Selective neuronal loss in the substantia nigra (SNc), as described for Parkinson's disease (PD) in humans and for Pitx3 deficiency in mice,highlights the existence of neuronal subpopulations. As yet unknown subset-specific gene cascades might underlie the observed differences in neuronal vulnerability. We identified a developmental cascade in mice in which Ahd2 (Aldh1a1) is under the transcriptional control of Pitx3. Interestingly, Ahd2 distribution is restricted to a subpopulation of the meso-diencephalic dopaminergic (mdDA) neurons that is affected by Pitx3 deficiency. Ahd2 is involved in the synthesis of retinoic acid(RA), which has a crucial role in neuronal patterning, differentiation and survival in the brain. Most intriguingly, restoring RA signaling in the embryonic mdDA area counteracts the developmental defects caused by Pitx3 deficiency. The number of tyrosine hydroxylase-positive (TH+)neurons was significantly increased after RA treatment in the rostral mdDA region of Pitx3-/- embryos. This effect was specific for the rostral part of the developing mdDA area, and was observed exclusively in Pitx3-/- embryos. The effect of RA treatment during the critical phase was preserved until later in development, and our data suggest that RA is required for the establishment of proper mdDA neuronal identity. This positions Pitx3 centrally in a mdDA developmental cascade linked to RA signaling. Here, we propose a novel mechanism in which RA is involved in mdDA neuronal development and maintenance, providing new insights into subset-specific vulnerability in PD.
BackgroundWomen are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI.Methodology/Principal FindingsIn order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring.ConclusionsThese results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.
This study presents concentrations of perfluorinated compounds in food and the dietary intake of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in The Netherlands. The concentrations of perfluorinated compounds in food were analyzed in pooled samples of foodstuffs randomly purchased in several Dutch retail store chains with nation-wide coverage. The concentrations analyzed for PFOS and PFOA were used to assess the exposure to these compounds in The Netherlands. As concentrations in drinking water in The Netherlands were missing for these compounds, conservative default concentrations of 7 pg/g for PFOS and 9 pg/g for PFOA, as reported by European Food Safety Authority, were used in the exposure assessment. In food, 6 out of 14 analyzed perfluorinated compounds could be quantified in the majority of the food categories (perfluoroheptanoic acid (PFHpA), PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoro-1-hexanesulfonate (PFHxS), and PFOS). The highest concentration of the sum of these six compounds was found in crustaceans (825 pg/g product, PFOS: 582 pg/g product) and in lean fish (481 pg/g product, PFOS: 308 pg/g product). Lower concentrations were found in beef, fatty fish, flour, butter, eggs, and cheese (concentrations between 20 and 100 pg/g product; PFOS, 29-82 pg/g product) and milk, pork, bakery products, chicken, vegetable, and industrial oils (concentration lower than 10 pg/g product; PFOS not detected). The median long-term intake for PFOS was 0.3 ng/kg bw/day and for PFOA 0.2 ng/kg bw/day. The corresponding high level intakes (99th percentile) were 0.6 and 0.5 ng/kg bw/day, respectively. These intakes were well below the tolerable daily intake values of both compounds (PFOS, 150 ng/kg bw/day; PFOA, 1500 ng/kg bw/day). The intake calculations quantified the contribution of drinking water to the PFOS and PFOA intake in The Netherlands. Important contributors of PFOA intake were vegetables/fruit and flour. Milk, beef, and lean fish were important contributors of PFOS intake.
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