Self-reported Exposure to Neurotoxic Chemical Combinations in the Gulf War&lt;subtitle&gt;A Cross-sectional Epidemiologic Study&lt;/subtitle&gt;

Haley, Robert W.; Kurt, Thomas L.

doi:10.1001/jama.1997.03540270057027

Cited by 239 publications

(30 citation statements)

References 45 publications

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“…19 The sample population used in these studies was very narrow, consisting of 249 subjects, comprising 41% of a single overseas-deployed naval construction battalion. 24,36 It is thus possible that, although neurologic symptoms exhibited by these subjects were likely related to toxicant exposure and relative capacity of each individual to clear certain pollutants, their experience may not be representative of neurological disorders among Gulf War veterans as a group. One possibility is that the battalion’s in-theater mission assignment resulted in a particularly unlucky convergence of heavy toxicant exposures.…”

Section: Discussionmentioning

confidence: 99%

Activity of Paraoxonase/Arylesterase and Butyrylcholinesterase in Peripheral Blood of Gulf War Era Veterans With Neurologic Symptom Complexes or Post-Traumatic Stress Disorder

Haines

Ottenweller

Dickens

et al. 2017

Journal of Occupational &Amp; Environmental Medicine

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Objective Two groups of Gulf War era veterans, one exhibiting blurred vision, balance problems/dizziness, tremors/shaking, and speech difficulty and a second group with post-traumatic stress disorder (PTSD), but not the neurologic syndrome, were assessed for organophosphate-detoxifying enzyme paraoxonase/arylesterase (PON1) and its Q/R isoforms, butyrylcholinesterase (BuChE) and its U/A isoforms and cytokines. Methods Defibrinated peripheral blood was evaluated for enzymes and cytokines. Results Trends toward elevation of Th2 cytokines interleukin-4 (IL-4) and IL-13 were observed in subjects with neurologic syndrome. Neither the activities nor isoforms of the enzyme, the neurologic symptoms, nor PTSD had any relationship to wartime deployment to the theater of combat. Conclusions The negative outcomes described above suggest that exposure to organophosphates or other agents normally detoxified by PON1 and BuChE may not have contributed significantly to neurologic components of Gulf War Illness.

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Section: Discussionmentioning

confidence: 99%

Activity of Paraoxonase/Arylesterase and Butyrylcholinesterase in Peripheral Blood of Gulf War Era Veterans With Neurologic Symptom Complexes or Post-Traumatic Stress Disorder

Haines

Ottenweller

Dickens

et al. 2017

Journal of Occupational &Amp; Environmental Medicine

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“…The troops experienced exposure to a variety of chemicals during deployment, which included the intake of prophylactic drugs for variable durations for protection against nerve gas and other hazardous agents, widespread spraying and usage of mosquito repellants and pesticides to keep insects and rodents at bay in the desert region, exposure to low-level chemical warfare agents due to demolition of Iraqi facilities storing those agents, and smoke from oil-well fires (White et al, 2016). Thus, the concomitant exposure to pyridostigmine bromide (PB), which is an anti-nerve gas agent, and pesticides, such as N,N-diethyl-meta-toluamide (DEET) permethrin (PM), along with war-related stress or low-level exposures to chemical warfare agents, have been proposed as the chief causes of GWI (Haley and Kurt, 1997; Institute of Medicine [IOM], 2010, 2014; Steele et al, 2012; White et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness

Shetty

Hattiangady

Upadhya

et al. 2017

Front. Mol. Neurosci.

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Memory and mood dysfunction are the key symptoms of Gulf war illness (GWI), a lingering multi-symptom ailment afflicting >200,000 veterans who served in the Persian Gulf War-1. Research probing the source of the disease has demonstrated that concomitant exposures to anti-nerve gas agent pyridostigmine bromide (PB), pesticides, and war-related stress are among the chief causes of GWI. Indeed, exposures to GWI-related chemicals (GWIR-Cs) and mild stress in animal models cause memory and mood impairments alongside reduced neurogenesis and chronic low-level inflammation in the hippocampus. In the current study, we examined whether exposure to GWIR-Cs and stress causes chronic changes in the expression of genes related to increased oxidative stress, mitochondrial dysfunction, and inflammation in the hippocampus. We also investigated whether GWI is linked with chronically increased activation of Nrf2 (a master regulator of antioxidant response) in the hippocampus, and inflammation and enhanced oxidative stress at the systemic level. Adult male rats were exposed daily to low-doses of PB and pesticides (DEET and permethrin), in combination with 5 min of restraint stress for 4 weeks. Analysis of the hippocampus performed 6 months after the exposure revealed increased expression of many genes related to oxidative stress response and/or antioxidant activity (Hmox1, Sepp1, and Srxn1), reactive oxygen species metabolism (Fmo2, Sod2, and Ucp2) and oxygen transport (Ift172 and Slc38a1). Furthermore, multiple genes relevant to mitochondrial respiration (Atp6a1, Cox6a1, Cox7a2L, Ndufs7, Ndufv1, Lhpp, Slc25a10, and Ucp1) and neuroinflammation (Nfkb1, Bcl6, Csf2, IL6, Mapk1, Mapk3, Ngf, N-pac, and Prkaca) were up-regulated, alongside 73–88% reduction in the expression of anti-inflammatory genes IL4 and IL10, and nuclear translocation and increased expression of Nrf2 protein. These hippocampal changes were associated with elevated levels of pro-inflammatory cytokines and chemokines (Tnfa, IL1b, IL1a, Tgfb, and Fgf2) and lipid peroxidation byproduct malondialdehyde in the serum, suggesting the presence of an incessant systemic inflammation and elevated oxidative stress. These results imply that chronic oxidative stress, inflammation, and mitochondrial dysfunction in the hippocampus, and heightened systemic inflammation and oxidative stress likely underlie the persistent memory and mood dysfunction observed in GWI.

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“…Epidemiological studies report different side effects of the use of DEET including neurologic side effects37, seizures38 and cancer639, the last of which is a pathophysiological situation in which angiogenesis plays an important role40. Angiogenesis is critical for tumor development, and it is considered as a pre-requisite for the rapid expansion of tumor cells associated with formation of macroscopic tumors16.…”

Section: Discussionmentioning

confidence: 99%

The insect repellent N,N-diethyl-m-toluamide (DEET) induces angiogenesis via allosteric modulation of the M3 muscarinic receptor in endothelial cells

Legeay

Clere

Hilairet

et al. 2016

Sci Rep

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The insect repellent N,N-diethyl-m-toluamide (DEET) has been reported to inhibit AChE (acetylcholinesterase) and to possess potential carcinogenic properties with excessive vascularization. In the present paper, we demonstrate that DEET specifically stimulates endothelial cells that promote angiogenesis which increases tumor growth. DEET activates cellular processes that lead to angiogenesis including proliferation, migration and adhesion. This is associated with an enhancement of NO production and VEGF expression in endothelial cells. M3 silencing or the use of a pharmacological M3 inhibitor abrogates all of these effects which reveals that DEET-induced angiogenesis is M3 sensitive. The experiments involving calcium signals in both endothelial and HEK cells overexpressing M3 receptors, as well as binding and docking studies demonstrate that DEET acts as an allosteric modulator of the M3 receptor. In addition, DEET inhibited AChE which increased acetylcholine bioavailability and binding to M3 receptors and also strengthened proangiogenic effects by an allosteric modulation.

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Self-reported Exposure to Neurotoxic Chemical Combinations in the Gulf War<subtitle>A Cross-sectional Epidemiologic Study</subtitle>

Cited by 239 publications

References 45 publications

Activity of Paraoxonase/Arylesterase and Butyrylcholinesterase in Peripheral Blood of Gulf War Era Veterans With Neurologic Symptom Complexes or Post-Traumatic Stress Disorder

Activity of Paraoxonase/Arylesterase and Butyrylcholinesterase in Peripheral Blood of Gulf War Era Veterans With Neurologic Symptom Complexes or Post-Traumatic Stress Disorder

Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness

The insect repellent N,N-diethyl-m-toluamide (DEET) induces angiogenesis via allosteric modulation of the M3 muscarinic receptor in endothelial cells

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