Repercussões da dieta ocidental e da exposição ao ácido 2,4-diclorofenoxiacético (2,4-d) sobre a próstata de camundongos
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2023-07-28
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Universidade Estadual Paulista (Unesp)
Resumo
A dieta ocidental (DO), rica em gorduras saturadas e carboidratos simples, está associada ao desenvolvimento de “patologias da civilização”, incluindo distúrbios reprodutivos e aumentando a probabilidade dos indivíduos desenvolverem doenças prostáticas. Adicionalmente, o uso de herbicidas, como o 2,4-D, um interferente endócrino, gera resíduos nos alimentos e em ambiente doméstico acima dos níveis permitidos. A literatura tem avaliado a ação desses fatores separadamente, no entanto, eles coexistem no ambiente e podem atuar como fatores sinérgicos, predispondo doenças crônicas sistêmicas e aumentando a susceptibilidade à carcinogênese. Dessa forma, como intuito de avaliar a ação do herbicida 2,4-D sobre a próstata de camundongos expostos cronicamente à DO, camundongos machos C57Bl/6J receberam simultaneamente uma dieta hiperlipídica, rica em sacarose e solução de açúcares, e 2,4-D nas doses de 0,02, 2,0 ou 20,0 mg/kg p.c./dia por via oral, por 6 meses. Dados de consumo de ração, peso corpóreo e peso de gordura foram registrados. Após o tratamento, foi realizado o teste de tolerância à glicose (GTT) e após laparotomia, a próstata ventral foi coletada para avaliações histológicas e moleculares, onde a expressão gênica foi quantificada por RT-qPCR. Nossos resultados mostraram que a DO foi capaz de induzir obesidade nos animais. O tratamento com a DO aumentou o peso e a gordura corpórea, induziu intolerância a glicose e alterações morfológicas com modificação nos compartimentos da glândula prostática, aumento na quantidade de colágeno e mastócitos. A imunohistoquímica revelou aumento de células positivas para o PCNA (proliferação celular) no grupo DO. Na análise molecular foi observado aumento na expressão gênica do Ar; de importantes genes antioxidantes (Sod1, Cat, Gsr); de citocinas relacionadas a inflamação (Il10, Il6, Tnfα); de genes relacionados ao reparo e turnover celular (Tp53, Ki67, Casp3) e de alvos relacionados a metilação de DNA (Dnmt1) e biossíntese de miRNAs (Dicer e Drosha) no grupo DO em relação ao controle. O 2,4-D, no tratamento combinado, mostrou modular os parâmetros metabólicos, a morfologia prostática e a expressão dos genes alterados pela DO, sobretudo nas duas menores doses, assemelhando-se aos valores observados no controle negativo. Em contrapartida, o grupo tratado com a maior dose do herbicida no contexto da DO, apresentou redução no consumo da ração e redução no peso corpóreo, além de aumento da expressão de Ar, Ki67, Casp3 e Dnmt1 em relação ao controle negativo. Nossos resultados dão suporte a novas pesquisas para permitir uma melhor compreensão do papel do 2,4D no tratamento combinado com a DO sobre a próstata.
The Western diet (WD), which is rich in saturated fats and simple carbohydrates, is associated with the development of "pathologies of civilization", including reproductive disorders and increasing the likelihood of individuals developing prostate diseases. In addition, the use of herbicides such as 2,4-D, an endocrine disruptor, generates residues in food and in the domestic environment above permitted levels. The literature has evaluated the action of these factors separately; however, they coexist in the environment and can act as synergistic factors, predisposing to chronic systemic diseases and increasing susceptibility to carcinogenesis. Therefore, in order to evaluate the action of the herbicide 2,4-D on the prostate of mice chronically exposed to DO, male C57Bl/6J mice were simultaneously given a high-fat diet, rich in sucrose and sugar solution, and 2,4-D at doses of 0.02, 2.0 or 20.0 mg/kg b.w./day orally for 6 months. Data on feed consumption, body weight and fat weight were recorded. After treatment, the glucose tolerance test (GTT) was performed and after laparotomy, the ventral prostate was collected for histological and molecular evaluations, where gene expression was quantified by RT-qPCR. Our results showed that OD was able to induce obesity in the animals. Treatment with DO increased body weight and fat, induced glucose intolerance and morphological alterations with changes in the compartments of the prostate gland, an increase in the amount of collagen and mast cells. Immunohistochemistry revealed an increase in cells positive for PCNA (cell proliferation) in the DO group. Molecular analysis showed an increase in gene expression of Ar; important antioxidant genes (Sod1, Cat, Gsr); inflammation-related cytokines (Il10, Il6, Tnfα); genes related to cell repair and turnover (Tp53, Ki67, Casp3) and targets related to DNA methylation (Dnmt1) and biosynthesis of miRNAs (Dicer and Drosha) in the DO group compared to the control. In the combined treatment, 2,4-D was shown to modulate metabolic parameters, prostate morphology and the expression of genes altered by DO, especially at the two lowest doses, similar to the values observed in the negative control. On the other hand, the group treated with the highest dose of the herbicide in the context of OD showed a reduction in feed consumption and a reduction in body weight, as well as an increase in the expression of Ar, Ki67, Casp3 and Dnmt1 compared to the negative control. Our results support further research to allow a better understanding of the role of 2,4D in combined treatment with OD on the prostate.
The Western diet (WD), which is rich in saturated fats and simple carbohydrates, is associated with the development of "pathologies of civilization", including reproductive disorders and increasing the likelihood of individuals developing prostate diseases. In addition, the use of herbicides such as 2,4-D, an endocrine disruptor, generates residues in food and in the domestic environment above permitted levels. The literature has evaluated the action of these factors separately; however, they coexist in the environment and can act as synergistic factors, predisposing to chronic systemic diseases and increasing susceptibility to carcinogenesis. Therefore, in order to evaluate the action of the herbicide 2,4-D on the prostate of mice chronically exposed to DO, male C57Bl/6J mice were simultaneously given a high-fat diet, rich in sucrose and sugar solution, and 2,4-D at doses of 0.02, 2.0 or 20.0 mg/kg b.w./day orally for 6 months. Data on feed consumption, body weight and fat weight were recorded. After treatment, the glucose tolerance test (GTT) was performed and after laparotomy, the ventral prostate was collected for histological and molecular evaluations, where gene expression was quantified by RT-qPCR. Our results showed that OD was able to induce obesity in the animals. Treatment with DO increased body weight and fat, induced glucose intolerance and morphological alterations with changes in the compartments of the prostate gland, an increase in the amount of collagen and mast cells. Immunohistochemistry revealed an increase in cells positive for PCNA (cell proliferation) in the DO group. Molecular analysis showed an increase in gene expression of Ar; important antioxidant genes (Sod1, Cat, Gsr); inflammation-related cytokines (Il10, Il6, Tnfα); genes related to cell repair and turnover (Tp53, Ki67, Casp3) and targets related to DNA methylation (Dnmt1) and biosynthesis of miRNAs (Dicer and Drosha) in the DO group compared to the control. In the combined treatment, 2,4-D was shown to modulate metabolic parameters, prostate morphology and the expression of genes altered by DO, especially at the two lowest doses, similar to the values observed in the negative control. On the other hand, the group treated with the highest dose of the herbicide in the context of OD showed a reduction in feed consumption and a reduction in body weight, as well as an increase in the expression of Ar, Ki67, Casp3 and Dnmt1 compared to the negative control. Our results support further research to allow a better understanding of the role of 2,4D in combined treatment with OD on the prostate.
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Palavras-chave
2,4-D, Próstata, Obesidade, Herbicidas, Toxicologia reprodutiva, Prostate, Obesity, Herbicides, Reproductive toxicology