Environmental and genetic factors contribute to the development of schizophrenia. For example, epidemiological evidence has linked infections during pregnancy with increased incidence of schizophrenia in the adult offspring. At the same time mutation to DISC1, a protein involved in neurone migration and synaptic plasticity, is an important genetic risk for the disorder. Accordingly, the aim of this project was to determine if these environmental and genetic influences converge along a common pathogenic pathway leading to schizophrenia. Using a model of prenatal infection by bacterial endotoxin in rodents, we demonstrated a 50% reduction in DISC1 protein expression in the hippocampus and cortex of juvenile offspring. In addition, we found a significant induction of prostaglandins (final mediators of the inflammatory process) in the fetal brain while many cytokines remained unaltered. Taken together our results identify prostaglandins as potential mediators of the teratogenic effects of prenatal infection and show that prenatal infection itself can affect systems related to genetic risk factors for schizophrenia, in this case DISC1.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

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

Thesis (Ph. D.)--West Virginia University, 1999. / Title from document title page. Document formatted into pages; contains xiv, 223 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 187-220).

Iron deficiency (ID) is especially common in pregnant women and may even persist following childbirth. This is of concern in light of reports demonstrating that ID may be sufficient to produce homeostatic dysregulation of other metals, including manganese (Mn). These results are particularly important considering the potential introduction of the Mn-containing gas additive, methyl cyclopentadienyl manganese tricarbonyl (MMT), in various countries around the world. In order to model this potentially vulnerable population, we fed female rats fed either control (35 mg Fe/kg chow; 10 mg Mn/kg chow) or low iron/high-manganese (IDMn; 3.5 mg Fe/kg chow; 100 mg Mn/kg chow) diet, and examined whether these changes had any long-term behavioral effects on the animals' spatial abilities, as tested by the Morris water maze (MWM). We also analyzed behavioral performance on auditory sensorimotor gating utilizing prepulse inhibition (PPI), which may be related to overall cognitive performance. Furthermore, brain and blood metal levels were assessed, as well as regional brain isoprostane production. We found that treated animals were slightly ID, with statistically significant increases in both iron (Fe) and Mn in the hippocampus, but statistically significantly less Fe in the cerebellum. Additionally, isoprostane levels, markers of oxidative stress, were increased in the brain stem of IDMn animals. Although treated animals were indistinguishable from controls in the PPI experiments, they performed less well than controls in the MWM. Taken together, our data suggest that vulnerable ID populations exposed to high levels of Mn may indeed be at risk of potentially dangerous alterations in brain metal levels which could also lead to behavioral deficits.

No description available.

No description available.

Diversos estudos observaram uma correlação entre doenças na idade adulta e o ambiente durante a vida fetal. O estudo realizado por Barker e colaboradores foi um dos primeiros a relatar a hipótese de um possível envolvimento do ambiente intra-uterino com o desenvolvimento de doenças cardiovasculares, mas os mecanismos responsáveis por esta associação ainda não são totalmente conhecidos. Estudos demonstraram uma associação entre baixo peso ao nascimento com resistência à insulina e intolerância à glicose na vida adulta. Recentemente, verificamos que o consumo de dieta hipossódica, conhecido modelo de resistência à insulina, durante a gestação e lactação está vinculado a menor sensibilidade à insulina na prole adulta. Visto que a presença de resistência à insulina durante a gestação leva a diversas alterações metabólicas na prole adulta, pode-se supor que a sobrecarga de sacarose, um modelo de resistência à insulina, durante a gestação e lactação influencie no desenvolvimento da prole. Assim, o objetivo do presente estudo foi verificar a repercussão da resistência à insulina, durante a gestação sobre a prole adulta. Para tanto, ratas Wistar foram alimentadas com dieta hipo (HO) ou normossódica (NR) suplementadas ou não com sacarose (NR+SAC - 20g/dL) ou maltodextrina (NR+MALTO - 20g/dL) desde a oitava semana de vida até o final da gestação e amamentação. Na prole resultante destes animais foi observado menor peso ao nascimento nos grupos HO, NR+SAC e NR+MALTO. Esta alteração resultou no desenvolvimento de maior insulinemia, pressão arterial e maior captação de glicose na prole de fêmeas das mães do grupo NR+SAC. Os machos apresentaram menor índice de adiposidade e maior expressão gênica renal dos componentes do sistema renina-angiotensina. Tais resultados nos permitem concluir que a sobrecarga de carboidratos durante a gestação e lactação está associada a alterações no peso ao nascimento e no metabolismo da insulina na idade adulta. É possível que a ativação do sistema renina-angiotensina materno induzido pela sobrecarga de carboidrato esteja associada a alterações deste mesmo sistema observado na prole adulta. / Many studies observed a correlation between diseases in adult subjects and the environment during the fetal life. Barker and coworkers hypothesized that there is a possible intrauterine enviroment association with cardiovascular diseases in adulthood. The mechanisms responsible for this association are still not very well known. Recently, we have verified that low-salt diet consumption, a well-known model of insulin resistance, during pregnancy and lactation is associated with a lower insulin sensitivity in the adult offspring. Since insulin resistance during pregnancy leads to many metabolic alterations in the adult offspring, we suppose that sucrose overload during pregnancy and lactation could influence the offspring development. The aim of this study was to verify the effects on adult offspring of insulin resistance during pregnancy and lactation. Female Wistar rats were fed low (LSD) and normal-salt diet (NSD) supplemented or not with sucrose (SUC - 20 g/dL) or maltodextrin (MALTO - 20 g/dL) until the end of pregnancy and lactation. Lower birth weight was observed in offspring of LSD, SUC and MALTO groups. Higher plasma insulin level, blood pressure and glucose uptake was detected in the adult SUC female offspring. SUC male offspring had lower adiposity index and higher gene expression of the renal renin-angiotensin components. These results show that carbohydrate overload during pregnancy and lactation is associated with alterations in birth weight and in insulin metabolism at adult life. It is possible that the maternal renin-angiotensin system activation by the carbohydrate overload is associated with alterations in the same system observed in the adult offspring.

Although the association between high maternal alcohol consumption and adverse reproductive outcomes is well established, the effect of lower levels of consumption during pregnancy is unclear; few studies have investigated this exposure. A hospital-based case-control study of small-for-gestational age (SGA) newborns (birth weight below the 10th percentile, according national standards for gestational age and sex) was conducted in Montreal between 1998 and 2000. Controls were born at the same hospital and during the same period with birth weight at or above the 10th percentile. This analysis aims at investigating the effect of low alcohol consumption (0.25 to 3 alcoholic drinks weekly) during pregnancy on the risk of small-for-gestational-age (SGA) birth. Independent effects of wine, beer and spirits and of paternal alcohol consumption before conception were also assessed. The logistic regression analysis showed no significant effect of light maternal drinking during pregnancy on the risk of SGA birth. The association was also studied separately for consumption of wine, beer and spirits, and likewise for paternal alcohol consumption, with similarly negative results.

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