RESUMO
Maternal high fat diet (HFD) and obesity during pregnancy increase female offspring's mammary cancer risk in animal studies. We aimed to observe whether the consumption of grape juice during pregnancy can reverse this risk. During pregnancy and lactation, female Wistar rats were fed either a control or HFD and also received grape juice or tap water. At the age of 50 days, female offspring were euthanized, and mammary glands were collected to assess changes in biomarkers of increased mammary cancer risk. Maternal HFD increased the number of terminal end buds in offspring's mammary glands and promoted cell proliferation (ki67). Maternal grape consumption blocked these effects. Apoptosis marker caspase 7, but not caspase 3, was reduced in the HFD offspring. HFD offspring also exhibited a reduction in the indicators of cell cycle regulation (p27, p21) and an ability to maintain DNA integrity (reduced p53). Maternal grape juice did not have any effect on these endpoints in the HFD offspring but reduced caspase 7 and p53 levels in the control offspring, perhaps reflecting reduced cellular stress. Maternal HFD increased oxidative stress marker GPx1 mRNA expression, and grape juice increased the levels of GPx2 in both the control and HFD offspring. HFD increased XBP1/Xbp1s, Atf4 and Atf6 mRNA expression and reduced ATF6 and CHOP protein levels. Maternal grape juice reversed the increase in XBP1/Xbp1s, Atf4 and Atf6 in the HFD offspring. PPAR was downregulated in the HFD group, and grape juice reversed this effect. Grape juice also reduced the levels of HER2 and IRS, both in the control and HFD offspring. In conclusion, maternal grape juice supplementation reversed some of the biomarkers that are indicative of increased breast cancer risk in the HFD offspring.
Assuntos
Sucos de Frutas e Vegetais/efeitos adversos , Glândulas Mamárias Animais/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Resposta a Proteínas não Dobradas/fisiologia , Vitis , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos , Feminino , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos WistarRESUMO
The developmental origins of breast cancer have been considered predominantly from a maternal perspective. Although accumulating evidence suggests a paternal programming effect on metabolic diseases, the potential impact of fathers' experiences on their daughters' breast cancer risk has received less attention. In this chapter, we focus on the developmental origins of breast cancer and examine the emerging evidence for a role of fathers' experiences.
Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Suscetibilidade a Doenças , Animais , Neoplasias da Mama/patologia , Doença Crônica , Feminino , Humanos , Lactação , Exposição Materna , Herança Paterna , Gravidez , Efeitos Tardios da Exposição Pré-NatalRESUMO
Emerging experimental evidence show that fathers' experiences during preconception can influence their daughters' risk of developing breast cancer. Here we describe detailed protocols for investigation in rats and mice of paternally mediated breast cancer risk programming effects.
Assuntos
Neoplasias da Mama/etiologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Herança Paterna , Animais , Biópsia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Dieta , Feminino , Imuno-Histoquímica , Masculino , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais , Camundongos , Ratos , Carga TumoralRESUMO
BACKGROUND: Although males contribute half of the embryo's genome, only recently has interest begun to be directed toward the potential impact of paternal experiences on the health of offspring. While there is evidence that paternal malnutrition may increase offspring susceptibility to metabolic diseases, the influence of paternal factors on a daughter's breast cancer risk has been examined in few studies. METHODS: Male Sprague-Dawley rats were fed, before and during puberty, either a lard-based (high in saturated fats) or a corn oil-based (high in n-6 polyunsaturated fats) high-fat diet (60 % of fat-derived energy). Control animals were fed an AIN-93G control diet (16 % of fat-derived energy). Their 50-day-old female offspring fed only a commercial diet were subjected to the classical model of mammary carcinogenesis based on 7,12-dimethylbenz[a]anthracene initiation, and mammary tumor development was evaluated. Sperm cells and mammary gland tissue were subjected to cellular and molecular analysis. RESULTS: Compared with female offspring of control diet-fed male rats, offspring of lard-fed male rats did not differ in tumor latency, growth, or multiplicity. However, female offspring of lard-fed male rats had increased elongation of the mammary epithelial tree, number of terminal end buds, and tumor incidence compared with both female offspring of control diet-fed and corn oil-fed male rats. Compared with female offspring of control diet-fed male rats, female offspring of corn oil-fed male rats showed decreased tumor growth but no difference regarding tumor incidence, latency, or multiplicity. Additionally, female offspring of corn oil-fed male rats had longer tumor latency as well as decreased tumor growth and multiplicity compared with female offspring of lard-fed male rats. Paternal consumption of animal- or plant-based high-fat diets elicited opposing effects, with lard rich in saturated fatty acids increasing breast cancer risk in offspring and corn oil rich in n-6 polyunsaturated fatty acids decreasing it. These effects could be linked to alterations in microRNA expression in fathers' sperm and their daughters' mammary glands, and to modifications in breast cancer-related protein expression in this tissue. CONCLUSIONS: Our findings highlight the importance of paternal nutrition in affecting future generations' risk of developing breast cancer.
Assuntos
Neoplasias da Mama/etiologia , Exposição Paterna , Efeitos Tardios da Exposição Pré-Natal , Animais , Apoptose , Neoplasias da Mama/patologia , Proliferação de Células , Transformação Celular Neoplásica , Análise por Conglomerados , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Lipídeos/química , Masculino , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais , Neoplasias Mamárias Experimentais , Carne , MicroRNAs , Plantas/química , Gravidez , Proteômica/métodos , Ratos , Espermatozoides/metabolismoRESUMO
The persistent effects of animal fat consumption during pregnancy and nursing on the programming of breast cancer risk among female offspring were studied here. We have previously found that female offspring of rat dams that consumed a lard-based high-fat (HF) diet (60% fat-derived energy) during pregnancy, or during pregnancy and lactation, were at a reduced risk of developing mammary cancer. To better understand the unexpected protective effects of early life lard exposure, we have applied lipidomics and nutrigenomics approaches to investigate the fatty acid profile and global gene expression patterns in the mammary tissue of the female offspring. Consumption of this HF diet during gestation had few effects on the mammary tissue fatty acids profile of young adult offspring, while exposure from gestation throughout nursing promoted significant alterations in the fatty acids profile. Major differences were related to decreases in saturated fatty acids (SFA) and increases in omega-6 polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and conjugated linolenic acid (CLA) concentrations. In addition several differences in gene expression patterns by microarray analysis between the control and in utero or in utero and during lactation HF exposed offspring were identified. Differential dependency network (DDN) analysis indicated that many of the genes exhibited unique connections to other genes only in the HF offspring. These unique connections included Hrh1-Ythdf1 and Repin1-Elavl2 in the in utero HF offspring, and Rnf213-Htr3b and Klf5-Chrna4 in the in utero and lactation HF offspring, compared with the control offspring. We conclude that an exposure to a lard-based HF diet during early life changes the fatty acid profile and transcriptional network in mammary gland in young adult rats, and these changes appear to be consistent with reduced mammary cancer risk observed in our previous study.