Associação entre a curcumina e o bisfenol A e seus efeitos sobre o microambiente prostático do gerbilo da Mongólia
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Data
2019-04-30
Autores
Facina, Camila Helena
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Universidade Estadual Paulista (Unesp)
Resumo
Estudos recentes têm demonstrado que a exposição a substâncias químicas presentes no ambiente pode causar alterações morfofisiológicas permanentes na próstata. Estas substâncias, denominadas desreguladores endócrinos, mimetizam hormônios esteroides, agindo diretamente sobre os órgãos do trato reprodutivo. O bisfenol-A, uma das substâncias químicas de maior produção no mundo, é utilizado na composição de diversos produtos. Estudos epidemiológicos indicam que compostos polifenólicos naturais reduzem a incidência de vários tipos de canceres. Dentre eles, a curcumina possui um alto potencial farmacológico incluindo atividades anti-inflamatória e antitumoral, no entanto este fitoquímico possui baixa biodisponibilidade. A piperina pode aumentar a concentração de curcumina no soro e sua absorção e biodisponibilidade. Assim, este estudo tem como objetivo avaliar se a curcumina reverte as alterações impostas pelo bisfenol-A sobre a glândula prostática, bem como avaliar se o composto piperina aumenta a possível atividade protetora da curcumina. Foram utilizados gerbilos machos/adultos (Meriones unguiculatus) divididos em nove grupos experimentais: C: água ad libitum; CO: óleo de milho,via gavagem, a cada dois dias; BPA: BP-A 50μg/kg/dia na água; Cm: 100mg/kg/dia de curcumina, via gavagem, a cada dois dias; P: 20mg/kg/dia de piperina, via gavagem, a cada dois dias; BCm: BP-A 50μg/kg/dia na água+100mg/kg/dia de curcumina, via gavagem, a cada dois dias; BCmP: BP-A 50μg/kg/dia na água+100mg/kg/dia de curcumina+20mg/kg/dia de piperina, via gavagem, a cada dois dias; BP: BP-A 50μg/kg/dia na água+20mg/kg/dia de piperina, via gavagem, a cada dois dias; CmP: 100mg/kg/dia de curcumina+20mg/kg/dia de piperina, via gavagem, a cada dois dias. A eutanásia dos animais aconteceu vinte e nove semanas após o início do experimento e foram analisados os lobos Ventral e Dorsolateral prostáticos. As metodologias utilizadas envolveram análises quantitativas e estatísticas da ingestão de bisfenol-A, peso corpóreo e prostático, dosagens hormonais, cálculo da incidência e multiplicidade de lesões prostáticas e inflamações, fator forma nuclear, análises estereológicas bem como análises morfológicas e imunohistoquímicas. Lesões de caráter pré-maligno e maligno foram constatadas em ambos os lobos prostáticos. Contudo, os animais dos grupos BPA e BCm apresentaram uma maior incidência e multiplicidade de lesões prostáticas. Este dado enfatiza que, a dose ambiental de 50 μg kg/dia de bisfenol-A não é segura para a homeostase prostática. Por outro lado, os animais dos grupos BP e BCmP apresentaram redução na frequência dessas lesões, revelando incidência e multiplicidade com valores bem próximos aos do grupo controle. O compartimento estromal dos grupos BPA e BCm apresentou remodelação das fibras de colágeno, além de diversos pontos de desestruturação da camada de células musculares lisas, favorecendo a invasão estromal. A expressão de VEGF, MMP-9, MMP-2, IL-6 e IL-10 aumentou significantemente nestes grupos, enquanto que nos demais grupos estes elementos não sofreram alteração. A curcumina isoladamente promoveu efeitos benéficos sutis nos lobos prostáticos. A adição de piperina resultou em efeitos mais significativos para a glândula prostática, como a redução das lesões pré-malignas e a ausência das lesões malignas em ambos os lobos. O entendimento dos fatores capazes de modular o microambiente prostático torna possível o desenvolvimento de estratégias terapêuticas na prevenção ou na redução da evolução dos distúrbios prostáticos.
Recent studies have shown that exposure to chemicals present in the environment can cause permanent morphophysiological changes in the prostate. These substances, called endocrine disrupters, mimic steroid hormones, acting directly on the organs of the reproductive tract. Bisphenol-A, one of the highest-producing chemicals in the world, is used in the composition of various products. Epidemiological studies indicate that natural polyphenolic compounds reduce the incidence of various types of cancers. Among them, curcumin has a high pharmacological potential including anti-inflammatory and antitumor activities, however this phytochemical has low bioavailability. Piperine can increase the concentration of curcumin in serum and its absorption and bioavailability. Thus, the objectives of this study were to evaluate whether curcumin reverses the changes imposed by bisphenol-A on the prostate gland, as well as assess whether the piperine compound increases the possible protective activity of curcumin. Adult male gerbils (Meriones unguiculatus) were divided into nine experimental groups: C: water ad libitum; CO: corn oil, via gavage, every two days; BPA: BP-A 50μg/kg/day in water; Cm: 100mg/kg/day of curcumin, via gavage, every two days; P: 20mg/kg/day of piperine, via gavage, every two days; BCm: BP-A 50μg/kg/day in water+100mg/kg/day of curcumin, via gavage, every two days; BCmP: BP-A 50μg/kg/day in water+100mg/kg/day of curcumin+20mg/kg/day of piperine, via gavage, every two days; BP: BP-A 50μg/kg/day in water+20mg/kg/day of piperine, via gavage, every two days; CmP: 100mg/kg/day of curcumin+20mg/kg/day of piperine, via gavage, every two days. Euthanasia of the animals occurred twenty-nine weeks after the beginning of the experiment and the Ventral and Dorsolateral lobes of the prostate were analyzed. The methodologies used involved quantitative and statistical analyzes of bisphenol-A intake, body and prostate weight, hormonal dosages, calculation of the incidence and multiplicity of prostatic lesions and inflammations, nuclear form factor, stereological analyzes as well as morphological and immunohistochemical analyzes. Pre-malignant and malignant lesions were found in both prostate lobes. However, the animals of the BPA and BCm groups had a higher incidence and multiplicity of prostatic lesions. This data emphasizes that the environmental dose of 50 μg/kg/day of bisphenol-A is not safe for prostate homeostasis. On the other hand, the animals of the BP and BCmP groups presented a reduction in the frequency of these lesions, revealing incidence and multiplicity with values very close to those of the control group. The stromal compartment of the BPA and BCm groups showed remodeling of the collagen fibers, as well as several points of disassembly of the smooth muscle cell layer, favoring stromal invasion. The expression of VEGF, MMP-9, MMP-2, IL-6 and IL-10 increased significantly in these groups, whereas in the other groups these elements did not change. Curcumin alone promoted subtle benefic effects in the prostate lobes. The addition of piperine resulted in more significant effects on the prostate gland, such as reduction of premalignant lesions and absence of malignant lesions in both lobes. The understanding of factors capable of modulating the prostatic microenvironment makes possible the development of therapeutic strategies in the prevention or reduction of the evolution of prostatic disorders.
Recent studies have shown that exposure to chemicals present in the environment can cause permanent morphophysiological changes in the prostate. These substances, called endocrine disrupters, mimic steroid hormones, acting directly on the organs of the reproductive tract. Bisphenol-A, one of the highest-producing chemicals in the world, is used in the composition of various products. Epidemiological studies indicate that natural polyphenolic compounds reduce the incidence of various types of cancers. Among them, curcumin has a high pharmacological potential including anti-inflammatory and antitumor activities, however this phytochemical has low bioavailability. Piperine can increase the concentration of curcumin in serum and its absorption and bioavailability. Thus, the objectives of this study were to evaluate whether curcumin reverses the changes imposed by bisphenol-A on the prostate gland, as well as assess whether the piperine compound increases the possible protective activity of curcumin. Adult male gerbils (Meriones unguiculatus) were divided into nine experimental groups: C: water ad libitum; CO: corn oil, via gavage, every two days; BPA: BP-A 50μg/kg/day in water; Cm: 100mg/kg/day of curcumin, via gavage, every two days; P: 20mg/kg/day of piperine, via gavage, every two days; BCm: BP-A 50μg/kg/day in water+100mg/kg/day of curcumin, via gavage, every two days; BCmP: BP-A 50μg/kg/day in water+100mg/kg/day of curcumin+20mg/kg/day of piperine, via gavage, every two days; BP: BP-A 50μg/kg/day in water+20mg/kg/day of piperine, via gavage, every two days; CmP: 100mg/kg/day of curcumin+20mg/kg/day of piperine, via gavage, every two days. Euthanasia of the animals occurred twenty-nine weeks after the beginning of the experiment and the Ventral and Dorsolateral lobes of the prostate were analyzed. The methodologies used involved quantitative and statistical analyzes of bisphenol-A intake, body and prostate weight, hormonal dosages, calculation of the incidence and multiplicity of prostatic lesions and inflammations, nuclear form factor, stereological analyzes as well as morphological and immunohistochemical analyzes. Pre-malignant and malignant lesions were found in both prostate lobes. However, the animals of the BPA and BCm groups had a higher incidence and multiplicity of prostatic lesions. This data emphasizes that the environmental dose of 50 μg/kg/day of bisphenol-A is not safe for prostate homeostasis. On the other hand, the animals of the BP and BCmP groups presented a reduction in the frequency of these lesions, revealing incidence and multiplicity with values very close to those of the control group. The stromal compartment of the BPA and BCm groups showed remodeling of the collagen fibers, as well as several points of disassembly of the smooth muscle cell layer, favoring stromal invasion. The expression of VEGF, MMP-9, MMP-2, IL-6 and IL-10 increased significantly in these groups, whereas in the other groups these elements did not change. Curcumin alone promoted subtle benefic effects in the prostate lobes. The addition of piperine resulted in more significant effects on the prostate gland, such as reduction of premalignant lesions and absence of malignant lesions in both lobes. The understanding of factors capable of modulating the prostatic microenvironment makes possible the development of therapeutic strategies in the prevention or reduction of the evolution of prostatic disorders.
Descrição
Palavras-chave
Bisfenol A, Desregulador endócrino, Curcumina, Piperina, Fitoquímicos, Gerbilo da Mongólia, Próstata, Bisphenol A, Endocrine disruptor, Curcumin, Piperine, Phytochemicals, Mongolian’s gerbil, Prostate