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VanderGiessen M, de Jager C, Leighton J, Xie H, Theus M, Johnson E, Kehn-Hall K. Neurological manifestations of encephalitic alphaviruses, traumatic brain injuries, and organophosphorus nerve agent exposure. Front Neurosci 2024; 18:1514940. [PMID: 39734493 PMCID: PMC11671522 DOI: 10.3389/fnins.2024.1514940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/20/2024] [Indexed: 12/31/2024] Open
Abstract
Encephalitic alphaviruses (EEVs), Traumatic Brain Injuries (TBI), and organophosphorus nerve agents (NAs) are three diverse biological, physical, and chemical injuries that can lead to long-term neurological deficits in humans. EEVs include Venezuelan, eastern, and western equine encephalitis viruses. This review describes the current understanding of neurological pathology during these three conditions, provides a comparative review of case studies vs. animal models, and summarizes current therapeutics. While epidemiological data on clinical and pathological manifestations of these conditions are known in humans, much of our current mechanistic understanding relies upon animal models. Here we review the animal models findings for EEVs, TBIs, and NAs and compare these with what is known from human case studies. Additionally, research on NAs and EEVs is limited due to their classification as high-risk pathogens (BSL-3) and/or select agents; therefore, we leverage commonalities with TBI to develop a further understanding of the mechanisms of neurological damage. Furthermore, we discuss overlapping neurological damage mechanisms between TBI, NAs, and EEVs that highlight novel medical countermeasure opportunities. We describe current treatment methods for reducing neurological damage induced by individual conditions and general neuroprotective treatment options. Finally, we discuss perspectives on the future of neuroprotective drug development against long-term neurological sequelae of EEVs, TBIs, and NAs.
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Affiliation(s)
- Morgen VanderGiessen
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
| | - Caroline de Jager
- Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, VA, United States
| | - Julia Leighton
- Neuroscience Department, Medical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, United States
| | - Hehuang Xie
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
| | - Michelle Theus
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
| | - Erik Johnson
- Neuroscience Department, Medical Toxicology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, United States
| | - Kylene Kehn-Hall
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
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2
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Camacho-Pérez MR, Díaz-Resendiz KJG, Ortiz-Butrón R, Covantes-Rosales CE, Benitez-Trinidad AB, Girón-Pérez DA, Toledo-Ibarra GA, Pavón L, Girón-Pérez MI. In vitro effect of diazoxon on cell signaling and second messengers in Nile tilapia (Oreochromis niloticus) leukocytes. J Leukoc Biol 2024; 116:77-83. [PMID: 38547424 DOI: 10.1093/jleuko/qiae081] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/28/2024] [Accepted: 03/15/2024] [Indexed: 06/30/2024] Open
Abstract
The physiological and molecular responses of leukocytes are altered by organophosphate pesticides. Some reports have shown that diazinon causes immunotoxic effects; diazoxon, the oxon metabolite of diazinon, is attributed to influence the immune response by affecting the leukocyte cholinergic system. In this study, the in vitro effects of diazoxon on molecules involved in cell signaling (cAMP, IP3, DAG, JAK1, and STAT3), which play a crucial role in the activation, differentiation, and survival of leukocytes, were evaluated. Data indicate that diazoxon leads to a decrease in cAMP concentration and an increase in basal IP3 levels. However, diazoxon does not affect basal levels of JAK1 and STAT3 phosphorylation. Instead, diazoxon inhibits leukocyte responsiveness to phorbol myristate acetate and ionomycin, substances that, under normal conditions, enhance JAK/STAT signaling. These findings demonstrate that diazoxon significantly affects key molecular parameters related to cell signaling.
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Affiliation(s)
- Milton Rafael Camacho-Pérez
- Programa de Maestría en Ciencias Biológico Agropecuarias, Universidad Autónoma de Nayarit, Carretera Tepic-Compostela Km. 9. Xalisco, Nayarit C.P. 63780, México
- Laboratorio de Inmunotoxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura S/N, Centro, Tepic, Nayarit C.P. 63000, México
- Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Calle Tres S/N. Colonia, Cd. Industrial, Tepic, Nayarit C.P. 63000, México
| | - Karina Janice Guadalupe Díaz-Resendiz
- Laboratorio de Inmunotoxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura S/N, Centro, Tepic, Nayarit C.P. 63000, México
- Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Calle Tres S/N. Colonia, Cd. Industrial, Tepic, Nayarit C.P. 63000, México
| | - Rocío Ortiz-Butrón
- Departamento de Fisiología "Mauricio Russek", Escuela Nacional de Ciencias Biológicas, IPN, Prol. Carpio y Plan de Ayala, S/N, CDMX C.P. 11340, México
| | - Carlos Eduardo Covantes-Rosales
- Laboratorio de Inmunotoxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura S/N, Centro, Tepic, Nayarit C.P. 63000, México
- Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Calle Tres S/N. Colonia, Cd. Industrial, Tepic, Nayarit C.P. 63000, México
| | - Alma Betsaida Benitez-Trinidad
- Laboratorio de Inmunotoxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura S/N, Centro, Tepic, Nayarit C.P. 63000, México
- Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Calle Tres S/N. Colonia, Cd. Industrial, Tepic, Nayarit C.P. 63000, México
| | - Daniel Alberto Girón-Pérez
- Laboratorio de Inmunotoxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura S/N, Centro, Tepic, Nayarit C.P. 63000, México
- Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Calle Tres S/N. Colonia, Cd. Industrial, Tepic, Nayarit C.P. 63000, México
| | - Gladys Alejandra Toledo-Ibarra
- Laboratorio de Inmunotoxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura S/N, Centro, Tepic, Nayarit C.P. 63000, México
- Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Calle Tres S/N. Colonia, Cd. Industrial, Tepic, Nayarit C.P. 63000, México
| | - Lenin Pavón
- Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias del Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Colonia San Lorenzo Huipulco, Calzada México-Xochimilco 101, Tlalpan Ciudad de México C.P. 14370, México
| | - Manuel Iván Girón-Pérez
- Laboratorio de Inmunotoxicología, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Ciudad de la Cultura S/N, Centro, Tepic, Nayarit C.P. 63000, México
- Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Calle Tres S/N. Colonia, Cd. Industrial, Tepic, Nayarit C.P. 63000, México
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Neurotoxicity evoked by organophosphates and available countermeasures. Arch Toxicol 2023; 97:39-72. [PMID: 36335468 DOI: 10.1007/s00204-022-03397-w] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/11/2022] [Indexed: 11/07/2022]
Abstract
Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABAAR by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.
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Fowler CH, Bagdasarov A, Camacho NL, Reuben A, Gaffrey MS. Toxicant exposure and the developing brain: A systematic review of the structural and functional MRI literature. Neurosci Biobehav Rev 2023; 144:105006. [PMID: 36535373 PMCID: PMC9922521 DOI: 10.1016/j.neubiorev.2022.105006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 09/29/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Youth worldwide are regularly exposed to pollutants and chemicals (i.e., toxicants) that may interfere with healthy brain development, and a surge in MRI research has begun to characterize the neurobiological consequences of these exposures. Here, a systematic review following PRISMA guidelines was conducted on developmental MRI studies of toxicants with known or suspected neurobiological impact. Associations were reviewed for 9 toxicant classes, including metals, air pollution, and flame retardants. Of 1264 identified studies, 46 met inclusion criteria. Qualitative synthesis revealed that most studies: (1) investigated air pollutants or metals, (2) assessed exposures prenatally, (3) assessed the brain in late middle childhood, (4) took place in North America or Western Europe, (5) drew samples from existing cohort studies, and (6) have been published since 2017. Given substantial heterogeneity in MRI measures, toxicant measures, and age groups assessed, more research is needed on all toxicants reviewed here. Future studies should also include larger samples, employ personal exposure monitoring, study independent samples in diverse world regions, and assess toxicant mixtures.
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Affiliation(s)
| | | | | | - Aaron Reuben
- Duke University, 417 Chapel Drive, Durham, NC 27708, USA
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Golomb BA, Devaraj S, Messner AK, Koslik HJ, Han JH, Yik B. Lower blood malondialdehyde is associated with past pesticide exposure: findings in Gulf War illness and healthy controls. Mil Med Res 2021; 8:46. [PMID: 34399857 PMCID: PMC8369730 DOI: 10.1186/s40779-021-00337-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/03/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Malondialdehyde (MDA) is a candidate general marker of oxidative stress (OS). We sought to assess the relation of MDA to Gulf War illness (GWI) and to a variety of exposures. METHODS This is an observational study involving subjects from Southern California recruited from October 2011 to May 2014. MDA was assessed in 81 participants (41 GWI-cases, 40 controls). General and Gulf-specific exposures were elicited. MDA case-control comparison was restricted to 40 matched pairs. The potential association between MDA and exposures was assessed using regression analyses. Gulf-specific exposures were incorporated into a case-specific model. RESULTS Plasma MDA was significantly lower in GWI-cases than controls. Composite pesticide and fuel-solvent exposures negatively predicted MDA in the total sample, as well as in the analyses that included either GWI-cases or controls only. Self-reported exposure to organophosphate (OP) nerve gas was a strong predictor for lower MDA level in veterans with GWI. CONCLUSION Past pesticide exposures predicted lower MDA in both veterans with GWI and in healthy controls.
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Affiliation(s)
- Beatrice Alexandra Golomb
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
| | - Sridevi Devaraj
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Alexis K Messner
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.,Swedish Medical Center, Seattle, WA, 98109, USA
| | - Hayley Jean Koslik
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.,Henry M. Jackson Foundation for the Advancement of Military Medicine, San Diego, CA, 92134, USA
| | - Jun Hee Han
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Barnabas Yik
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.,Santa Clara Valley Medical Center, San Jose, CA, 95128, USA
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6
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Ribeiro ACR, Deshpande LS. A review of pre-clinical models for Gulf War Illness. Pharmacol Ther 2021; 228:107936. [PMID: 34171340 DOI: 10.1016/j.pharmthera.2021.107936] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 02/08/2023]
Abstract
Gulf War Illness (GWI) is a chronic multisymptomatic disorder that afflicts over 1/3rd of the 1991 GW veterans. It spans multiple bodily systems and presents itself as a syndrome exhibiting diverse symptoms including fatigue, depression, mood, and memory and concentration deficits, musculoskeletal pain and gastrointestinal distress in GW veterans. The etiology of GWI is complex and many factors, including chemical, physiological, and environmental stressors present in the GW arena, have been implicated for its development. It has been over 30 years since the end of the GW but, GWI has been persistent in suffering veterans who are also dealing with paucity of effective treatments. The multifactorial aspect of GWI along with genetic heterogeneity and lack of available data surrounding war-time exposures have proved to be challenging in developing pre-clinical models of GWI. Despite this, over a dozen GWI animal models exist in the literature. In this article, following a brief discussion of GW history, GWI definitions, and probable causes for its pathogenesis, we will expand upon various experimental models used in GWI laboratory research. These animal models will be discussed in the context of their attempts at mimicking GW-related exposures with regards to the variations in chemical combinations, doses, and frequency of exposures. We will discuss their advantages and limitations in modeling GWI followed by a discussion of behavioral and molecular findings in these models. The mechanistic data obtained from these preclinical studies have offered multiple molecular pathways including chronic inflammation, mitochondrial dysfunction, oxidative stress, lipid disturbances, calcium homeostatic alterations, changes in gut microbiota, and epigenetic modifications, amongst others for explaining GWI development and its persistence. Finally, these findings have also informed us on novel druggable targets in GWI. While, it has been difficult to conceive a single pre-clinical model that could express all the GWI signs and exhibit biological complexity reflective of the clinical presentation in GWI, animal models have been critical for identifying molecular underpinnings of GWI and evaluating treatment strategies for GWI.
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Affiliation(s)
- Ana C R Ribeiro
- Departments of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Laxmikant S Deshpande
- Departments of Neurology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Departments of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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7
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Pesticides, cognitive functions and dementia: A review. Toxicol Lett 2020; 326:31-51. [PMID: 32145396 DOI: 10.1016/j.toxlet.2020.03.005] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/02/2020] [Accepted: 03/03/2020] [Indexed: 12/13/2022]
Abstract
Pesticides are widely-used chemicals commonly applied in agriculture for the protection of crops from pests. Depending on the class of pesticides, the specific substances may have a specific set of adverse effects on humans, especially in cases of acute poisoning. In past years, evidence regarding sequelae of chronic, low-level exposure has been accumulating. Cognitive impairment and dementia heavily affect a person's quality of life and scientific data has been hinting towards an association between them and antecedent chronic pesticide exposure. Here, we reviewed animal and human studies exploring the association between pesticide exposure, cognition and dementia. Additionally, we present potential mechanisms through which pesticides may act neurotoxically and lead to neurodegeneration. Study designs rarely presented homogeneity and the estimation of the exposure to pesticides has been most frequently performed without measuring the synergic effects and the possible interactions between the toxicants within mixtures, and also overlooking low exposures to environmental toxicants. It is possible that a Real-Life Risk Simulation approach would represent a robust alternative for future studies, so that the safe exposure limits and the net risk that pesticides confer to impaired cognitive function can be examined. Previous studies that evaluated the effect of low dose chronic exposure to mixtures of pesticides and other chemicals intending to simulate real life exposure scenarios showed that hormetic neurobehavioral effects can appear after mixture exposure at doses considered safe for individual compounds and these effects can be exacerbated by a coexistence with specific conditions such as vitamin deficiency. However, there is an overall indication, derived from both epidemiologic and laboratory evidence, supporting an association between exposure to neurotoxic pesticides and cognitive dysfunction, dementia and Alzheimer's disease.
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8
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Miller JV, LeBouf RF, Kelly KA, Michalovicz LT, Ranpara A, Locker AR, Miller DB, O'Callaghan JP. The Neuroinflammatory Phenotype in a Mouse Model of Gulf War Illness is Unrelated to Brain Regional Levels of Acetylcholine as Measured by Quantitative HILIC-UPLC-MS/MS. Toxicol Sci 2019; 165:302-313. [PMID: 29846716 DOI: 10.1093/toxsci/kfy130] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Many veterans of the 1991 Persian Gulf War (GW) returned with a chronic multisymptom illness that has been termed Gulf War Illness (GWI). Previous GWI studies have suggested that exposure to acetylcholinesterase inhibitors (AChEIs) in theater, such as sarin and/or pesticides, may have contributed to the symptomatology of GWI. Additionally, concomitant high physiological stress experienced during the war may have contributed to the initiation of the GWI phenotype. Although inhibition of AChE leading to accumulation of acetylcholine (ACh) will activate the cholinergic anti-inflammatory pathway, the signature symptomatology of GWI has been shown to be associated with neuroinflammation. To investigate the relationship between ACh and neuroinflammation in discrete brain regions, we used our previously established mouse model of GWI, which combines an exposure to a high physiological stress mimic, corticosterone (CORT), with GW-relevant AChEIs. The AChEIs used in this study were diisopropyl fluorophosphate (DFP), chlorpyrifos oxon (CPO), and physostigmine (PHY). After AChEI exposure, ACh concentrations for cortex (CTX), hippocampus (HIP), and striatum (STR) were determined using hydrophilic interaction liquid chromatography with ultraperformance liquid chromatography-tandem-mass spectrometry (MS/MS). CORT pretreatment ameliorated the DFP-induced ACh increase in HIP and STR, but not CTX. CORT pretreatment did not significantly alter ACh levels for CPO and PHY. Further analysis of STR neuroinflammatory biomarkers revealed an exacerbated CORT + AChEI response, which does not correspond to measured brain ACh. By utilizing this new analytical method for discrete brain region analysis of ACh, this work suggests the exacerbated neuroinflammatory effects in our mouse model of GWI are not driven by the accumulation of brain region-specific ACh.
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Affiliation(s)
| | - Ryan F LeBouf
- Respiratory Health Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505
| | | | | | - Anand Ranpara
- Respiratory Health Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505
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9
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Ševelová L, Vachek J, Bajgar J. Inhalation Apparatus for Generating Sarin and Soman Toxic Vapors. ACTA MEDICA (HRADEC KRÁLOVÉ) 2019. [DOI: 10.14712/18059694.2019.26] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The developed inhalation system is a dynamic and whole-body exposure model designated for generating sarin or soman vapors. It consists of an evaporating apparatus, an inhalation chamber and a carbon filter. The inhalation chamber is made of stainless steel and its total volume is 36 l. The concentration of organophosphorus compound depends on airflow through the chamber, syringe volume of the dosing pump and dosing speed. For determination of organophosphorus compound (OPC) concentration, a modification of Ellman method is used. At generating of vapors in the inhalation chamber the means of the yield were 61.4 ± 6.6 % for sarin and 35.8 ± 3.5 % for soman. The better yield for sarin than for soman, because of the higher volatility of sarin in comparison with soman was achieved. The stable concentration of the OPC for several hours could be maintained in the inhalation chamber when only relatively small amount of the OPC is used. Using the developed inhalation system LCt50 for sarin and for soman in rats was determined. At 1 h exposure the LCt50 values were 4.72 mg.h-1.m-3 for sarin and 4.81 mg.h-1.m-3 for soman. The results presented show that the inhalation chamber successfully fulfils the role of instrument for inhalation intoxication of small laboratory animals with highly toxic OPC.
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10
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Guignet M, Lein PJ. Neuroinflammation in organophosphate-induced neurotoxicity. ROLE OF INFLAMMATION IN ENVIRONMENTAL NEUROTOXICITY 2019. [DOI: 10.1016/bs.ant.2018.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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11
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Shaffo FC, Grodzki AC, Fryer AD, Lein PJ. Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma. Am J Physiol Lung Cell Mol Physiol 2018; 315:L485-L501. [PMID: 29952220 PMCID: PMC6230874 DOI: 10.1152/ajplung.00211.2018] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 06/15/2018] [Accepted: 06/18/2018] [Indexed: 12/14/2022] Open
Abstract
Numerous epidemiologic studies have identified an association between occupational exposures to organophosphorus pesticides (OPs) and asthma or asthmatic symptoms in adults. Emerging epidemiologic data suggest that environmentally relevant levels of OPs may also be linked to respiratory dysfunction in the general population and that in utero and/or early life exposures to environmental OPs may increase risk for childhood asthma. In support of a causal link between OPs and asthma, experimental evidence demonstrates that occupationally and environmentally relevant OP exposures induce bronchospasm and airway hyperreactivity in preclinical models. Mechanistic studies have identified blockade of autoinhibitory M2 muscarinic receptors on parasympathetic nerves that innervate airway smooth muscle as one mechanism by which OPs induce airway hyperreactivity, but significant questions remain regarding the mechanism(s) by which OPs cause neuronal M2 receptor dysfunction and, more generally, how OPs cause persistent asthma, especially after developmental exposures. The goals of this review are to 1) summarize current understanding of OPs in asthma; 2) discuss mechanisms of OP neurotoxicity and immunotoxicity that warrant consideration in the context of OP-induced airway hyperreactivity and asthma, specifically, inflammatory responses, oxidative stress, neural plasticity, and neurogenic inflammation; and 3) identify critical data gaps that need to be addressed in order to better protect adults and children against the harmful respiratory effects of low-level OP exposures.
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Affiliation(s)
- Frances C Shaffo
- Department of Molecular Biosciences, University of California , Davis, California
| | - Ana Cristina Grodzki
- Department of Molecular Biosciences, University of California , Davis, California
| | - Allison D Fryer
- Pulmonary Critical Care Medicine, Department of Medicine, Oregon Health & Science University , Portland, Oregon
| | - Pamela J Lein
- Department of Molecular Biosciences, University of California , Davis, California
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12
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Ashbrook DG, Hing B, Michalovicz LT, Kelly KA, Miller JV, de Vega WC, Miller DB, Broderick G, O'Callaghan JP, McGowan PO. Epigenetic impacts of stress priming of the neuroinflammatory response to sarin surrogate in mice: a model of Gulf War illness. J Neuroinflammation 2018; 15:86. [PMID: 29549885 PMCID: PMC5857314 DOI: 10.1186/s12974-018-1113-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 03/01/2018] [Indexed: 12/12/2022] Open
Abstract
Background Gulf War illness (GWI) is an archetypal, medically unexplained, chronic condition characterised by persistent sickness behaviour and neuroimmune and neuroinflammatory components. An estimated 25–32% of the over 900,000 veterans of the 1991 Gulf War fulfil the requirements of a GWI diagnosis. It has been hypothesised that the high physical and psychological stress of combat may have increased vulnerability to irreversible acetylcholinesterase (AChE) inhibitors leading to a priming of the neuroimmune system. A number of studies have linked high levels of psychophysiological stress and toxicant exposures to epigenetic modifications that regulate gene expression. Recent research in a mouse model of GWI has shown that pre-exposure with the stress hormone corticosterone (CORT) causes an increase in expression of specific chemokines and cytokines in response to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. Methods C57BL/6J mice were exposed to CORT for 4 days, and exposed to DFP on day 5, before sacrifice 6 h later. The transcriptome was examined using RNA-seq, and the epigenome was examined using reduced representation bisulfite sequencing and H3K27ac ChIP-seq. Results We show transcriptional, histone modification (H3K27ac) and DNA methylation changes in genes related to the immune and neuronal system, potentially relevant to neuroinflammatory and cognitive symptoms of GWI. Further evidence suggests altered proportions of myelinating oligodendrocytes in the frontal cortex, perhaps connected to white matter deficits seen in GWI sufferers. Conclusions Our findings may reflect the early changes which occurred in GWI veterans, and we observe alterations in several pathways altered in GWI sufferers. These close links to changes seen in veterans with GWI indicates that this model reflects the environmental exposures related to GWI and may provide a model for biomarker development and testing future treatments. Electronic supplementary material The online version of this article (10.1186/s12974-018-1113-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- David G Ashbrook
- Department of Biological Sciences and Center for Environmental Epigenetics and Development and Department of Cell and Systems Biology, University of Toronto, Scarborough campus, Toronto, ON, Canada.,Present address: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38103, USA
| | - Benjamin Hing
- Department of Biological Sciences and Center for Environmental Epigenetics and Development and Department of Cell and Systems Biology, University of Toronto, Scarborough campus, Toronto, ON, Canada.,Present address: Department of Psychiatry, Medical Laboratories, The University of Iowa, Iowa City, Iowa, 52246, USA
| | | | | | - Julie V Miller
- CDC-NIOSH, 1095 Willowdale Road, Morgantown, WV, 26505, USA
| | - Wilfred C de Vega
- Department of Biological Sciences and Center for Environmental Epigenetics and Development and Department of Cell and Systems Biology, University of Toronto, Scarborough campus, Toronto, ON, Canada
| | - Diane B Miller
- CDC-NIOSH, 1095 Willowdale Road, Morgantown, WV, 26505, USA
| | - Gordon Broderick
- Center for Clinical Systems Biology, Rochester General Hospital Research Institute, Rochester, NY, USA
| | | | - Patrick O McGowan
- Department of Biological Sciences and Center for Environmental Epigenetics and Development and Department of Cell and Systems Biology, University of Toronto, Scarborough campus, Toronto, ON, Canada. .,Department of Psychology, University of Toronto, Toronto, ON, Canada. .,Department of Physiology, University of Toronto, Toronto, ON, Canada.
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13
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Evidence of Hippocampal Structural Alterations in Gulf War Veterans With Predicted Exposure to the Khamisiyah Plume. J Occup Environ Med 2017; 59:923-929. [DOI: 10.1097/jom.0000000000001082] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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14
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Abou-Donia MB, Siracuse B, Gupta N, Sobel Sokol A. Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review. Crit Rev Toxicol 2016; 46:845-875. [PMID: 27705071 PMCID: PMC5764759 DOI: 10.1080/10408444.2016.1220916] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Sarin (GB, O-isopropyl methylphosphonofluoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as "cholinergic crisis" (i.e. diarrhea, sweating, salivation, miosis, bronchoconstriction). Exposure to high doses of sarin can result in tremors, seizures, and hypothermia. More seriously, build-up of ACh at neuromuscular junctions also can cause paralysis and ultimately peripherally-mediated respiratory arrest which can lead to death via respiratory failure. In addition to its primary action on the cholinergic system, sarin possesses other indirect effects. These involve the activation of several neurotransmitters including gamma-amino-butyric acid (GABA) and the alteration of other signaling systems such as ion channels, cell adhesion molecules, and inflammatory regulators. Sarin exposure is associated with symptoms of organophosphate-induced delayed neurotoxicity (OPIDN) and organophosphate-induced chronic neurotoxicity (OPICN). Moreover, sarin has been involved in toxic and immunotoxic effects as well as organophosphate-induced endocrine disruption (OPIED). The standard treatment for sarin-like nerve agent exposure is post-exposure injection of atropine, a muscarinic receptor antagonist, accompanied by an oxime, an AChE reactivator, and diazepam.
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Affiliation(s)
- Mohamed B Abou-Donia
- a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA
| | - Briana Siracuse
- a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA
| | - Natasha Gupta
- a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA
| | - Ashly Sobel Sokol
- a Department of Pharmacology and Cancer Biology , Duke University , Durham , NC , USA
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15
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Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime. J Med Toxicol 2016; 11:433-8. [PMID: 25925946 DOI: 10.1007/s13181-015-0480-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Humans and rats poisoned with sarin develop chronic neurological disabilities that are not prevented with standardized antidotal therapy. We hypothesized that rats poisoned with the sarin analogue diisopropylfluorophosphate (DFP) and resuscitated with atropine and pralidoxime would have long-term memory deficits that were preventable with naltrexone treatment. Long Evans rats (250-275 g) were randomized to: DFP (N = 8): single subcutaneous (SC) injection of DFP (5 mg/kg). Treatment (N = 9): DFP (5 mg/kg) followed by chronic naltrexone (5 mg/kg/day × 12 weeks). Control (N = 12): single SC injection of isopropyl alcohol, (DFP vehicle) followed by chronic naltrexone (5 mg/kg/day). If toxicity developed after injection, antidotal therapy was initiated with atropine (2 mg/kg) and pralidoxime (25 mg/kg) and repeated as needed. After 12 weeks, rats underwent testing for place learning (acquisition) across 5 days of training using the Morris Water Maze. On day 6 a memory retention test was performed. Statistical analysis was performed using IBM SPSS Statistics. Rats receiving DFP rapidly developed toxicity requiring antidotal rescue. No differences in acquisition were seen between the DFP vs. DFP + naltrexone rats. During memory testing, DFP-poisoned rats spent significantly less time (29.4 ± 2.11 versus 38.5 ± 2.5 s, p < 0.05) and traveled less distance (267 ± 24.6 versus 370 ± 27.5 cm, p < 0.05) in the target quadrant compared to the treatment group. Treatment rats performed as well as control rats (p > 0.05) on the test for memory retention. Poisoning with DFP induced impaired memory retention. Deficits were not prevented by acute rescue with atropine and pralidoxime. Chronic naltrexone treatment led to preserved memory after DFP poisoning.
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16
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Turner MP, Hubbard NA, Himes LM, Faghihahmadabadi S, Hutchison JL, Bennett IJ, Motes MA, Haley RW, Rypma B. Cognitive Slowing in Gulf War Illness Predicts Executive Network Hyperconnectivity: Study in a Population-Representative Sample. Neuroimage Clin 2016; 12:535-541. [PMID: 27672557 PMCID: PMC5030369 DOI: 10.1016/j.nicl.2016.08.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 06/06/2016] [Accepted: 08/24/2016] [Indexed: 12/30/2022]
Abstract
Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.
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Affiliation(s)
- Monroe P. Turner
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Nicholas A. Hubbard
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Lyndahl M. Himes
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | | | - Joanna L. Hutchison
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ilana J. Bennett
- Center for the Neurobiology of Learning and Memory, University of California-Irvine, Irvine, CA, USA
| | - Michael A. Motes
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Robert W. Haley
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bart Rypma
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
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17
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Smith C, Lee R, Moran A, Sipos M. Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs. Neurotoxicol Teratol 2016; 54:36-45. [DOI: 10.1016/j.ntt.2016.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 12/21/2015] [Accepted: 01/28/2016] [Indexed: 10/22/2022]
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18
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Phillips KF, Deshpande LS. Repeated low-dose organophosphate DFP exposure leads to the development of depression and cognitive impairment in a rat model of Gulf War Illness. Neurotoxicology 2015; 52:127-33. [PMID: 26619911 DOI: 10.1016/j.neuro.2015.11.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/20/2015] [Accepted: 11/22/2015] [Indexed: 02/02/2023]
Abstract
Approximately 175,000-250,000 of the returning veterans from the 1991 Persian Gulf War exhibit chronic multi-symptom illnesses that includes neurologic co-morbidities such as depression, anxiety and cognitive impairments. Amongst a host of causative factors, exposure to low levels of the nerve agent Sarin has been strongly implicated for expression of Gulf War Illness (GWI). Nerve agents similar to pesticides are organophosphate (OP) compounds. There is evidence from civilian population that exposure to OPs such as in agricultural workers and nerve agents such as the survivors and first-responders of the Tokyo subway Sarin gas attack suffer from chronic neurological problems similar to GWI symptoms. Given this unique chemical profile, OPs are ideal to study the effects of nerve agents and develop models of GWI in civilian laboratories. In this study, we used repeated low-dose exposure to OP agent diisopropyl fluorophosphate (DFP) over a 5-day period to approximate the duration and level of Sarin exposure during the Persian Gulf War. We tested the rats at 3-months post DFP exposure. Using a battery of behavioral assays, we observed the presence of symptoms of chronic depression, anxiety and memory problems as characterized by increased immobility time in the Forced Swim Test, anhedonia in the Sucrose Preference Test, anxiety in the Elevated Plus Maze, and spatial memory impairments in the Object Location Test, respectively. Chronic low dose DFP exposure was also associated with hippocampal neuronal damage as characterized by the presence of Fluoro-Jade staining. Given that OP exposure is considered a leading cause of GWI related morbidities, this animal model will be ideally suited to study underlying molecular mechanisms for the expression of GWI neurological symptoms and identify drugs for the effective treatment of GWIs.
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Affiliation(s)
- Kristin F Phillips
- Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA
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19
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White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, Bloom FE, Bunker JA, Crawford F, Graves JC, Hardie A, Klimas N, Knox M, Meggs WJ, Melling J, Philbert MA, Grashow R. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex 2015; 74:449-75. [PMID: 26493934 PMCID: PMC4724528 DOI: 10.1016/j.cortex.2015.08.022] [Citation(s) in RCA: 301] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 08/19/2015] [Accepted: 08/28/2015] [Indexed: 11/01/2022]
Abstract
Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called "toxic wounds" by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.
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Affiliation(s)
- Roberta F White
- Department of Environmental Health, Boston University School of Public Health, Boston, MA, United States.
| | - Lea Steele
- Baylor University Institute of Biomedical Studies, Waco, TX, United States.
| | - James P O'Callaghan
- Molecular Neurotoxicology, Toxicology & Molecular Biology Branch (MS-3014), Health Effects Laboratory Division, Centers for Disease Control and Prevention - NIOSH, Morgantown, WV, United States.
| | - Kimberly Sullivan
- Boston University School of Public Health, Department of Environmental Health, Boston, MA, United States.
| | - James H Binns
- Research Advisory Committee on Gulf War Veterans' Illnesses, Phoenix, AZ, United States.
| | | | - Floyd E Bloom
- Molecular & Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA, United States.
| | - James A Bunker
- National Gulf War Resource Center, Topeka, KS, United States.
| | - Fiona Crawford
- Director, TBI Research Program, Roskamp Institute, Sarasota, FL, United States.
| | - Joel C Graves
- Captain, U.S. Army, Retired, Crestview, FL, United States.
| | - Anthony Hardie
- Veterans for Common Sense, Bradenton, FL, United States.
| | - Nancy Klimas
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Miami, FL, United States.
| | - Marguerite Knox
- McEntire Joint National Guard Base, Eastover, SC, United States.
| | - William J Meggs
- Department of Emergency Medicine, 3ED311, The Brody School of Medicine, East Carolina University School of Medicine, Greenville, NC, United States.
| | - Jack Melling
- U.S. Government Accountability Office, Salisbury, Wiltshire, UK.
| | | | - Rachel Grashow
- Northeastern University, Department of Civil and Environmental Engineering, Boston, MA, United States.
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20
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Moffett K, Crosson B, Spence JS, Case K, Levy I, Gopinath K, Shah P, Goyal A, Fang Y, Briggs RW, Hart J, Moore A, Haley RW. Word-finding impairment in veterans of the 1991 Persian Gulf War. Brain Cogn 2015; 98:65-73. [PMID: 26114921 DOI: 10.1016/j.bandc.2015.05.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 04/15/2015] [Accepted: 05/27/2015] [Indexed: 11/25/2022]
Abstract
Approximately one quarter of 1991 Persian Gulf War Veterans experience cognitive and physiological sequelae that continue to be unexplained by known medical or psychological conditions. Difficulty coming up with words and names, familiar before the war, is a hallmark of the illness. Three Gulf War Syndrome subtypes have been identified and linked to specific war-time chemical exposures. The most functionally impaired veterans belong to the Gulf War Syndrome 2 (Syndrome 2) group, for which subcortical damage due to toxic nerve gas exposure is the suspected cause. Subcortical damage is often associated with specific complex language impairments, and Syndrome 2 veterans have demonstrated poorer vocabulary relative to controls. 11 Syndrome 1, 16 Syndrome 2, 9 Syndrome 3, and 14 age-matched veteran controls from the Seabees Naval Construction Battalion were compared across three measures of complex language. Additionally, functional magnetic resonance imaging (fMRI) was collected during a covert category generation task, and whole-brain functional activity was compared between groups. Results demonstrated that Syndrome 2 veterans performed significantly worse on letter and category fluency relative to Syndrome 1 veterans and controls. They also exhibited reduced activity in the thalamus, putamen, and amygdala, and increased activity in the right hippocampus relative to controls. Syndrome 1 and Syndrome 3 groups tended to show similar, although smaller, differences than the Syndrome 2 group. Hence, these results further demonstrate specific impairments in complex language as well as subcortical and hippocampal involvement in Syndrome 2 veterans. Further research is required to determine the extent of language impairments in this population and the significance of altered neurologic activity in the aforementioned brain regions with the purpose of better characterizing the Gulf War Syndromes.
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Affiliation(s)
- Kristin Moffett
- Department of Clinical and Health Psychology, University of Florida, 1225 Center Drive, Room 3151, Gainesville, FL 32611, USA.
| | - Bruce Crosson
- Department of Veterans Affairs Rehabilitation Research and Development, Brain Rehabilitation Research Center of Excellence, Malcolm Randall VA Medical Center, 1601 S.W. Archer Road, Gainesville, FL 32608-1197, USA; Department of Veterans Affairs Rehabilitation Research and Development, Center of Excellence for Visual and Neurocognitive Rehabilitation, 1670 Clairmont Rd., Decatur, GA 30033, USA; Departments of Neurology and Radiology, Emory University, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322, USA; Department of Psychology, Georgia State University, PO Box 5010, Atlanta, GA 303025010, USA.
| | - Jeffrey S Spence
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA.
| | - Kimberly Case
- Department of Clinical and Health Psychology, University of Florida, 1225 Center Drive, Room 3151, Gainesville, FL 32611, USA.
| | - Ilana Levy
- Department of Clinical and Health Psychology, University of Florida, 1225 Center Drive, Room 3151, Gainesville, FL 32611, USA.
| | - Kaundinya Gopinath
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA.
| | - Parina Shah
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA.
| | - Aman Goyal
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA.
| | - Yan Fang
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA.
| | - Richard W Briggs
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA; Department of Physics & Astronomy, Georgia State University, Atlanta, GA 30302-5060, USA.
| | - John Hart
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA.
| | - Anna Moore
- Center for Rehabilitation Medicine, Emory University, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322, USA.
| | - Robert W Haley
- Departments of Internal Medicine (Epidemiology Division) and Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8874, USA.
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Lasram MM, Dhouib IB, Annabi A, El Fazaa S, Gharbi N. A review on the molecular mechanisms involved in insulin resistance induced by organophosphorus pesticides. Toxicology 2014; 322:1-13. [DOI: 10.1016/j.tox.2014.04.009] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 04/23/2014] [Accepted: 04/24/2014] [Indexed: 02/06/2023]
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Viviani B, Boraso M, Marchetti N, Marinovich M. Perspectives on neuroinflammation and excitotoxicity: a neurotoxic conspiracy? Neurotoxicology 2014; 43:10-20. [PMID: 24662010 DOI: 10.1016/j.neuro.2014.03.004] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 03/11/2014] [Accepted: 03/11/2014] [Indexed: 12/16/2022]
Abstract
Emerging evidences underline the ability of several environmental contaminants to induce an inflammatory response within the central nervous system, named neuroinflammation. This can occur as a consequence of a direct action of the neurotoxicant to the CNS and/or as a response secondary to the activation of the peripheral inflammatory response. In both cases, neuroinflammation is driven by the release of several soluble factors among which pro-inflammatory cytokines. IL-1β and TNF-α have been extensively studied for their effects within the CNS and emerged for their role in the modulation of the neuronal response, which allow the immune response to integrate with specific neuronal functions, as neurotransmission and synaptic plasticity. In particular, it has been evidenced a potential detrimental link between these cytokines and the glutamatergic system that seems to be part of increased brain excitability and excitotoxicity occurring in different pathological conditions. Aim of this mini-review will be to present experimental evidence on the way IL-1β and TNF-α impact neurons, focusing on the glutamatergic signalling, to provide a perspective on novel pathways possibly involved in environmental contaminants neurotoxicity.
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Affiliation(s)
- Barbara Viviani
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
| | - Mariaserena Boraso
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Natalia Marchetti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Marina Marinovich
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
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A critical role of acute bronchoconstriction in the mortality associated with high-dose sarin inhalation: effects of epinephrine and oxygen therapies. Toxicol Appl Pharmacol 2013; 274:200-8. [PMID: 24269878 DOI: 10.1016/j.taap.2013.11.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 10/25/2013] [Accepted: 11/10/2013] [Indexed: 01/26/2023]
Abstract
Sarin is an organophosphate nerve agent that is among the most lethal chemical toxins known to mankind. Because of its vaporization properties and ease and low cost of production, sarin is the nerve agent with a strong potential for use by terrorists and rouge nations. The primary route of sarin exposure is through inhalation and, depending on the dose, sarin leads to acute respiratory failure and death. The mechanism(s) of sarin-induced respiratory failure is poorly understood. Sarin irreversibly inhibits acetylcholine esterase, leading to excessive synaptic levels of acetylcholine and, we have previously shown that sarin causes marked ventilatory changes including weakened response to hypoxia. We now show that LD50 sarin inhalation causes severe bronchoconstriction in rats, leading to airway resistance, increased hypoxia-induced factor-1α, and severe lung epithelium injury. Transferring animals into 60% oxygen chambers after sarin exposure improved the survival from about 50% to 75% at 24h; however, many animals died within hours after removal from the oxygen chambers. On the other hand, if LD50 sarin-exposed animals were administered the bronchodilator epinephrine, >90% of the animals survived. Moreover, while both epinephrine and oxygen treatments moderated cardiorespiratory parameters, the proinflammatory cytokine surge, and elevated expression of hypoxia-induced factor-1α, only epinephrine consistently reduced the sarin-induced bronchoconstriction. These data suggest that severe bronchoconstriction is a critical factor in the mortality induced by LD50 sarin inhalation, and epinephrine may limit the ventilatory, inflammatory, and lethal effects of sarin.
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Hubbard NA, Hutchison JL, Motes MA, Shokri-Kojori E, Bennett IJ, Brigante RM, Haley RW, Rypma B. Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness. Clin Psychol Sci 2013; 2:319-327. [PMID: 25767746 DOI: 10.1177/2167702613506580] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Gulf War Illness is associated with toxic exposure to cholinergic disruptive chemicals. The cholinergic system has been shown to mediate the central executive of working memory (WM). The current work proposes that impairment of the cholinergic system in Gulf War Illness patients (GWIPs) leads to behavioral and neural deficits of the central executive of WM. A large sample of GWIPs and matched controls (MCs) underwent functional magnetic resonance imaging during a varied-load working memory task. Compared to MCs, GWIPs showed a greater decline in performance as WM-demand increased. Functional imaging suggested that GWIPs evinced separate processing strategies, deferring prefrontal cortex activity from encoding to retrieval for high demand conditions. Greater activity during high-demand encoding predicted greater WM performance. Behavioral data suggest that WM executive strategies are impaired in GWIPs. Functional data further support this hypothesis and suggest that GWIPs utilize less effective strategies during high-demand WM.
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Affiliation(s)
- Nicholas A Hubbard
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Joanna L Hutchison
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA ; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Michael A Motes
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA ; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ehsan Shokri-Kojori
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Ilana J Bennett
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Ryan M Brigante
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Robert W Haley
- Epidemiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bart Rypma
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA ; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Goines PE, Ashwood P. Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol Teratol 2013; 36:67-81. [PMID: 22918031 PMCID: PMC3554862 DOI: 10.1016/j.ntt.2012.07.006] [Citation(s) in RCA: 220] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 07/03/2012] [Accepted: 07/31/2012] [Indexed: 02/07/2023]
Abstract
Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of individuals. The etiological basis of ASD is unclear, and evidence suggests it involves both genetic and environmental factors. There are many reports of cytokine imbalances in ASD. These imbalances could have a pathogenic role, or they may be markers of underlying genetic and environmental influences. Cytokines act primarily as mediators of immunological activity but they also have significant interactions with the nervous system. They participate in normal neural development and function, and inappropriate activity can have a variety of neurological implications. It is therefore possible that cytokine dysregulation contributes directly to neural dysfunction in ASD. Further, cytokine profiles change dramatically in the face of infection, disease, and toxic exposures. Imbalances in cytokines may represent an immune response to environmental contributors to ASD. The following review is presented in two main parts. First, we discuss select cytokines implicated in ASD, including IL-1Β, IL-6, IL-4, IFN-γ, and TGF-Β, and focus on their role in the nervous system. Second, we explore several neurotoxic environmental factors that may be involved in the disorders, and focus on their immunological impacts. This review represents an emerging model that recognizes the importance of both genetic and environmental factors in ASD etiology. We propose that the immune system provides critical clues regarding the nature of the gene by environment interactions that underlie ASD pathophysiology.
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Affiliation(s)
- Paula E. Goines
- University of California, Davis, School of Veterinary Medicine, Department of Molecular Biosciences
| | - Paul Ashwood
- University of California, Davis, School of Medicine, Department of Medical Microbiology and Immunology
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Tuite JJ, Haley RW. Meteorological and intelligence evidence of long-distance transit of chemical weapons fallout from bombing early in the 1991 Persian Gulf War. Neuroepidemiology 2012; 40:160-77. [PMID: 23257977 DOI: 10.1159/000345123] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 10/03/2012] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Coalition bombings on the night of 18-19 January 1991, early in the Gulf War, targeted the Iraqi chemical weapons infrastructure. On 19 January 1991, nerve agent alarms sounded within Coalition positions hundreds of kilometers to the south, and the trace presence of sarin vapor was identified by multiple technologies. Considering only surface dispersion of plumes from explosions, officials concluded that the absence of casualties around bombed sites precluded long-distance transit of debris to US troop positions to explain the alarms and detections. Consequently, they were discounted as false positives, and low-level nerve agent exposure early in the air war was disregarded in epidemiologic investigations of chronic illnesses. INTELLIGENCE DATA Newly assembled evidence indicates that plumes from those nighttime bombings of Iraqi chemical facilities would have traversed the stable nocturnal boundary layer and penetrated the residual layer where they would be susceptible to rapid transit by supergeostrophic winds. This explanation is supported by plume height predictions, available weather charts, weather satellite images showing transit of a hot air mass, effects of solar mixing of atmospheric layers, and observations of a stationary weather front and thermal inversion in the region. CONCLUSIONS Current evidence supports long-distance transit. Epidemiologic studies of chronic postwar illness should be reassessed using veterans' reports of hearing nerve agent alarms as the measure of exposure.
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Nambiar MP, Wright BS, Rezk PE, Smith KB, Gordon RK, Moran TS, Richards SM, Sciuto AM. Development of a microinstillation model of inhalation exposure to assess lung injury following exposure to toxic chemicals and nerve agents in Guinea pigs. Toxicol Mech Methods 2012; 16:295-306. [PMID: 20021028 DOI: 10.1080/15376510600748760] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Respiratory disturbances due to chemical warfare nerve agents (CWNAs) are the starting point of mass casualty and the primary cause of death by these weapons of terror and mass destruction. However, very few studies have been implemented to assess respiratory toxicity and exacerbation induced by CWNAs, especially methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX). In this study, we developed a microinstillation technique of inhalation exposure to assess lung injury following exposure to CWNAs and toxic chemicals. Guinea pigs were gently intubated by placing a microcatheter into the trachea 1.5 to 2.0 cm centrally above the bifurcation. This location is crucial to deliver aerosolized agents uniformly to the lung's lobes. The placement of the tube is calculated by measuring the distance from the upper front teeth to the tracheal bifurcation, which is typically 8.5 cm for guinea pigs of equivalent size and a weight range of 250 g to 300 g. The catheter is capable of withstanding 100 psi pressure; the terminus has five peripheral holes to pump air that aerosolizes the nerve agent that is delivered in the central hole. The microcatheter is regulated by a central control system to deliver the aerosolized agent in a volume lower than the tidal volume of the guinea pigs. The average particle size of the nerve agent delivered was 1.48 +/- 0.07 micrometer. The microinstillation technology has been validated by exposing the animals to Coomassie brilliant blue, which showed a uniform distribution of the dye in different lung lobes. In addition, the concentration of the dye in the lungs correlated with the dose/time of exposure. Furthermore, histopathological analysis confirmed the absence of barotraumas following micoinstillation. This novel technique delivers the agent safely, requires less amount of agent, avoids exposure to skin, pelt, and eye, and circumvents the concern of deposition of the particles in the nasal and palette due to the switching of breathing from nasal to oronasal in whole-body dynamic chamber or nose only exposure. Currently, we are using this inhalation exposure technique to investigate lung injuries and respiratory disturbances following direct exposure to VX.
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Affiliation(s)
- Madhusoodana P Nambiar
- Department of Biochemical Pharmacology/Division of Biochemistry, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910-7500, USA
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Banks CN, Lein PJ. A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation. Neurotoxicology 2012; 33:575-84. [PMID: 22342984 DOI: 10.1016/j.neuro.2012.02.002] [Citation(s) in RCA: 169] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Revised: 01/31/2012] [Accepted: 02/01/2012] [Indexed: 01/14/2023]
Abstract
Organophosphorus (OP) nerve agents and pesticides inhibit acetylcholinesterase (AChE), and this is thought to be a primary mechanism mediating the neurotoxicity of these compounds. However, a number of observations suggest that mechanisms other than or in addition to AChE inhibition contribute to OP neurotoxicity. There is significant experimental evidence that acute OP intoxication elicits a robust inflammatory response, and emerging evidence suggests that chronic repeated low-level OP exposure also upregulates inflammatory mediators. A critical question that is just beginning to be addressed experimentally is the pathophysiologic relevance of inflammation in either acute or chronic OP intoxication. The goal of this article is to provide a brief review of the current status of our knowledge linking inflammation to OP intoxication, and to discuss the implications of these findings in the context of therapeutic and diagnostic approaches to OP neurotoxicity.
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Affiliation(s)
- Christopher N Banks
- Department of Molecular Biosciences, UC Davis School of Veterinary Medicine, One Shields Ave., Davis, CA 95616, USA.
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Li X, Spence JS, Buhner DM, Hart J, Cullum CM, Biggs MM, Hester AL, Odegard TN, Carmack PS, Briggs RW, Haley RW. Hippocampal dysfunction in Gulf War veterans: investigation with ASL perfusion MR imaging and physostigmine challenge. Radiology 2011; 261:218-25. [PMID: 21914840 DOI: 10.1148/radiol.11101715] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
PURPOSE To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. MATERIALS AND METHODS The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups-syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)-and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. RESULTS Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. CONCLUSION Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition.
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Affiliation(s)
- Xiufeng Li
- Departments of Radiology, Division of Neuroradiology, Internal Medicine, Clinical Sciences, Psychiatry, and Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8874, USA
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30
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Liu P, Aslan S, Li X, Buhner DM, Spence JS, Briggs RW, Haley RW, Lu H. Perfusion deficit to cholinergic challenge in veterans with Gulf War Illness. Neurotoxicology 2010; 32:242-6. [PMID: 21147163 DOI: 10.1016/j.neuro.2010.12.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2010] [Revised: 12/02/2010] [Accepted: 12/06/2010] [Indexed: 10/18/2022]
Abstract
A highly plausible etiology for Gulf War Illness (GWI) is that the neural damage and cognitive deficits are associated with excessive exposure to cholinesterase-inhibiting cholinergic stimulants. Our previous SPECT study provided strong indication that cerebral blood flow (CBF) in veterans with GWI may be different from those of unaffected control veterans. The present study confirmed and extended previous findings that patients with GWI have abnormal response to an inhibitory cholinergic challenge, physostigmine infusion, when compared to age-gender-education matched control veterans. The MRI-based arterial spin labeling (ASL) and phase-contrast techniques have several key advantages over SPECT, including shorter experiment duration, complete non-invasiveness, and higher spatial and temporal resolutions, and therefore may provide a cost-effective biomarker for characterization of GWI.
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Affiliation(s)
- Peiying Liu
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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31
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Johnson FO, Atchison WD. The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis. Neurotoxicology 2009; 30:761-5. [PMID: 19632272 PMCID: PMC2761528 DOI: 10.1016/j.neuro.2009.07.010] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2009] [Revised: 07/08/2009] [Accepted: 07/16/2009] [Indexed: 12/12/2022]
Abstract
Exposure to an environmental toxicant as a risk factor in the development of amyotrophic lateral sclerosis (ALS) was first hinted at (demonstrated) in the Chamorro indigenous people of Guam. During the 1950s and 1960s these indigenous people presented an extremely high incidence of ALS which was presumed to be associated with the consumption of flying fox and cycad seeds. No other strong association between ALS and environmental toxicants has since been reported, although circumstantial epidemiological evidence has implicated exposure to heavy metals such as lead and mercury, industrial solvents and pesticides especially organophosphates and certain occupations such as playing professional soccer. Given that only approximately 10% of all ALS diagnosis have a genetic basis, a gene-environmental interaction provides a plausible explanation for the other 90% of cases. This mini-review provides an overview of our current knowledge of environmental etiologies of ALS with emphasis on the effects of mercury, lead and pesticides as potential risk factors in developing ALS. Epidemiologic and experimental evidence from animal models investigating the possible association between exposure to environmental toxicant and ALS disease has proven inconclusive. Nonetheless, there are indications that there may be causal links, and a need for more research.
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Affiliation(s)
- Frank O Johnson
- Center for Integrative Toxicology and Neuroscience Program and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, United States
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32
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Haley RW, Spence JS, Carmack PS, Gunst RF, Schucany WR, Petty F, Devous MD, Bonte FJ, Trivedi MH. Abnormal brain response to cholinergic challenge in chronic encephalopathy from the 1991 Gulf War. Psychiatry Res 2009; 171:207-20. [PMID: 19230625 DOI: 10.1016/j.pscychresns.2008.05.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2007] [Revised: 04/10/2008] [Accepted: 05/06/2008] [Indexed: 01/14/2023]
Abstract
Several case definitions of chronic illness in veterans of the 1991 Persian Gulf War have been linked epidemiologically with environmental exposure to cholinesterase-inhibiting chemicals, which cause chronic changes in cholinergic receptors in animal models. Twenty-one chronically ill Gulf War veterans (5 with symptom complex 1, 11 with complex 2, and 5 with complex 3) and 17 age-, sex- and education-matched controls, underwent an 99mTc-HMPAO-SPECT brain scan following infusion of saline and >48 h later a second scan following infusion of physostigmine in saline. From each SPECT image mean normalized regional cerebral blood flow (nrCBF) from 39 small blocks of correlated voxels were extracted with geostatistical spatial modeling from eight deep gray matter structures in each hemisphere. Baseline nrCBF in symptom complex 2 was lower than controls throughout deep structures. The change in nrCBF after physostigmine (challenge minus baseline) was negative in complexes 1 and 3 and controls but positive in complex 2 in some structures. Since effects were opposite in different groups, no finding typified the entire patient sample. A hold-out discriminant model of nrCBF from 17 deep brain blocks predicted membership in the clinical groups with sensitivity of 0.95 and specificity of 0.82. Gulf War-associated chronic encephalopathy in a subset of veterans may be due to neuronal dysfunction, including abnormal cholinergic response, in deep brain structures.
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Affiliation(s)
- Robert W Haley
- Epidemiology Division, Departments of Internal Medicine and Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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33
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Assessment of low level whole-body soman vapor exposure in rats. Neurotoxicol Teratol 2009; 31:110-8. [DOI: 10.1016/j.ntt.2008.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Revised: 10/28/2008] [Accepted: 10/28/2008] [Indexed: 11/22/2022]
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Che MM, Conti M, Boylan M, Sciuto AM, Gordon RK, Nambiar MP. Blood and bronchoalveolar lavage fluid acetylcholinesterase levels following microinstillation inhalation exposure to sarin in Guinea pigs. Inhal Toxicol 2008; 20:821-8. [PMID: 18645722 DOI: 10.1080/08958370802050957] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
We determined acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in the bronchoalveolar lavage fluid (BALF) following inhalation exposure to chemical threat nerve agent (CTNA) sarin. Age- and weight-matched male guinea pigs were exposed to five different doses of sarin (169.3, 338.7, 508, 677.4, and 846.5 mg/m(3)) using a microinstillation inhalation exposure technique for 4 min. The technique involves aerosolization of the agent in the trachea using a microcatheter with a center hole that delivers the agent and multiple peripheral holes that pumps air to aerosolize the agent at the tip. Animals exposed to higher doses of sarin occasionally developed seizures and succumbed to death within 15 min after exposure. The LCt(50) for sarin using the microinstillation technique was determined to be close to 677.4 mg/m(3). Ear blood AChE activity showed a dose-dependent inhibition at 15 min postexposure. The inhibition of blood AChE remained constant over 35 and 55 min after sarin exposure indicating that there was no lung depot effect. Cardiac blood AChE and butyrylcholinesterase (BChE) activity in surviving animals euthanized at 24 h postexposure showed a dose-dependent inhibition with an inhibition of 60% at 677.4 and 846.5 mg/m(3) sarin exposure. AChE and BChE activity in bronchoalveolar lavage fluid (BALF) showed a slight increase at 338.7 to 677.4 mg/m(3) sarin exposure but a marginal inhibition at 169.3 mg/m(3). In contrast, the AChE protein levels determined by immunoblotting showed an increase at 169.3 mg/m(3) in the BALF. The BALF protein level, a biomarker of lung injury, was increased maximally at 338.7 mg/m(3) and that increase was dropped with an increase in the dose of sarin. The BALF protein levels correlated with the AChE and BChE activity. These data suggest that sarin microinstillation inhalation exposure results in respiratory toxicity and lung injury characterized by changes in lavage AChE, BChE, and protein levels.
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Affiliation(s)
- Magnus M Che
- Division of Biochemistry, Department of Biochemical Pharmacology, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, USA
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35
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Rocksén D, Elfsmark D, Heldestad V, Wallgren K, Cassel G, Göransson Nyberg A. An animal model to study health effects during continuous low-dose exposure to the nerve agent VX. Toxicology 2008; 250:32-8. [DOI: 10.1016/j.tox.2008.05.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Revised: 05/07/2008] [Accepted: 05/25/2008] [Indexed: 11/25/2022]
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Bloch-Shilderman E, Rabinovitz I, Egoz I, Raveh L, Allon N, Grauer E, Gilat E, Weissman BA. Subchronic exposure to low-doses of the nerve agent VX: Physiological, behavioral, histopathological and neurochemical studies. Toxicol Appl Pharmacol 2008; 231:17-23. [DOI: 10.1016/j.taap.2008.03.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2007] [Revised: 03/19/2008] [Accepted: 03/31/2008] [Indexed: 11/25/2022]
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Mach M, Grubbs RD, Price WA, Nagaoka M, Dubovický M, Lucot JB. Delayed behavioral and endocrine effects of sarin and stress exposure in mice. J Appl Toxicol 2008; 28:132-9. [PMID: 17503400 DOI: 10.1002/jat.1258] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The organophosphorus agent sarin is a potent inhibitor of acetylcholinesterase. Experiments tested the influence of exposure to low doses of sarin along with psychological stress on delayed behavioral and endocrine changes in mice. Motor activity, acoustic startle response (ASR), pre-pulse inhibition (PPI) of ASR, activity of cholinesterase in blood and catecholamine levels in adrenals were evaluated after low dose sarin exposure (3 x 0.4 LD50 subcutaneously) combined with chronic intermittent stress in C57BL/6J mice. While sarin alone produced depression of motor activity, no interaction of the stress with sarin exposure was observed. Cholinesterase activity was significantly reduced 24 h after exposure to sarin; however, the basal activity was re-established 3 weeks later. The combination of low dose sarin exposure and stress produced delayed behavioral change manifested as excessive grooming together with endocrine alterations in adrenals 7 weeks after exposure. The size of the adrenals in the combined exposure group was increased and the concentration of catecholamines was significantly decreased. In conclusion, these findings indicate that sarin in low doses is more dangerous when combined with shaker stress inducing delayed behavioral and endocrine changes.
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Affiliation(s)
- Mojmir Mach
- Wright State University, Boohnshoft School of Medicine, Dayton, OH 45435, USA.
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38
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Acetylcholinesterase inhibitors and Gulf War illnesses. Proc Natl Acad Sci U S A 2008; 105:4295-300. [PMID: 18332428 DOI: 10.1073/pnas.0711986105] [Citation(s) in RCA: 163] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Increasing evidence suggests excess illness in Persian Gulf War veterans (GWV) can be explained in part by exposure of GWV to organophosphate and carbamate acetylcholinesterase inhibitors (AChEis), including pyridostigmine bromide (PB), pesticides, and nerve agents. Evidence germane to the relation of AChEis to illness in GWV was assessed. Many epidemiological studies reported a link between AChEi exposure and chronic symptoms in GWV. The link is buttressed by a dose-response relation of PB pill number to chronic symptoms in GWV and by a relation between avidity of AChEi clearance and illness, based on genotypes, concentrations, and activity levels of enzymes that detoxify AChEis. Triangulating evidence derives from studies linking occupational exposure to AChEis to chronic health symptoms that mirror those of ill GWV. Illness is again linked to lower activity of AChEi detoxifying enzymes and genotypes conferring less-avid AChEi detoxification. AChEi exposure satisfies Hill's presumptive criteria for causality, suggesting this exposure may be causally linked to excess health problems in GWV.
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Heaton KJ, Palumbo CL, Proctor SP, Killiany RJ, Yurgelun-Todd DA, White RF. Quantitative magnetic resonance brain imaging in US army veterans of the 1991 Gulf War potentially exposed to sarin and cyclosarin. Neurotoxicology 2007; 28:761-9. [PMID: 17485118 DOI: 10.1016/j.neuro.2007.03.006] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2006] [Revised: 01/29/2007] [Accepted: 03/09/2007] [Indexed: 11/29/2022]
Abstract
BACKGROUND In March 1991, a munitions storage complex at Khamisiyah, Iraq was destroyed, potentially exposing more than 100,000 US troops to low levels of the organophosphate nerve agents sarin and cyclosarin. Little is known about the neurophysiological effects of low-dose exposure to sarin/cyclosarin in humans, although some research has indicated subtle but persistent neurobehavioral and neurochemical changes in individuals exposed to sarin/cyclosarin at levels insufficient to produce obvious clinical symptoms. However, the neuroanatomical correlates of these changes are unclear. The current study examined the association between modeled estimates of sarin/cyclosarin exposure levels and volumetric measurements of gross neuroanatomical structures in 1991 Gulf War veterans with varying degrees of possible low-level sarin/cyclosarin exposure. METHODS Twenty-six GW-deployed veterans recruited from the Devens Cohort Study participated. Magnetic resonance images of the brain were acquired and analyzed using morphometric techniques, producing volumetric measurements of white matter, gray matter, right and left lateral ventricles, and cerebrospinal fluid. Volumetric data were analyzed using exposure estimates obtained from refined models of the 1991 Khamisiyah presumed exposure hazard area. RESULTS Binary comparisons of sarin/cyclosarin 'exposed' (N=13) and 'unexposed' (N=13) veterans revealed no differences in volumetric measurements of discrete brain tissues. However, linear trend analyses showed a significant association between higher levels of estimated sarin/cyclosarin exposure and both reduced white matter (adjusted parameter estimate=-4.64, p<0.0001) and increased right lateral ventricle (adjusted parameter estimate=.11, p=0.0288) and left lateral ventricle (adjusted parameter estimate=.13, p<0.0001) volumes. CONCLUSIONS These findings suggest subtle but persistent central nervous system pathology in Gulf War veterans potentially exposed to low levels of sarin/cyclosarin and argue for further investigation of the long-term effects of low-dose sarin/cyclosarin exposures in humans.
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Affiliation(s)
- Kristin J Heaton
- Boston Environmental Hazards Research Center, VA Boston Healthcare System, Boston, MA, USA.
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40
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Proctor SP, Heaton KJ, Heeren T, White RF. Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioral functioning in US army veterans. Neurotoxicology 2006; 27:931-9. [PMID: 16982099 DOI: 10.1016/j.neuro.2006.08.001] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2006] [Revised: 08/02/2006] [Accepted: 08/02/2006] [Indexed: 11/19/2022]
Abstract
BACKGROUND During the Gulf War (GW), in early March 1991, a munitions dump at Khamisiyah, Iraq, was destroyed. Later, in 1996, the dump was found to have contained the organophosphate chemical warfare agents, sarin and cyclosarin. METHODS Data collected in a study conducted between 1994 and 1996, before the Khamisiyah incident was publicly disclosed, were used to examine neurobehavioral task performances of GW veterans (n=140) categorized as having received high, moderate, or low-to-no exposure dose levels to sarin and cyclosarin at Khamisiyah, Iraq. Exposure levels were based on modeled estimates of the exposure plume and on troop location information at the time of the Khamisiyah event. Based on recent findings observed in follow-up studies of persons exposed to sarin during the 1995 terrorist attacks in Japan, we hypothesized that exposure to sarin and cyclosarin would be associated with poorer performances on objective neurobehavioral tasks in specific functional domains (particularly in visuospatial abilities and psychomotor functioning) in a dose-dependent manner. RESULTS Sarin and cyclosarin exposure was significantly associated with less proficient neurobehavioral functioning on tasks involving fine psychomotor dexterity and visuospatial abilities 4-5 years after exposure. CONCLUSIONS Findings suggest a dose-response association between low-level exposure to sarin and cyclosarin and specific functional central nervous system effects 4-5 years after exposure.
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Affiliation(s)
- Susan P Proctor
- Boston Environmental Hazards Center, VA Boston Healthcare System, Boston, MA 02130-4893, USA.
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41
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Morris M, Key MP, Farah V. Sarin produces delayed cardiac and central autonomic changes. Exp Neurol 2006; 203:110-5. [PMID: 16996499 DOI: 10.1016/j.expneurol.2006.07.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2006] [Revised: 07/12/2006] [Accepted: 07/24/2006] [Indexed: 10/24/2022]
Abstract
The aim was to evaluate the acute and delayed effects of low dose sarin exposure on cardiac autonomic and brainstem catecholaminergic function in mice. The rationale was to expand our knowledge of the cardiovascular effects of this neurotoxic, acetylcholinesterase (AChE) inhibitor. C57BL/6 male mice with telemetric arterial catheters were injected with saline or sarin (8 microg/kg, 0.05x LD(50); sc, two injections) with blood pressure (BP) measurements made at 1 and 10 weeks after sarin exposure. BP and pulse interval variability (PI) and low and high frequency spectral oscillations were measured using autoregressive spectral analysis. In situ hybridization (ISH) was used to quantify tyrosine hydroxylase (TH) mRNA expression in brainstem cardiovascular centers. Sarin had no effect on blood AChE activity, heart rate (HR) or BP. There was a biphasic response in PI variance, an early increase (+140%) and a delayed decrease (-62%) at more than 2 months after sarin exposure. There were no changes in BP variance. Assuming that increased PI variance is a positive outcome, the short-term response to sarin should be protective. This is opposite for the delayed decrease in PI variance which is associated with adverse cardiovascular effects. There was an increase in TH mRNA in both locus coeruleus (0.18+/-0.05 vs. 1.4+/-0.2 microCi/g; control vs. sarin) and dorsal vagal complex (0.09+/-0.06 vs. 1.17+/-0.03 microCi/g; control vs. sarin). Results show that a dose of sarin which had no peripheral cholinergic effects caused changes in autonomic modulation, a short-term enhancement followed by a delayed impairment in heart rate variability. Sarin-induced cardiac effects suggest a controversial aspect to the use of pharmacological agents which target AChE for management of cardiovascular risk.
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Affiliation(s)
- Mariana Morris
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA.
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Pabello N, Lawrence D. Neuroimmunotoxicology: Modulation of neuroimmune networks by toxicants. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/j.cnr.2006.04.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Watson A, Opresko D, Young R, Hauschild V. Development and application of acute exposure guideline levels (AEGLs) for chemical warfare nerve and sulfur mustard agents. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2006; 9:173-263. [PMID: 16621779 DOI: 10.1080/15287390500194441] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Acute exposure guideline levels (AEGLs) have been developed for the chemical warfare agents GB, GA, GD, GF, VX, and sulfur mustard. These AEGLs were approved by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances after Federal Register publication and comment, and judged as scientifically valid by the National Research Council Committee on Toxicology Subcommittee on AEGLs. AEGLs represent general public exposure limits for durations ranging from 10 min to 8 h, and for three levels of severity (AEGL-1, AEGL-2, AEGL-3). Mild effects are possible at concentrations greater than AEGL-1, while life-threatening effects are expected at concentrations greater than AEGL-3. AEGLs can be applied to various civilian and national defense purposes, including evacuation and shelter-in-place protocols, reentry levels, protective clothing specifications, and analytical monitoring requirements. This report documents development and derivation of AEGL values for six key chemical warfare agents, and makes recommendations for their application to various potential exposure scenarios.
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Affiliation(s)
- Annetta Watson
- Toxicology and Hazard Assessment Group, Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830-6480, USA.
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Gray GC, Kang HK. Healthcare utilization and mortality among veterans of the Gulf War. Philos Trans R Soc Lond B Biol Sci 2006; 361:553-69. [PMID: 16687261 PMCID: PMC1569626 DOI: 10.1098/rstb.2006.1816] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The authors conducted an extensive search for published works concerning healthcare utilization and mortality among Gulf War veterans of the Coalition forces who served during the 1990-1991 Gulf War. Reports concerning the health experience of US, UK, Canadian, Saudi and Australian veterans were reviewed. This report summarizes 15 years of observations and research in four categories: Gulf War veteran healthcare registry studies, hospitalization studies, outpatient studies and mortality studies. A total of 149728 (19.8%) of 756373 US, UK, Canadian and Australian Gulf War veterans received health registry evaluations revealing a vast number of symptoms and clinical conditions but no suggestion that a new unique illness was associated with service during the Gulf War. Additionally, no Gulf War exposure was uniquely implicated as a cause for post-war morbidity. Numerous large, controlled studies of US Gulf War veterans' hospitalizations, often involving more than a million veterans, have been conducted. They revealed an increased post-war risk for mental health diagnoses, multi-symptom conditions and musculoskeletal disorders. Again, these data failed to demonstrate that Gulf War veterans suffered from a unique Gulf War-related illness. The sparsely available ambulatory care reports documented that respiratory and gastrointestinal complaints were quite common during deployment. Using perhaps the most reliable data, controlled mortality studies have revealed that Gulf War veterans were at increased risk of injuries, especially those due to vehicular accidents. In general, healthcare utilization data are now exhausted. These findings have now been incorporated into preventive measures in support of current military forces. With a few diagnostic exceptions such as amyotrophic lateral sclerosis, mental disorders and cancer, it now seems time to cease examining Gulf War veteran morbidity and to direct future research efforts to preventing illness among current and future military personnel.
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Affiliation(s)
- Gregory C Gray
- Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, 52242, USA.
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Chapman S, Kadar T, Gilat E. Seizure duration following sarin exposure affects neuro-inflammatory markers in the rat brain. Neurotoxicology 2006; 27:277-83. [PMID: 16406030 DOI: 10.1016/j.neuro.2005.11.009] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2005] [Revised: 11/20/2005] [Accepted: 11/20/2005] [Indexed: 10/25/2022]
Abstract
The current study was aimed to characterize for the first time the alterations in the characteristic neuro-inflammatory markers triggered by sarin exposure in the rat's brain, and to investigate its dependency on seizure duration. Centrally mediated seizures are a common consequence of exposure to organophosphates (OP) despite conventional treatment with atropine and an oxime. In the present study midazolam, was used to control duration and intensity of seizures. The levels of the pro-inflammatory cytokine peptides IL-1beta, IL-6, TNF-alpha and prostaglandin E2 (PGE2) were monitored at various times after sarin exposure in the hippocampus and cortex of rats treated with midazolam following 5 or 30 min of seizure activity. Biochemical evaluation of brain tissues revealed a significant increase in the level of the pro-inflammatory peptides starting at 2 h and peaking at 2-24 h following sarin. Hippocampal values of IL1-beta increased from 1.2+/-0.1 pg/mg tissue (control), to 2.4+/-0.3 at 2 h (5 min seizure) and to 9.3+/-2.5 at 8h (30 min seizure). PGE2 level in the hippocampus increased up to 24 h following exposure (from 56+/-3 to 175+/-26 and 277+/-28 pg/mg tissue) following 5 and 30 min of seizure activity respectively. Thus, unlike limitation of seizures to 5 min by midazolam, delayed treatment (30 min) resulted in prolonged seizures and pronounced increase in cytokines and PGE2. In addition, a second increase in inflammatory markers was observed 30 days following sarin exposure only in rats treated following 30 min of seizure activity. Histological evaluation of the rat brain, conducted in this study, revealed lack of damage in the hippocampus and piriform cortex with minor lateral ventricles enlargement in few animals following 5 min of sarin-induced seizure activity. In contrast, marked histological damage to the brain was demonstrated following 30 min of seizure activity, consisting severe damage to the hippocampus, piriform cortex and some thalamic nuclei. In summary, a novel characterization of the prolonged central neuro-inflammatory process that accompanies sarin exposure is presented. The timing of the anticonvulsive treatment was shown to be crucial in modulation of the neuro-inflammatory response, and may implicate the consequent long-term brain damage.
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Affiliation(s)
- S Chapman
- Department of Pharmacology, Israel Institute for Biological Research, P.O. Box 19, Ness Ziona 74100, Israel
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López-Grancha M, Sánchez-Amate C, Navarro M, Carvajal F, Sánchez-Santed F, Cubero I. Lateral Parabrachial Lesions Disrupt Paraoxon-Induced Conditioned Flavor Avoidance. Toxicol Sci 2006; 91:210-7. [PMID: 16476685 DOI: 10.1093/toxsci/kfj126] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Preliminary clinical evidence obtained in Gulf War veterans and patients suffering multiple chemical sensitivity points to the existence of a potential link between environmental exposure to organosphosphates (OPs) and the emergence of unspecific sickness syndromes in which associative Pavlovian conditioning might be partly involved. A laboratory animal model might be a useful tool for analyzing the involvement of conditioning in sickness syndromes potentially linked to OP poisoning. The first objective in the present study was to determine if paraoxon (PX), the neuroactive metabolite of the OP parathion, elicits a conditioned avoidance response to a novel stimulus (a taste-odor compound) in a conditioned flavor aversion procedure. Data obtained in Experiment 1 show conditioned flavor avoidance, demonstrative of the associative nature of the sickness properties of PX. The second objective was to characterize the nature of the specific physiological cue serving as the unconditioned stimulus in PX-induced conditioned avoidance. Despite PX administration did induce cholinergic hyperactivity, as measured by body hypothermia and increased jaw movements, lesions of the lateral parabrachial area (lPB) disrupted PX-elicited flavor avoidance responses, indicating that cholinergic signs were not sufficient as unconditioned stimuli supporting avoidance responses. Given that lPB neural integrity is necessary to process aversive interoceptive information, disruption of conditioned flavor avoidance as a result of lPB lesions is consistent with a central interruption of interoceptive processing in PX-poisoned animals. Data are discussed under the light of the hypothesis claiming the importance of associative processes and noncholinesterase targets in sickness syndromes potentially induced by OP exposure.
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Affiliation(s)
- Matilde López-Grancha
- Departamento de Neurociencia y Ciencias de la Salud, University of Almeria, 04120 Almeria, Spain
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Gordon CJ, Leon LR. Thermal stress and the physiological response to environmental toxicants. REVIEWS ON ENVIRONMENTAL HEALTH 2005; 20:235-63. [PMID: 16422347 DOI: 10.1515/reveh.2005.20.4.235] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Most toxicological and pharmacological studies are performed in laboratory animals maintained under comfortable environmental conditions. Yet, the exposure to environmental toxicants as well as many drugs can occur under stressful environmental conditions during rest or while exercising. The intake and biological efficacy of many toxicants is exacerbated by exposure to heat stress, which can occur in several ways. The increase in pulmonary ventilation during exposure to hot environments results in an increase in the uptake of airborne toxicants. Furthermore, the transcutaneous absorption of pesticides on the skin as well as drugs delivered by skin patches is increased during heat stress because of the combined elevation in skin blood flow coupled with moist skin from sweat. The thermoregulatory response to toxicant exposure, such as hypothermia in relatively small rodents and fever in humans, also modulates the physiological response to most chemical agents. This paper endeavors to review the issue of environmental heat stress and exercise and how they influence thermoregulatory and related pathophysiological responses to environmental toxicants, as well as exposure to drugs.
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Affiliation(s)
- Christopher J Gordon
- Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
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Sun FP, Song YG. Effect of environmental hyperthermia on gastrin, somatostatin and motilin in rat ulcerated antral mucosa. World J Gastroenterol 2004; 10:3528-30. [PMID: 15526379 PMCID: PMC4576241 DOI: 10.3748/wjg.v10.i23.3528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the effect of environmental hyperthermia on gastrin, somatostatin and motilin in rat ulcerated antral mucosa.
METHODS: Forty-two Wistar rats were equally divided into six groups, according to the room temperature (high and normal) and the treatment (acetic acid, normal saline and no treatment). Levels of gastrin, somatostatin and motilin in rat ulcerated antral mucosa were measured with a radioimmunoassay method.
RESULTS: The average temperature and humidity were 32.5 °C and 66.7% for the high temperature group, and 21.1 °C and 49.3% for the normal temperature group, respectively. Gastric ulcer model was successfully induced in rat injected with 0.05 mL acetic acid into the antrum. In rats with gastric ulcers, the levels of gastrin and motilin increased, whereas the somatostatin level declined in antral mucosa, compared with those in rats treated with normal saline and the controls. However, the change extent in the levels of gastrin, motilin and somatostatin in antral mucosa was less in the high temperature group than in the normal temperature group.
CONCLUSION: The levels of gastrin, somatostatin and motilin in rat ulcerated antral mucosal tissue remain relatively stable in a high temperature environment, which may relate to the equilibration of the dynamic system.
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Affiliation(s)
- Feng-Peng Sun
- Department of Gastroenterology, Nanfang Hospital, First Military medical University, Guangzhou 510515, Guangdong Province, China.
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Haley RW, Vongpatanasin W, Wolfe GI, Bryan WW, Armitage R, Hoffmann RF, Petty F, Callahan TS, Charuvastra E, Shell WE, Marshall WW, Victor RG. Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. Am J Med 2004; 117:469-78. [PMID: 15464703 DOI: 10.1016/j.amjmed.2004.03.041] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2002] [Accepted: 03/06/2004] [Indexed: 11/30/2022]
Abstract
PURPOSE To test the hypothesis that subtle abnormalities of the autonomic nervous system underlie the chronic symptoms reported by many Gulf War veterans, such as chronic diarrhea, dizziness, fatigue, and sexual dysfunction. METHODS Twenty-two ill Gulf War veterans and 19 age-, sex-, and education-matched control veterans underwent measurement of circadian rhythm of heart rate variability by 24-hour electrocardiography, ambulatory blood pressure recording, Valsalva ratio testing, sympathetic skin response evaluation, sweat imprint testing, and polysomnography. Investigators were blinded to case- or control-group status. RESULTS High-frequency spectral power of heart rate variability increased normally 2.2-fold during sleep in controls but only 1.2-fold in ill veterans (P <0.0001). In ill veterans as compared with controls, it was lower at night (P = 0.0006), higher during the morning (P = 0.007), but no different during the rest of the day (P = 0.8). The mean heart rate of ill veterans also declined less at night (P = 0.0002), and their corrected QT intervals tended to be longer over the full 24 hours (P = 0.07), particularly at night (P = 0.03). Blunting of the nocturnal heart rate dip in ill veterans was confirmed by 24-hour automatic ambulatory blood pressure monitoring (P = 0.05) and polysomnography (P = 0.03). These differences remained significant after adjusting for potential confounders. Cases and controls were similar on measures of sympathetic adrenergic and sudomotor function, sleep architecture, respiratory function, and circadian variation in blood pressure and body temperature. CONCLUSION Some symptoms of Gulf War syndrome may be due to subtle autonomic nervous system dysfunction.
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Affiliation(s)
- Robert W Haley
- Divisions of Epidemiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8874, USA.
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