intensa na região apical e somente os grupos G3 e G4 apresentaram imunorreatividade no envoltório nuclear. Verificamos a expressão de NFkB no núcleo e a diminuição da expressão de TLR4 e TNFα principalmente na região do Golgi, bem como o aumento da expressão de TLR4 na membrana apical das células epiteliais luminais, que pode ser associado ao agravamento das lesões prostáticas, corroborando com o papel desses marcadores do processo inflamatório, nas etapas iniciais da carcinogênese. Assim, podemos concluir que o DDVP em concentrações permitidas altera a imunolocalização de marcadores moleculares da inflamação na próstata ventral de ratos. Além disso, o DDVP associado à indução química pode acentuar essas alterações dos marcadores.
Brazil is the largest consumer of pesticides in the world. Organophosphates, such as Diclorvos (DDVP), are among the most used because of their efficiency and relatively low toxicity. DDVP can act as an endocrine disrupter, contributing to the development of prostate lesions. In recent years, prostate cancer has been the number one cancer incidence in the United States, and in Brazil it is estimated 66.12 new cases per 100,000 men, the most common cancer among men. The inflammatory process predisposes individuals to various types of cancer, as it induces the production of cytokines such as TNFα, which is involved in the development of prostate cancer. Inflammation can be activated by Toll-Like receptors which can result in the activation of two pathways, NFκB and JNK. The NFκB signaling pathway plays an important role in cancer responses, inflammation, stress, and cell differentiation. Thus, the present study aimed to evaluate the influence of the Diclorvos pesticide at permissible concentrations in the ventral prostate of rats under control and after chemical induction by MNU (N-methyl-N-nitrosourea) on TLR4-mediated inflammation. 40 rats of the Fischer 344 strain, aged 90 days, were used. The rats were separated into four experimental groups: Sham (G1), Sham + DDVP (G2), MNU (G3), MNU + DDVP (G4). Histopathological and immunohistochemical analyzes of the ventral prostate of rats were performed. Three types of lesions were found in the ventral prostate of rats: Dysplasia, Prostatic Intraepithelial Neoplasia (PIN) and High Grade Intraepithelial Neoplasia (HGPIN). TLR4 presented in luminal epithelial cells of the ventral prostate of all experimental groups. In groups G1, G2 and G3 there was staining throughout the cytoplasm, being the most intense staining in the region of the Golgi apparatus. In group G4 this staining was moderate in the region of the Golgi apparatus and intense in the apical membrane of the cells. TNFα was detected in all cytoplasms of the luminal epithelial cells of the ventral prostate of all experimental groups, standing out intensely in the apical region and moderately in the region of the Golgi apparatus. NFκB was immunolocalized in all cytoplasm of luminal epithelial cells of the ventral prostate in all experimental groups, being more intense in the apical region. Groups G1 and G2 presented intense immunoreactivity in the apical region and only the G3 and G4 groups showed immunoreactivity in the nuclear envelope. We verified the expression of NFκB in the nucleus and decreased expression of TLR4 and TNFα mainly in the Golgi region, as well as the increase in TLR4 expression in the apical membrane of the luminal epithelial cells, which may be associated with worsening of the prostatic lesions, corroborating with the role of these markers of the inflammatory process, in the early stages of carcinogenesis. Thus, we can conclude that DDVP at permissible concentrations alters the immunolocalization of molecular markers of inflammation in the ventral prostate of rats. In addition, the DDVP associated with chemical induction may accentuate these marker changes
Brazil is the largest consumer of pesticides in the world. Organophosphates, such as Diclorvos (DDVP), are among the most used because of their efficiency and relatively low toxicity. DDVP can act as an endocrine disrupter, contributing to the development of prostate lesions. In recent years, prostate cancer has been the number one cancer incidence in the United States, and in Brazil it is estimated 66.12 new cases per 100,000 men, the most common cancer among men. The inflammatory process predisposes individuals to various types of cancer, as it induces the production of cytokines such as TNFα, which is involved in the development of prostate cancer. Inflammation can be activated by Toll-Like receptors which can result in the activation of two pathways, NFκB and JNK. The NFκB signaling pathway plays an important role in cancer responses, inflammation, stress, and cell differentiation. Thus, the present study aimed to evaluate the influence of the Diclorvos pesticide at permissible concentrations in the ventral prostate of rats under control and after chemical induction by MNU (N-methyl-N-nitrosourea) on TLR4-mediated inflammation. 40 rats of the Fischer 344 strain, aged 90 days, were used. The rats were separated into four experimental groups: Sham (G1), Sham + DDVP (G2), MNU (G3), MNU + DDVP (G4). Histopathological and immunohistochemical analyzes of the ventral prostate of rats were performed. Three types of lesions were found in the ventral prostate of rats: Dysplasia, Prostatic Intraepithelial Neoplasia (PIN) and High Grade Intraepithelial Neoplasia (HGPIN). TLR4 presented in luminal epithelial cells of the ventral prostate of all experimental groups. In groups G1, G2 and G3 there was staining throughout the cytoplasm, being the most intense staining in the region of the Golgi apparatus. In group G4 this staining was moderate in the region of the Golgi apparatus and intense in the apical membrane of the cells. TNFα was detected in all cytoplasms of the luminal epithelial cells of the ventral prostate of all experimental groups, standing out intensely in the apical region and moderately in the region of the Golgi apparatus. NFκB was immunolocalized in all cytoplasm of luminal epithelial cells of the ventral prostate in all experimental groups, being more intense in the apical region. Groups G1 and G2 presented intense immunoreactivity in the apical region and only the G3 and G4 groups showed immunoreactivity in the nuclear envelope. We verified the expression of NFκB in the nucleus and decreased expression of TLR4 and TNFα mainly in the Golgi region, as well as the increase in TLR4 expression in the apical membrane of the luminal epithelial cells, which may be associated with worsening of the prostatic lesions, corroborating with the role of these markers of the inflammatory process, in the early stages of carcinogenesis. Thus, we can conclude that DDVP at permissible concentrations alters the immunolocalization of molecular markers of inflammation in the ventral prostate of rats. In addition, the DDVP associated with chemical induction may accentuate these marker changes
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Palavras-chave
Diclorvós, Inflamação, Próstata, NFkB, TNFα, TLR4, Dichlorvos, inflammation, prostate