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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
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
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
Get PDFIn 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
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
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
Developmental neurotoxicity of diesel exhaust in a Gclm heterozygous mouse model
No full textThesis (Master's)--University of Washington, 2022The 2018 Environmental Performance Index (EPI) named air pollution as the number one environmental threat to public health. Traffic-related air pollution (TRAP) is a sizable contributor to global air pollution, and diesel exhaust (DE) is a major source of TRAP (Yale Center for Environmental Law & Policy, 2018). Though the connection between air pollution and respiratory or cardiovascular diseases is widely known, more recent studies have begun to establish a connection between air pollution and diseases of the central nervous system (CNS). Epidemiological and animal studies have revealed both biochemical and behavioral variations in children or young animals exposed to elevated levels of air pollution, including increased risk of the development of autism spectrum disorder (ASD) (Flores-Pajot et al., 2016). These studies also suggest, much like with cardiovascular impacts, that oxidative stress and neuroinflammation play a large role in the CNS effects. Children diagnosed with ASD show morphological differences in the brain, high oxidative stress, and neuroinflammation as well as systemic inflammation. Growing evidence supports the notion that ASD is a result of interactions between genetic and environmental factors (Costa et al., 2022, chapter 42). This project measured the gene-environment interaction between the gene encoding glutamate-cysteine ligase modifier subunit (Gclm), the modulatory subunit of the rate limiting enzyme in glutathione (GSH) synthesis, and neurodevelopmental effects of TRAP exposure. GSH has a key function in combatting oxidative stress and children diagnosed with ASD have shown a 37% increase in GCLM protein and a 38% decrease in glutamate-cysteine ligase (GCL) activity. To study this gene-environment interaction for effects on the neurodevelopmental toxicity of DE, we used a Gclm heterozygous (Gclm+/-) mouse model, which exhibits decreased GSH-synthesizing activity when challenged with oxidative stress, due to the presence of only one functional Gclm allele, hypothesizing that Gclm+/- mice would see exacerbated effects from exposure to diesel exhaust (DE). C57Bl/6 wild-type (WT) dams bred with Gclm+/- sires were exposed to DE or filtered air (FA) throughout gestation, and litters containing the Gclm+/- and Gclm+/+ offspring continued to be exposed from post-natal day (PND) 0 to 21. Behavioral endpoints, measured in the offspring at 12 and 24 weeks old, showed deficits in repetitive behaviors and social novelty with DE exposure, but surprisingly these effects were not increased in the Gclm+/- mice. Biochemical endpoints were measured in the brain at 29 weeks old. Lipid peroxidation was higher in the brains of DE-exposed mice, and this effect was exacerbated in Gclm+/- males, but not Gclm+/- females. Finally, a clear effect of DE exposure was seen on neuroinflammation and microglial activation. These effects were not significantly exacerbated in the Gclm+/- mouse model, contrary to what was expected. Thus, the Gclm genotype of the offspring, and presumably their altered ability to induce GSH, was not sufficient to modulate the neurodevelopmental effects of DE exposure
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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