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Developmental Neurotoxicity (developmental + neurotoxicity)
Selected AbstractsEthanol neurotoxicity and dentate gyrus developmentCONGENITAL ANOMALIES, Issue 3 2008Takanori Miki ABSTRACT Maternal alcohol ingestion during pregnancy adversely affects the developing fetus, often leading to fetal alcohol syndrome (FAS). One of the most severe consequences of FAS is brain damage that is manifested as cognitive, learning, and behavioral deficits. The hippocampus plays a crucial role in such abilities; it is also known as one of the brain regions most vulnerable to ethanol-induced neurotoxicity. Our recent studies using morphometric techniques have further shown that ethanol neurotoxicity appears to affect the development of the dentate gyrus in a region-specific manner; it was found that early postnatal ethanol exposure causes a transitory deficit in the hilus volume of the dentate gyrus. It is strongly speculated that such structural modifications, even transitory ones, appear to result in developmental abnormalities in the brain circuitry and lead to the learning disabilities observed in FAS children. Based on reports on possible factors deciding ethanol neurotoxicity to the brain, we review developmental neurotoxicity to the dentate gyrus of the hippocampal formation. [source] Principles of risk assessment for determining the safety of chemicals: Recent assessment of residual solvents in drugs and di(2-ethylhexyl) phthalateCONGENITAL ANOMALIES, Issue 2 2004Ryuichi Hasegawa ABSTRACT Risk assessment of chemicals is essential for the estimation of chemical safety, and animal toxicity data are typically used in the evaluation process, which consists of hazard identification, dose,response assessment, exposure assessment, and risk characterization. Hazard identification entails the collection of all available toxicity data and assessment of toxicity endpoints based on findings for repeated dose toxicity, carcinogenicity or genotoxicity and species-specificity. Once a review is compiled, the allowable lifetime exposure level of a chemical is estimated from a dose,response assessment based on several measures. For non-carcinogens and non-genotoxic carcinogens, the no-observed-adverse-effect-level (NOAEL) is divided by uncertainty factors (e.g. with environmental pollutants) or safety factors (e.g. with food additives) to derive a tolerable daily intake (TDI) or acceptable daily intake (ADI), respectively. These factors include interspecies and individual differences, duration of exposure, quality of data, and nature of toxicity such as carcinogenicity or neurotoxicity. For genotoxic carcinogens, low dose extrapolation is accomplished with mathematical modeling (e.g. linearized multistage model) from the point of departure to obtain exposure levels that will be associated with an excess lifetime cancer risk of a certain level. Data for levels of chemicals in food, water and air, are routinely used for exposure assessment. Finally, risk characterization is performed to ensure that the established ,safe' level of exposure exceeds the estimated level of actual exposure. These principles have led to the evaluation of several existing chemicals. To establish a guideline for residual solvents in medicine, the permitted daily exposure (PDE), equivalent to TDI, of N,N-dimethylformamide was derived on the basis of developmental toxicity (malformation) and of N-methylpyrrolidone on the basis of the developmental neurotoxicity. A TDI for di(2-ethylhexyl)phthalate was derived from assessment of testicular toxicity. [source] Methanol exposure interferes with morphological cell movements in the Drosophila embryo and causes increased apoptosis in the CNSDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2004Dervla M. Mellerick Abstract Despite the significant contributions of tissue culture and bacterial models to toxicology, whole animal models for developmental neurotoxins are limited in availability and ease of experimentation. Because Drosophila is a well understood model for embryonic development that is highly accessible, we asked whether it could be used to study methanol developmental neurotoxicity. In the presence of 4% methanol, approximately 35% of embryos die and methanol exposure leads to severe CNS defects in about half those embryos, where the longitudinal connectives are dorsally displaced and commissure formation is severely reduced. In addition, a range of morphological defects in other germ layers is seen, and cell movement is adversely affected by methanol exposure. Although we did not find any evidence to suggest that methanol exposure affects the capacity of neuroblasts to divide or induces inappropriate apoptosis in these cells, in the CNS of germ band retracted embryos, the number of apoptotic nuclei is significantly increased in methanol-exposed embryos in comparison to controls, particularly in and adjacent to the ventral midline. Apoptosis contributes significantly to methanol neurotoxicity because embryos lacking the cell death genes grim, hid, and reaper have milder CNS defects resulting from methanol exposure than wild-type embryos. Our data suggest that when neurons and glia are severely adversely affected by methanol exposure, the damaged cells are cleared by apoptosis, leading to embryonic death. Thus, the Drosophila embryo may prove useful in identifying and unraveling mechanistic aspects of developmental neurotoxicity, specifically in relation to methanol toxicity. © 2004 Wiley Periodicals, Inc. J Neurobiol 60: 308,318, 2004 [source] Effects of postnatal ethanol exposure on neurotrophic factors and signal transduction pathways in rat brainJOURNAL OF APPLIED TOXICOLOGY, Issue 3 2008Vittorio Fattori Abstract Exposure to ethanol during development induces severe brain damage, resulting in a number of CNS dysfunctions including microencephaly and mental retardation. Potential targets of ethanol-induced neurotoxicity include neurotrophic factors and their signal transduction pathways. In the present study, rat pups were given ethanol at the dose of 5 g kg,1 via gavage from postnatal day (PND) 5 to 8, and mRNA expression of nerve growth-factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophic factor-3 (NT-3) in the cerebral cortex was examined, with attention to signal transduction, on PND 8. The mRNA level of BDNF was decreased by ethanol while those of NGF or NT-3 were not changed. Brain weights were decreased and the levels of phospho-MAPK, phospho-p70S6K and phospho Akt were decreased while phosphor-PKC, and phospho-CREB remained unchanged. These results suggest that BDNF and its related signal pathways involving Akt, MAPK and p70S6K are potential targets of ethanol-induced developmental neurotoxicity. Copyright © 2007 John Wiley & Sons, Ltd. [source] Ethanol Inhibits Muscarinic Receptor-Induced Axonal Growth in Rat Hippocampal NeuronsALCOHOLISM, Issue 11 2009Kathryn L. VanDeMark Background:, In utero alcohol exposure can lead to fetal alcohol spectrum (FAS) disorders characterized by cognitive and behavioral deficits. In vivo and in vitro studies have shown that ethanol alters neuronal development. One mechanism through which ethanol has been shown to exert its effects is the perturbation of activated signaling cascades. The cholinergic agonist carbachol has been shown to induce axonal outgrowth through intracellular calcium mobilization, protein kinase C (PKC) activation, and ERK1/2 phosphorylation. This study investigated the effect of ethanol on the differentiation of rat hippocampal pyramidal neurons induced by carbachol as a possible mechanism involved in the developmental neurotoxicity of ethanol. Methods:, Prenatal rat hippocampal pyramidal neurons were treated with ethanol (50 to 75 mM) in the presence or absence of carbachol for 24 hours. Neurite outgrowth was assessed spectrophotometrically; axonal length was measured in neurons fixed and immunolabeled with the neuron-specific ,III tubulin antibody; cytotoxicity was analyzed using the thiazolyl blue tetrazolium bromide assay. The effect of ethanol on carbachol-stimulated intracellular calcium mobilization was assessed utilizing the fluorescent calcium probe, Fluo-3AM. The PepTag® assay for nonradioactive detection of PKC from Promega was used to measure PKC activity, and ERK1/2 activation was determined by densitometric analysis of Western blots probed for phospo-ERK1/2. Results:, Ethanol treatment (50 to 75 mM) caused an inhibition of carbachol-induced axonal growth, without affecting neuronal viability. Neuron treatment for 15 minutes with ethanol did not inhibit the carbachol-stimulated rise in intracellular calcium, while inhibiting PKC activity at the highest tested concentration and ERK1/2 phosphorylation at both the concentrations used in this study. On the other hand, neuron treatment for 24 hours with ethanol significantly inhibited carbachol-induced increase in intracellular calcium. Conclusions:, Ethanol inhibited carbachol-induced neurite outgrowth by inhibiting PKC and ERK1/2 activation. These effects may be, in part, responsible for some of the cognitive deficits associated with in utero alcohol exposure. [source] | ||||||||||