Orientador: Francisco Eduardo Martinez / Resumo: Introdução: O alcoolismo é doença relacionada a fatores hereditários. Seu consumo pode prejudicar à saúde reprodutiva do consumidor. Alterações observadas na prole pelo consumo parental ascendem os mecanismos epigenéticos, contudo, ainda são limitadas as investigações da ingestão precoce e a influência na vida adulta. Nós avaliamos se os parâmetros reprodutivos de ratos predispostos ao consumo e expostos ao etanol diferem de ratos não predispostos, com resposta dose-dependente, se o consumo é proporcional entre os sexos e se consumo parental pós-púbere interfere no desenvolvimento da prole não exposta. Material e métodos: Ratos das variedades Wistar e Wistar UCh (consumidores voluntários de etanol) foram divididos em: Controle - Wistar (C), pouco bebedor - UChA (A), bebedor - UChB (B) e sem etanol - UChB não exposto (SE). Os ratos A e B foram expostos ao etanol (10%) dos 65 aos 80 dias. Os UChA ingerem entre 0,1 a 1,9 g etanol/kg/dia e os UChB mais que 2 g etanol/kg/dia. Os casais C, A, B e SE foram acasalados aos 100 dias. O estudo foi conduzido em duas fases: 1ª) análise dos efeitos da predisposição genética e da dose alcoólica na reprodução, constituída por C, A e B. O consumo de etanol, a massa corpórea, o tamanho da ninhada, a proporção sexual, os parâmetros gestacionais, os órgãos reprodutivos e a morfologia espermática foram verificados; 2ª) análise dos efeitos do consumo alcoólico parental pós-púbere na prole não exposta, sendo os ratos UChB divididos em: grupo parent... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Alcoholism is characterized as a disease to hereditary factors. The consumption can impairs the consumer reproductive health. Changes in offspring due to parental consumption highlights epigenetic mechanism, however, investigations of early consumption and the influence on reproductive parameters in adulthood are limited. We evaluated the reproducers parameters of rats predisposed to low and high consumption and exposed to post-puberty ethanol differs from non-predisposed rats, with the dose-dependent response, if alcohol consumption is proportional between sexes and if high consumption parental impairs the development somatic and reproductive function on unexposed offspring. Material and methods: Rats Wistar and Wistar UCh (voluntary consumers) were distributed in Control - Wistar (C), low drinker - UChA (A), drinker - UChB (B) and no exposed to ethanol- unexposed UChB (SE). The A and B were exposed to 10% ethanol from 65 to 80 days of age. The UChA drink between 0.1 and 1.9 g ethanol/kg/day and the UChB more than 2 g ethanol/kg/day. The animals C, A, B, and SE were mated on 100 days. This study was conducted in two phases: 1st: analyzed of the effects of genetic predisposition and alcoholic dose on reproduction, in C, A, and B. Ethanol consumption, body weight, litter size, sex ratio of offspring, gestational parameters, reproductive organs, and sperm morphology were observed. 2nd: analyzed the effects of parental alcohol consumption on unexposed offspring. For ... (Complete abstract click electronic access below) / Mestre

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The most common neoplasm found in young to middle-aged men is testicular cancer (TCa). This disease not only poses a risk of early death, but can also affect a male's fertility and testosterone levels and can diminish one's mental health and/or quality of life. One particular line of research that is emerging in the field is a possible genetic association of TCa with female reproductive cancers. We employed a systematic review to assess the methodological quality of articles that met the inclusionary criteria. To be selected for this review, articles had to go through a primary, secondary, and tertiary screening procedure using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. Four studies were selected, and the Newcastle-Ottawa Scale (NOS) was used to measure the quality of each nonrandomized, case-control or cohort study. Two articles received perfect scores, one case-control study received a near-perfect score of 8 out of 9 stars, and only one out of the four included studies received 5 out of 9 stars. Upon organizing and analyzing the data, we found a significantly increased risk (20%) of female reproductive cancer among women who had a father with TCa. Also, we found that men were 12% more likely to develop TCa if they had a sister with female reproductive cancer, and 16% more likely if their mother had ovarian, endometrial, breast or cervical cancer. The goal of this review was to assess the overall strength of association, or lack thereof, between TCa and female reproductive cancers. Findings of this review suggest that an association exists between these discordant forms of cancer. There were significant risks found between mothers and sons, backed by substantial evidence of an X-linked inheritance pattern. This information has the potential to improve our knowledge of cancer etiology and treatment.

Muitos estudos têm sido conduzidos em diferentes populações visando a identificação da proporção da variância fenotípica total atribuída a efeitos genéticos. A herdabilidade de fatores de risco relacionados à Síndrome Metabólica apresenta variações entre populações, tanto por causa da diferente distribuição de fatores de risco ambientais quanto pela variação genética presente em populações distintas. O objetivo desta análise foi avaliar as influências genéticas e ambientais dos componentes da Síndrome Metabólica, usando uma análise de componentes de variância, estimando a herdabilidade destes fatores em uma amostra de extensas famílias. Nós examinamos 1.712 indivíduos de 119 famílias selecionadas randomicamente da população geral de uma cidade do Brasil. Um total de 1.666 indivíduos de 81 famílias foi usado para análises. O tamanho das famílias variou de 3 a 156 indivíduos com uma média de 21 indivíduos por família. Antes de ajustes, as herdabilidades poligênicas da pressão sistólica (PAS) e diastólica (PAD) foram de 15 e 16,4%, circunferência abdominal de 26,1%, glicemia de 32,8%, triglicérides de 25,7% e HDL-c de 31,2%. Ajuste para idade, sexo, idade2 e interação sexo x idade aumentou as estimativas de herdabilidade para todos os traços: PAS (25,9%), PAD (26,2%), circunferência abdominal (40,1%), glicemia de jejum (34,5%), triglicérides (28,8%) e HDL-c (32,0%). Quando os fatores de risco para Síndrome Metabólica foram tratados como traços discretos, utilizando pontos de corte segundo critérios do ATPIII, as estimativas de herdabilidade, após ajuste para covariáveis, foram: 24,5% para SM, 37,5% para pressão arterial, 40,6% para circunferência abdominal, 54,5% para glicemia, 25,5% para triglicérides e 37,8% para HDL-c. Em conclusão, as estimativas de herdabilidade para os traços da síndrome metabólica em uma amostra da população brasileira são altas e não significativamente diferente de outros estudos em populações mundiais / Many studies have been conducted in different populations aiming at the identification of the proportion of total phenotypic variance that is attributable to genetic effects. The heritability of Metabolic Syndrome (MS) factors is expected to differ between populations because of the different distribution of environmental risk factors, as well as the genetic make-up of different human populations. The purpose of this analysis was to evaluate genetic and environmental influences on metabolic syndrome traits, using a variance component analysis, by estimating the heritability of these traits in a sample of extended pedigrees. We examined 1,712 individuals of 119 randomly selected families from the general population of a city of Brazil. A total of 1,666 individuals of 81 families were used for analysis. Family size varied from 3 to 156 individuals with a mean of 21 subjects per family. Before adjustment, polygenic heritability of systolic (SBP) and diastolic (DBP) blood pressure were 15% and 16.4%, waist circumference 26.1%, fasting glucose 32.8%, triglycerides 25.7%, and HDL-c 31.2%. Adjustment for age, sex, age2, age and sex interaction increased polygenic heritability estimates for all traits: SBP (25.9%), DBP (26.2%), waist circumference (40.1%), fasting glucose (34.5%), triglycerides (28.8%), and HDL-c (32,0%). When the Metabolic Syndrome factors were treated as discrete traits, using ATPIII cut off, the estimates of heritability after adjusting for covariates were: 24.5% for MS, 37.5% for blood pressure, 40.6% for abdominal circumference, 54.5% for fasting glucose, 25.5% for triglycerides, and 37.8% for HDL-cholesterol. In conclusion, heritability estimates for metabolic syndrome traits in a sample of Brazilian population are high and not significantly different from other studied worldwide populations

The present study evaluated genetic and metabolic factors influencing the risk of acute cerebrovascular disease (CVD) and internal carotid artery stenosis (ICA stenosis) in a Swedish community. The threonine (T) containing protein of the FABP2 A54T gene polymorphism has a greater affinity for long chain fatty acids (FFAs) than the alanine (A) containing protein. This altered affinity for FFAs has been shown to affect the intestinal absorption of fatty acids and consequently the fatty acid composition of serum lipids, in particularly postprandially. Endothelium derived NO is a potent vasodilator and antiatherogenic agent. Asymmetric dimethyl arginine (ADMA) is an endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS). ADMA has been shown to be involved in the pathogenesis of atherosclerotic disease, and ADMA inhibits eNOS by displacement of L-arginine from the enzyme, which in turn is believed to affect the amount of NO available within the endothelium. The FABP2 A54T gene polymorphism was analyzed in 407 patients with acute CVD and also in a subset of these patients whose carotids had been evaluated with ultrasound. Both the FABP2 polymorphism and a common polymorphism of the eNOS gene, Glu298Asp, were analyzed in a different population consisting of 54 matched pairs of patients with ICA stenosis and controls. ADMA levels were measured in both study populations. We found that the T54 allele was more frequent in patients with transient ischaemic attacks (TIA), and that the TT genotype was more prevalent in young, non-smoking patients with CVD than in controls. Increased concentrations of ADMA were observed in cardio-embolic infarction and TIA, but not significantly in non-cardio-embolic infarction nor in haemorrhagic stroke. In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group. A decreased arginine/ADMA ratio, a measure of NO availability was associated with CVD in the entire study population. Patients with severe carotid stenosis had significantly higher ADMA levels than the controls. Allele and genotype frequencies of the FABP2 and eNOS polymorphisms did not differ between patients with ICA stenosis and controls. Our results indicate that ADMA is a strong marker for TIA and severe ICA stenosis, and that relative defiency of arginine, measured as L-arginine/ADMA, is present in acute CVD. We also conclude that a common polymorphism of the FABP2 gene increases susceptibility to ischaemic stroke and TIA. / Figure 4 on page 17 is publshed with kind permisson from The Journal of Physiology (http://jp.physoc.org/).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Alcohol dependence (alcoholism) is a complex disease influenced by both environmental factors and genetic predisposition. Mouse models have been used to study many alcohol dependence-related traits and the genetics that underlie them. Two of the most commonly used mice in alcohol research are the C57BL/6J (B6) and DBA/2J (D2) inbred strains, which diverge on several alcohol-related traits including the development of acute physical dependence. Here we utilized the B6 and D2 mice as a genetic model of acute physical dependence, coupled with mRNA Differential Display (DD) and cDNA microarray analysis, to uncover the transcriptional response of the brain to an acute dose of alcohol as a function of time. About 150 genetically divergent and alcohol-responsive genes were identified between the whole brains of B6 and D2 mice using DD and were added as additional targets to the mouse microarrays. Microarray analysis of the prefrontal cortex of B6 and D2 mice revealed strain-specific, acute alcohol-responsive transcriptome remodeling manifested as temporal patterns of gene expression. Distinct expression patterns were identified for physiologically relevant alcohol-related consequences including intoxication, withdrawal and neuroadaptation. In silico characterization of the differentially expressed genes showed genotype dependent and independent transcriptional regulation and functional classification. In addition, categorization of differentially expressed genes by their cellular profiles revealed that some of the genes were known to be more highly expressed in either excitatory or inhibitory neuronal cell types. Our results indicate that the B6 and D2 prefrontal cortices have very different cellular and molecular responses to acute alcohol exposure. The specific roles that the genes identified in this study may play in mediating the divergent alcohol-related behavior between the strains warrant further study. / text

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.