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Maternal hyperhomocysteinemia and epigenetic changes in fetal programming of genes involved in Alzheimer's Disease pathogenesis

Grant number: 10/00075-2
Support Opportunities:Regular Research Grants
Duration: April 01, 2010 - November 30, 2012
Field of knowledge:Health Sciences - Nutrition - Malnutrition and Physiological Development
Principal Investigator:Vânia D'Almeida
Grantee:Vânia D'Almeida
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil


Epidemiological and experimental studies indicate that fetal and neonatal environment exerts a profound influence on physiological functions and may increase the risk of developing chronic diseases in adulthood. The hypothesis of fetal origins of adult disease, called fetal programming, suggests a correlation between an adverse intrauterine environment (nutritional deficiency or environmental stimuli) and adaptive responses in the fetus. It is believed that nutrition exerts its role in programming gene expression through the metabolism of groups of a carbon flow governed by the methionine-homocysteine. On this route, the methyl groups are available, among other purposes, for methylation of DNA and proteins and are sensitive to the supply of amino acids, folic acid, vitamin B12 and vitamin B6. In addition, recent studies have shown a change in the rate of global methylation in placenta of rats associated with placental levels of S-adenosyl-methionine (SAM), when compared to rats with diet homocysteine / folate deficient and homocysteine / folate supplementation. Another study observed a decrease in capacity of exploratory behavior and learning and memory associated with early deprivation of vitamin B. There are few studies about the effects of maternal hyperhomocysteinemia in the programming of fetal gene expression. Therefore, this study aims to investigate the effects of maternal hyperhomocysteinemia in different stages of fetal development and postnatal programming of genes APP, PS1, PS2, ADAM10, TACE, BACE and p53 that are important in the Alzheimer's disease pathogenesis. Swiss strain mices will be used, assigned to two experimental groups one month before pregnancy: control group, supplemented with methionine and deficient diet (methyl donors, vitamins B12, B2 and folate). After birth and at predetermined times, the kittens will be sacrificed and brain and plasma stored at -80ºC. The levels of homocysteine, SAM and S-adenosyl-homocysteine will be assayed by high performance liquid chromatography- HPLC, and serum folic acid and vitamin B12 will be performed by immunoassay technique. The quantification of gene expression will be performed by real-time PCR and quantification of protein expression by western blot. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE REZENDE, MARINA MASTELARO; D'ALMEIDA, VANIA. Central and Systemic Responses to Methionine-Induced Hyperhomocysteinemia in Mice. PLoS One, v. 9, n. 8, . (10/00075-2, 11/15699-4)
CAVALCANTE-SILVA, VANESSA; DA SILVA VALLIM, JULIA RIBEIRO; FERNANDES, LEANDRO; DE OLIVEIRA, ALLAN CHIARATTI; D'ALMEIDA, VANIA. Maternal methionine supplementation in mice affects long-term body weight and locomotor activity of adult female offspring. BRITISH JOURNAL OF NUTRITION, v. 127, n. 8, p. 10-pg., . (10/00075-2)
DA SILVA, VANESSA CAVALCANTE; FERNANDES, LEANDRO; HASEYAMA, EDUARDO JUN; DIAS ABDO AGAMME, ANA LUIZA; GUERRA SHINOHARA, ELVIRA MARIA; CARTAXO MUNIZ, MARIA TEREZA; D'ALMEIDA, VANIA. Effect of Vitamin B Deprivation during Pregnancy and Lactation on Homocysteine Metabolism and Related Metabolites in Brain and Plasma of Mice Offspring. PLoS One, v. 9, n. 4, . (10/00075-2)

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