Efeitos de dieta materna rica em carboidratos simples e gordura nas fases de pré e pós-concepção na mucosa colônica após administração da 1,2- dimetilhidrazina na geração de fêmeas f1: modulação pela carnosina
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2023-03-01
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Universidade Estadual Paulista (Unesp)
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Dietas maternas, entre elas aquelas ricas em carboidratos simples e gorduras, ingeridas durante o período pré, pós-concepção e início de vida de seus descendentes, podem gerar estresse oxidativo e inflamação em diversos órgãos, incluindo o cólon. A carnosina (CAR) é um dipeptídeo que apresenta potencial antioxidante e anti-inflamatório. Dessa forma, este estudo visa avaliar o papel protetor da CAR sobre as alterações colônicas induzidas pela administração da 1,2-dimetilhidrazina (DMH) sob influência do consumo de dieta hipercalórica ou dieta normocalórica na geração F1 de ratas Sprague-Dawley (SD). Fêmeas (F0) com 3 semanas de idade foram alocadas em 2 grupos, um grupo recebeu a dieta hipercalórica (DHC) ou dieta normocalórica (DNC) por 90 dias. Após esse período, as fêmeas foram submetidas ao cruzamento e acompanhadas quanto ao consumo de ração e peso durante a pré, pós-concepção e lactação. A prole foi mantida com a mesma dieta das mães depois do desmame e até o dia pós-natal 31 (DPN31). A geração F1 de fêmeas foi subdividida em 4 grupos distribuídos em: G1 e G2, sendo que ambos ingerirem DNC e receberam duas doses de DMH (20 mg/kg) (DPN28 e DPN31); o G2 recebeu ainda uma dose diária de CAR (250 mg/kg) por 10 dias (DPN21 ao DPN31). Os grupos G3 e G4 receberam a DHC e duas doses de DMH (20 mg/kg) (DPN28 e DPN31) e o G4 recebeu também a CAR (250 mg/kg), por 10 dias (DPN21 ao DPN31). Em seguida, os animais foram eutanasiados (DPN32) e a mucosa colônica foi coletada para análise de alturas de criptas, himunohistoquímica, atividades antioxidantes e de expressão gênica, além de amostras de sangue para avaliação de glicose, triglicerídeos e colesterol. Observou-se diminuição de consumo de DHC em animais durante o período de pré, pós e lactação. Animais que receberam CAR, que foram os grupos G2 e G4 tiveram os níveis de colesterol e triglicerídeos normalizados. Do ponto de vista morfológico foi observado uma redução nas alturas médias das criptas colônicas do grupo G2 e G3, comparadas ao G1 e recuperação das alturas das criptas do grupo tratado com CAR associado à DHC (G4). O G2 teve uma diminuição dos níveis de proliferação celular (Ki-67). Quando avaliada a dosagem de glutationa oxidada (GSSG) na mucosa colônica observou-se uma diminuição no grupo que recebeu DHC+CAR (G4) em comparação ao grupo DHC (G3). Com base nos resultados de análises gênicas identificamos o cluster de proteínas com vias fortemente enriquecidas nas comparações realizadas e a participação de genes na via de câncer colorretal. Conclui-se que a ingestão de DHC materna e no período juvenil causou alterações na altura das criptas intestinais, estresse oxidativo e perfil bioquímico e de expressão gênica da mucosa colônica após insulto agudo da DMH. O tratamento da prole de fêmeas com a carnosina contribuiu para redução de respostas da predisposição à obesidade e doenças metabólicas, através da resposta antioxidante e diminuição de vias inflamatórias, reduzindo os efeitos citotóxicos de DMH e efeitos de alterações causadas pela ingestão materna de DHC
Maternal diets, including those rich in simple carbohydrates and lipids, ingested during the pre-, post-conception and early life offspring, can generate oxidative stress and inflammation in various organs, including the colon. Carnosine (CAR) is a dipeptide, it has antioxidant’s and anti-inflammatories’ potential. Thus, this study aims to evaluate the protective role of CAR on colonic changes induced by the administration of 1,2- dimethylhydrazine (DMH) under the influence of the consumption of a hypercaloric diet, rich in simple carbohydrates and lipids and a normocaloric diet in the F1 generation of Sprague-Dawley rats (SD). Three weeks old females (F0) were allocated into 2 groups, one group received either a hypercaloric (DHC) or a normocaloric diet (DNC) for 90 days. After this period, the females mated and were analised in terms of feed intake and weight during pre, post-conception and lactation. Offspring was maintained with same mother’s diet after weaning and until postnatal day 31 (DPN31). Female F1 was subdivided into four groups distributed in: G1 and G2, both of which ingested a normocaloric diet and two DMH insults (20 mg/kg) (DPN28 and DPN31); G2 also received the daily dose of CAR (250mg/kg) for 10 days (DPN21 to DPN31). Groups G3 and G4 received DHC, two DMH (20mg/kg)) insults (DPN28 and DPN31) and G4 received a CAR (250 mg/kg) for 10 days (DPN21 to DPN31). Then, the animals were euthanized (DPN32) and the colonic mucosa was collected for analysis of crypt height, immunohistochemistry assay, antioxidant activities and gene expression, in addition to a blood sample for biochemical analysis to evaluate glucose, triglycerides and cholesterol. Observed decrease in DHC consumption during the pre, post and lactation period. Females that received CAR, G2 and G4 had standardised cholesterol and triglyceride levels. From the morphological point of view, a reduction of average heights in colonic crypts in G2 and G3 groups was observed, recovery heights crypts in group treated with CAR associated with DHC (G4). G2 had a decrease in cellular proliferation levels (Ki67). When evaluating the dosage of oxidized glutathione (GSSG) in the colonic mucosa, a decrease was observed in treated group (G4) compared to the DHC group (G3). Based on the results of genetic analysis, we identified the cluster of proteins highly enriched pathways in the comparisons made and the participation of genes in the colorectal cancer pathway. Our findings showed maternal and juvenile DHC causes alterations in the height of the intestinal crypts, oxidative stress and biochemical levels and gene expression profile of the colonic mucosa after an acute DMH insult. Offspring’s females treated with carnosine contributed to reduced responses of predisposition to obesity and metabolic diseases, through the antioxidant response and decrease of inflammatory pathways, cytotoxic effects of DMH and consequences by the ingestion of DHC.
Maternal diets, including those rich in simple carbohydrates and lipids, ingested during the pre-, post-conception and early life offspring, can generate oxidative stress and inflammation in various organs, including the colon. Carnosine (CAR) is a dipeptide, it has antioxidant’s and anti-inflammatories’ potential. Thus, this study aims to evaluate the protective role of CAR on colonic changes induced by the administration of 1,2- dimethylhydrazine (DMH) under the influence of the consumption of a hypercaloric diet, rich in simple carbohydrates and lipids and a normocaloric diet in the F1 generation of Sprague-Dawley rats (SD). Three weeks old females (F0) were allocated into 2 groups, one group received either a hypercaloric (DHC) or a normocaloric diet (DNC) for 90 days. After this period, the females mated and were analised in terms of feed intake and weight during pre, post-conception and lactation. Offspring was maintained with same mother’s diet after weaning and until postnatal day 31 (DPN31). Female F1 was subdivided into four groups distributed in: G1 and G2, both of which ingested a normocaloric diet and two DMH insults (20 mg/kg) (DPN28 and DPN31); G2 also received the daily dose of CAR (250mg/kg) for 10 days (DPN21 to DPN31). Groups G3 and G4 received DHC, two DMH (20mg/kg)) insults (DPN28 and DPN31) and G4 received a CAR (250 mg/kg) for 10 days (DPN21 to DPN31). Then, the animals were euthanized (DPN32) and the colonic mucosa was collected for analysis of crypt height, immunohistochemistry assay, antioxidant activities and gene expression, in addition to a blood sample for biochemical analysis to evaluate glucose, triglycerides and cholesterol. Observed decrease in DHC consumption during the pre, post and lactation period. Females that received CAR, G2 and G4 had standardised cholesterol and triglyceride levels. From the morphological point of view, a reduction of average heights in colonic crypts in G2 and G3 groups was observed, recovery heights crypts in group treated with CAR associated with DHC (G4). G2 had a decrease in cellular proliferation levels (Ki67). When evaluating the dosage of oxidized glutathione (GSSG) in the colonic mucosa, a decrease was observed in treated group (G4) compared to the DHC group (G3). Based on the results of genetic analysis, we identified the cluster of proteins highly enriched pathways in the comparisons made and the participation of genes in the colorectal cancer pathway. Our findings showed maternal and juvenile DHC causes alterations in the height of the intestinal crypts, oxidative stress and biochemical levels and gene expression profile of the colonic mucosa after an acute DMH insult. Offspring’s females treated with carnosine contributed to reduced responses of predisposition to obesity and metabolic diseases, through the antioxidant response and decrease of inflammatory pathways, cytotoxic effects of DMH and consequences by the ingestion of DHC.
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Palavras-chave
Carnosina, Antioxidantes, Expressão gênica, Nutrição materna, Carnosine, Maternal nutrition, Antioxidant, Gene expression