Network on veterinary medicines initiated by the European Federation For Pharmaceutical Sciences.

The European Federation for Pharmaceutical Sciences (EUFEPS) was founded 25 years ago by more than 20 national pharmaceutical societies and faculty members. As a pan-European organization, it brings together pharmaceutical societies as well as academic, industrial and regulatory scientists engaged in drug research and development, drug regulation and education of professionals working in these fields. EUFEPS represents pharmaceutical sciences in Europe and is recognized as such by both the European Commission and the European Medicines Agency.

Towards a European strategy for medicines research (2014-2020): The EUFEPS position paper on Horizon 2020.

As to the alignment of "Horizon 2020", ir is a more integrated approach to European science policy than expressed in the proposals previously drafted, and specifically considers: (i) promoting excellence in Science, (ii) establishing a sound industrial leadership and (iii) expressing an ambition to address current and future societal challenges. In this respect, the quest for a knowledge-based economy in Europe should result in proposals for industrial and employment policies that will consolidate the major European advantages in the biomedical, healthcare and pharmaceutical sectors. Horizon 2020 also provides the possibility of adopting a more flexible and simplified management route to drive European research through innovation, research and development.

Mercury in the spinal cord after inhalation of mercury.

Amyotrophic lateral sclerosis (ALS) affects anterior horn cells of the spinal cord causing an indolent slow and steady deterioration of muscle strength leading inevitably to death in respiratory failure. ALS is a model condition for neurodegenerative disorders. Exposure to different agents dispersed in the environment has been suggested to cause neurodegeneration but no convincing evidence for such a link has yet been presented.

Effects of the histone deacetylase inhibitor valproic acid on human pericytes in vitro.

Microvascular pericytes are of key importance in neoformation of blood vessels, in stabilization of newly formed vessels as well as maintenance of angiostasis in resting tissues. Furthermore, pericytes are capable of differentiating into pro-fibrotic collagen type I producing fibroblasts. The present study investigates the effects of the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on pericyte proliferation, cell viability, migration and differentiation.

Short-time gene expression response to valproic acid and valproic acid analogs in mouse embryonic stem cells.

Prediction of developmental toxicity in vitro could be based on short-time toxicogenomic endpoints in embryo-derived cell lines. Microarray studies in P19 mouse embryocarcinoma cells and mouse embryos have indicated that valproic acid (VPA), an inducer of neural tube defects, deregulates the expression of many genes, including those critically involved in neural tube development. In this study, we exposed undifferentiated R1 mouse embryonic stem cells to VPA and VPA analogs for 6 h and used CodeLink whole-genome expression microarrays to define VPA-responsive genes correlating with teratogenicity.

Early transcriptional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicity.

Cell-based in vitro assays would potentially reduce animal testing in preclinical drug development. Mouse embryos exposed to the teratogenic drug valproic acid (VPA) in utero for 1.5, 3 or 6h on gestational day 8 were analyzed using microarrays.

Neuropeptidomic analysis of the embryonic Japanese quail diencephalon.

Background: Endogenous peptides such as neuropeptides are involved in numerous biological processes in the fully developed brain but very little is known about their role in brain development. Japanese quail is a commonly used bird model for studying sexual dimorphic brain development, especially adult male copulatory behavior in relation to manipulations of the embryonic endocrine system. This study uses a label-free liquid chromatography mass spectrometry approach to analyze the influence of age (embryonic days 12 vs 17), sex and embryonic day 3 ethinylestradiol exposure on the expression of multiple endogenous peptides in the developing diencephalon.

In vitro neurotoxicity of PBDE-99: immediate and concentration-dependent effects on protein expression in cerebral cortex cells.

Polybrominated diphenyl ethers (PBDEs) are commonly used flame retardants in various consumer products. Pre- and postnatal exposure to congeners of PBDEs disrupts normal brain development in rodents. Two-dimensional difference gel electrophoresis (2D-DIGE) was used to analyze concentration-dependent differences in protein expression in cultured cortical cells isolated from rat fetuses (GD 21) after 24 h exposure to PBDE-99 (3, 10, or 30 microM).

Valproic acid-induced deregulation in vitro of genes associated in vivo with neural tube defects.

The utility of an in vitro system to search for molecular targets and markers of developmental toxicity was explored, using microarrays to detect genes susceptible to deregulation by the teratogen valproic acid (VPA) in the pluripotent mouse embryonal carcinoma cell line P19. Total RNA extracted from P19 cells cultured in the absence or presence of 1, 2.5, or 10mM VPA for 1.

Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex.

Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear.

Faced with inequality: chicken do not have a general dosage compensation of sex-linked genes.

Background: The contrasting dose of sex chromosomes in males and females potentially introduces a large-scale imbalance in levels of gene expression between sexes, and between sex chromosomes and autosomes. In many organisms, dosage compensation has thus evolved to equalize sex-linked gene expression in males and females. In mammals this is achieved by X chromosome inactivation and in flies and worms by up- or down-regulation of X-linked expression, respectively.

Expression of ZnT-1 (Slc30a1) and MT-1 (Mt1) in the conceptus of cadmium treated mice.

There are indications that Cd-induced malformations in rodents are related to a disrupted flux of Zn to the developing embryo. The aim of the present study was to detect ZnT-1 (Slc30a1) and MT (Mt1) protein in structures within the decidua, yolk sac and embryo of mice and to determine whether Cd affects ZnT-1 or MT-1 gene expression in these tissues. ZnT-1 was detected in the placental labyrinth, in the ventral part around the floor plate, in the inner cell layers of the rhombencephalon and in the ventral area of the otic vesicle.

Molecular targets and early response biomarkers for the prediction of developmental toxicity in vitro.

There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead identification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed.

Cadmium-induced gene expression changes in the mouse embryo, and the influence of pretreatment with zinc.

Cadmium (Cd) administered to female C57BL/6 mice on gestation day 8 induces a high incidence of anterior neural tube defects (exencephaly). This adverse effect can be attenuated by maternal pretreatment with zinc (Zn). In this study we used replicated microarray analysis and real-time PCR to investigate gene expression changes induced in the embryo 5 and 10h after maternal Cd exposure in the absence or presence of Zn pretreatment.

Sex-dependent gene expression in early brain development of chicken embryos.

Background: Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms.

Results: Using cDNA microarrays and real-time PCR we found gene expression differences between the male and female embryonic brain (or whole head) that may be independent of morphological differentiation of the gonads.

Proteomic evaluation of neonatal exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether.

Exposure to the brominated flame retardant 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus.

Valproic acid teratogenicity: a toxicogenomics approach.

Embryonic development is a highly coordinated set of processes that depend on hierarchies of signaling and gene regulatory networks, and the disruption of such networks may underlie many cases of chemically induced birth defects. The antiepileptic drug valproic acid (VPA) is a potent inducer of neural tube defects (NTDs) in human and mouse embryos. As with many other developmental toxicants however, the mechanism of VPA teratogenicity is unknown.

Disturbing endoderm signaling to anterior neural plate of vertebrates by the teratogen cadmium.

Cadmium accumulation in the mouse gut endoderm occurs until the closure of the vitelline duct (day 9 post-coitus; p.c.), producing anterior neural tube defects (NTD).

Cadmium-induced changes in apoptotic gene expression levels and DNA damage in mouse embryos are blocked by zinc.

Cadmium is a potent teratogen in laboratory animals, causing exencephaly when administered at early stages of development. Due to its heterogenicity with respect to molecular targets, the mechanisms behind cadmium toxicity are not well understood. In the present study, C57BL/6 pregnant mice were treated with saline, cadmium, or zinc plus cadmium at 8 days post-coitus and studied 24 h after exposure.

Immunohistochemical localization of retinoid binding proteins at the materno-fetal interface of the porcine epitheliochorial placenta.

Retinol and retinoic acid that are potent modulators of gene expression are vital for development and growth of the conceptus. Apart from being transported across the placenta, retinol and retinoic acid may also be active in the placenta per se. Three proteins involved in 1) serum transport of retinol (retinol binding protein [RBP]), 2) cellular transport and metabolism of retinol (cellular RBP [CRBP] I), and 3) retinoic acid (cellular retinoic acid binding protein [CRABP] I), respectively, have been located by immunohistochemistry during gestation in the porcine placenta.

Gene structure, expression analysis, and membrane topology of RDH4.

The murine retinol dehydrogenase RDH4 oxidizes several cis-isomers of retinol into their corresponding aldehydes. We have determined the structure of the murine gene, investigated the temporal and spatial expression of the enzyme, and analyzed the membrane topology of the enzyme. The gene has four translated exons, and several alternatively spliced exons in the 5'-untranslated region were identified.

Measurement of DNA damage by the comet assay in rat embryos grown in media containing high concentrations of vitamin K(1).

It has been suggested that vitamin K(1) (phylloquinone) can cause genetic damage in rapidly dividing cells and that this should be considered in the risk/benefit analysis of the prophylactic use of vitamin K(1) in the newborn. Usual intramuscular administration of 1mg of vitamin K(1) to the newborn gives peak plasma levels of 1-2 microg/ml (approximately 2-4 microM). To investigate the possible harmful effects of high concentrations of vitamin K(1), rat embryos undergoing rapid cell division in the organogenic period were cultured for 46 hours in rat sera containing either 1, 10 or 100 microg of added vitamin K(1) per ml (2, 22 or 222 microM).

Retinoid binding proteins-expression patterns in the human placenta.

The present study examined the expression and occurrence of different retinoid binding proteins in human first trimester and term placenta. At both stages, messenger RNA for the serum transport vehicle for retinol, retinol-binding protein (RBP), was detected only in decidual cells of the basal plate. In contrast, immunoreactive RBP (irRBP) was present in syncytiotrophoblast, core mesenchyme and lumen of vessels in placental villi and in mesenchyme and decidual cells of the basal plate.