RESUMO
Zinc is required for fetal development and is involved in key processes associated with breast carcinogenesis. We evaluated whether maternal zinc deficiency or supplementation during gestation influences female offspring susceptibility to breast cancer in adulthood. C57BL/6 mice consumed during gestation control (30â¯p.p.m. zinc), zinc-deficient (8 p.p.m) or zinc-supplemented (45â¯p.p.m.) diets. Maternal zinc supplementation increased in female mice offspring the incidence of chemically-induced mammary adenocarcinomas that were heavier, compared to control group. This was accompanied by a decreased number of terminal end buds, increased cell proliferation and apoptosis, and increased tumor suppressors p21, p53 and Rassf1, Zfp382 and Stat3 expression in mammary glands, as well as increased zinc status. Although maternal zinc deficiency did not alter the incidence of these lesions, it also induced heavier mammary adenocarcinomas, compared to control group. These effects were accompanied by a decreased number of terminal end buds, increased proto-oncogenes c-Myc and Lmo4 expression and H3K9Me3 and H4K20Me3 epigenetic marks in mammary glands of offspring, and decreased zinc status and increased levels of oxidative marker malondialdehyde. The data suggest that both maternal zinc deficiency and supplementation during gestation programmed increased breast cancer susceptibility in adult mice offspring following a J-shaped pattern through distinct mechanisms.
Assuntos
Deficiências Nutricionais/complicações , Suplementos Nutricionais , Neoplasias Mamárias Experimentais/etiologia , Zinco/administração & dosagem , Zinco/deficiência , Animais , Apoptose , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Masculino , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proto-Oncogenes , Proteína Supressora de Tumor p53/metabolismoRESUMO
Among the primary neoplasias that affect the liver, hepatocellular carcinoma (HCC) is the most frequent and the third leading cause of death related to cancer. Several risk factors predispose individuals to HCC such as nonalcoholic fatty liver disease (NAFLD), whose incidence has significantly increased worldwide. ß-ionone (ßI) isoprenoid is a known chemopreventive of hepatocarcinogenesis. However, the effects of this compound on NAFLD isolated or in association with hepatocarcinogenesis have not yet been evaluated. A high-fat emulsion administered for 6 weeks resulted in NAFLD in male rats, and oral treatment with ßI during this period significantly attenuated its development. Moreover, the presence of NAFLD potentiated hepatocarcinogenesis induced by the resistant hepatocyte (RH) model in these animals by increasing the number and percentage of the liver section area occupied by placental glutathione S-transferase (GST-P)-positive persistent preneoplastic lesions (pPNLs), that are thought to evolve into HCC. This indicates that this NAFLD/RH protocol is suitable for studies of the influence of NAFLD on the HCC development. Therefore, here we also investigated the chemopreventive effect of ßI under these two associated conditions. In this context, ßI reduced the number and percentage of the liver section area occupied by pPNLs, as well as cell proliferation and the number of oval cells, which are considered potential targets for the development of HCC. Thus, ßI presents not only a promising inhibitory effect on NAFLD isolated but also chemopreventive activity when it is associated with hepatocarcinogenesis.
Assuntos
Carcinoma Hepatocelular/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Norisoprenoides/uso terapêutico , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Glutationa Transferase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/patologia , Norisoprenoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Triglicerídeos/análiseRESUMO
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.