1,394 research outputs found
Additional file 1 of Prenatal and early-life diesel exhaust exposure causes autism-like behavioral changes in mice
No full textFigure S1. Three chambered social preference test set up. Figure S2. Open Field Test. Figure S3. Pup USV call categories. (DOCX 688Â kb
Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism
No full textPURPOSE OF REVIEW: Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component.RECENT FINDINGS: Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions are certainly warranted
Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates
No full textParaoxonase (PON1) is an HDL-associated enzyme capable of hydrolyzing multiple substrates, including several organophosphorous insecticides and nerve agents, oxidized lipids, and a number of drugs or pro-drugs. Several polymorphisms in the paraoxonase (PON1) gene have been described, which have been shown to affect either the catalytic efficiency of hydrolysis or the expression level of PON1. This review discusses the relevance of these polymorphisms for modulating sensitivity to organophosphorous compounds. Animal studies characterizing the PON1 polymorphisms have demonstrated the relevance of PON1 in modulating OP toxicity and have indicated the importance of an individual's PON1 status (i.e., genotype and phenotype taken together) rather than genotyping alone. Nevertheless, direct confirmation in humans of the relevance of PON1 status in conferring susceptibility to OP toxicity is still elusive. Recent studies examining the involvement of PON1 status in determining OP susceptibility of Gulf War veterans, sheep dippers, and individuals poisoned with chemical warfare agents represent a step in the right direction, but more studies are needed, with better documentation of both the level of exposure and the consequences of exposure
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Acute exposure to diesel exhaust impairs adult neurogenesis in mice: prominence in males and protective effect of pioglitazone
No full textAdult neurogenesis is the process by which neural stem cells give rise to new functional neurons in specific regions of the adult brain, a process that occurs throughout life. Significantly, neurodegenerative and psychiatric disorders present suppressed neurogenesis, activated microglia, and neuroinflammation. Traffic-related air pollution has been shown to adversely affect the central nervous system. As the cardinal effects of air pollution exposure are microglial activation, and ensuing oxidative stress and neuroinflammation, we investigated whether acute exposures to diesel exhaust (DE) would inhibit adult neurogenesis in mice. Mice were exposed for 6 h to DE at a PM2.5 concentration of 250-300 mu g/m(3), followed by assessment of adult neurogenesis in the hippocampal subgranular zone (SGZ), the subventricular zone (SVZ), and olfactory bulb (OB). DE impaired cellular proliferation in the SGZ and SVZ in males, but not females. DE reduced adult neurogenesis, with male mice showing fewer new neurons in the SGZ, SVZ, and OB, and females showing fewer new neurons only in the OB. To assess whether blocking microglial activation protected against DE-induced suppression of adult hippocampal neurogenesis, male mice were pre-treated with pioglitazone (PGZ) prior to DE exposure. The effects of DE exposure on microglia, as well as neuroinflammation and oxidative stress, were reduced by PGZ. PGZ also antagonized DE-induced suppression of neurogenesis in the SGZ. These results suggest that DE exposure impairs adult neurogenesis in a sex-dependent manner, by a mechanism likely to involve microglia activation and neuroinflammation
Metals and Paraoxonases
No full textThe paraoxonases (PONs) are a three-gene family which includes PON1, PON2, and PON3. PON1 and PON3 are synthesized primarily in the liver and a portion is secreted in the plasma, where they are associated with high-density lipoproteins (HDLs), while PON2 is an intracellular enzyme, expressed in most tissues and organs, including the brain. PON1 received its name from its ability to hydrolyze paraoxon, the active metabolite of the organophosphorus (OP) insecticide parathion, and also more efficiently hydrolyzes the active metabolites of several other OPs. PON2 and PON3 do not have OP-esterase activity, but all PONs are lactonases and are capable of hydrolyzing a variety of lactones, including certain drugs, endogenous compounds, and quorum-sensing signals of pathogenic bacteria. In addition, all PONs exert potent antioxidant effects. PONs play important roles in cardiovascular diseases and other oxidative stress-related diseases, modulate susceptibility to infection, and may provide neuroprotection (PON2). Hence, significant attention has been devoted to their modulation by a variety of dietary, pharmacological, lifestyle, or environmental factors. A number of metals have been shown in in vitro, animal, and human studies to mostly negatively modulate expression of PONs, particularly PON1, the most studied in this regard. In addition, different levels of expression of PONs may affect susceptibility to toxicity and neurotoxicity of metals due to their aforementioned antioxidant properties
Pharmacogenomic considerations of the paraoxonase polymorphisms
No full textThe high density lipoprotein (HDL)-associated enzyme paraoxonase-1 (PON1) exhibits a substrate-dependent activity polymorphism as well as a large variability in plasma levels among individuals. The PON1 activity polymorphism is determined mainly by a glutamine (Q)/arganine(R) substitution at position 192 of PON1 (PON1Q192R). There is one additional polymorphism in the coding region at L55M, five in the 5â2 regulatory region and four in the 3â2 untranslated region. One of the five promoter polymorphisms (C-108T) appears to have a major effect on the levels of PON1 found in plasma. Two factors are important to consider in evaluating the pharmacogenetics of PON1 in an individual, the amino acid present at position 192 and the level of their plasma PON1. 'PON1 status', measured easily via a two-substrate assay, provides data for both of these critical factors. As such, PON1 status will be more useful than genotyping alone for identifying individuals at risk for cardiovascular disease, for predicting sensitivity to OP insecticides, and possibly nerve agents, for predicting the disposition of drugs known to be activated or hydrolyzed by PON1 and for developing robust pharmacokinetic models for each of these roles of these roles of PON1
Neurotoxicants are in the air: Convergence of human, animal, and in vitro studies on the effects of air pollution on the brain
No full textIn addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also negatively affect the brain and contribute to central nervous system diseases. Air pollution is a mixture comprised of several components, of which ultrafine particulate matter (UFPM; <100 nm) is of much concern, as these particles can enter the circulation and distribute to most organs, including the brain. A major constituent of ambient UFPM is represented by traffic-related air pollution, mostly ascribed to diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution may lead to neurotoxicity. In addition to a variety of behavioral abnormalities, two prominent effects caused by air pollution are oxidative stress and neuroinflammation, which are seen in both humans and animals and are confirmed by in vitro studies. Among factors which can affect neurotoxic outcomes, age is considered the most relevant. Human and animal studies suggest that air pollution (and DE) may cause developmental neurotoxicity and may contribute to the etiology of neurodevelopmental disorders, including autistic spectrum disorders. In addition, air pollution exposure has been associated with increased expression of markers of neurodegenerative disease pathologies. © 2014 Lucio G. Costa et al
Modulation of paraoxonase (PON1) activity
No full textParaoxonase 1 (PON1) is a serum enzyme closely associated with high density lipoprotein (HDL). PON1 hydrolyzes several organophosphorus compounds used as insecticides, as well as nerve agents; it metabolizes toxic oxidized lipids associated with both low density lipoprotein (LDL) and HDL; and it can hydrolyze a number of lactone-containing pharmaceutical compounds, inactivating some, while activating others. Serum PON1 activity in a given population can vary by 40-fold. Though most of this variation can be explained by polymorphisms in the coding region (Q192R) and the 5' regulatory region (T-108C), modulation of PON1 by a variety of other factors should be taken into account, including other polymorphisms recently discovered but not yet characterized. This paper examines the major factors (environmental chemicals, drugs, smoking, alcohol, diet, age, disease conditions) that have been shown to modulate PON1 activity in either direction. As PON1 plays a protective role in organophosphate toxicity, and, because of its antioxidant capacity, in cardiovascular disease, a better understanding of how PON1 can be modulated by environmental factors has potential toxicological and clinical consequences. (C) 2004 Elsevier Inc. All rights reserved
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