Examining Possible Causes of Gulf War Illness: RAND Policy Investigations and Reviews of the Scientific Literature

Hilborne, Lee H.; Golomb, Beatrice A.; Marshall, Grant N.; Davis, Lois M.; Sherbourne, Cathy D.; Augerson, William S.; Spektor, Dalia M.; Harley, Naomi H.; Foulkes, E. C.; Hudson, Arlene; Anthony, C. Ross; Cecchine, Gary; Marlowe, David H.; Rettig, Richard A.; Fricker, Ronald D.; Reardon, Elaine; Cotton, Sarah K.; Hawes-Dawson, Jennifer; Pace, Jennifer E.; Hosek, Susan D.

doi:10.7249/rb7544

Cited by 8 publications

(12 citation statements)

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“…To the best of our knowledge, the current study is the first report to demonstrate increased levels of ACh in the brains of mice at a late time point post-exposure to GW agents, which may indicate a disturbed homeostatic imbalance of the cholinergic system. Furthermore, organophosphorous insecticides, some of which have been attributed to the etiology behind GWI, are potent inhibitors of acetylcholinesterase (AChE) activity [ 1 , 24 , 67 , 68 ]. Exposure to these compounds has been shown to induce both acute toxicity and long-term neurological deficits [ 69 – 73 ].…”

Section: Discussionmentioning

confidence: 99%

Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

et al. 2015

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Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.

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Section: Discussionmentioning

confidence: 99%

Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

et al. 2015

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“…Detailed GWI retrospective reports have implicated a prominent role for the combined exposure of organophosphate and pyrethroid‐based pesticides (such as CPF and PER, respectively), and nerve agent pre‐treatment sets containing PB as causative (GW) agents responsible for the high prevalence of GWI among military personnel . We and others have extensively characterized PB and PER exposures alone and in combination with each other and other agents .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, of particular note is the pivotal role of combined GW agent exposure as a potential pathogenic risk factor implicated in GWI etiogenesis. This is demonstrated by a report documenting that nearly 25% of GW veterans during combat deployment reportedly were exposed to several “cocktails” of pesticides, at a frequency ranging from 51–120 times per month, while more than 50% of Army/Navy/Marine Corps personnel serving on the ground used large quantities of PB pills averaging a daily dose of 90 mg …”

Section: Introductionmentioning

confidence: 99%

“…Gulf War agents such as PB and CPF are thought to exert their effects by inhibiting the acetylcholine (ACh)‐hydrolyzing enzyme, acetylcholinesterase (AChE) (that maintains ambient levels of ACh neurotransmitters at the synapse), leading to its excessive release at cholinergic nerve terminals . The cholinergic system plays a diverse and intricate role in the nervous system, including regulation of synaptic plasticity, learning and memory processing, neuronal survival, neurogenesis (growth/differentiation) and inflammation .…”

Section: Introductionmentioning

confidence: 99%

“…Although a number of clinical and preclinical studies have been carried out on GWI patients and laboratory models of GW agent exposure, due to its multi‐symptomatic presentation and the lack of available human GWI brain tissue for analysis, very little is understood about the early histopathological profile of GWI as separate from other related neurological conditions where there is overt neurodegeneration. To begin to address this, we have investigated mice exposed to GW agents and specific combinations that have been particularly implicated in detailed retrospective GWI reports .…”

Section: Introductionmentioning

confidence: 99%

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Exposure to an organophosphate pesticide, individually or in combination with other Gulf War agents, impairs synaptic integrity and neuronal differentiation, and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure

et al. 2013

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Gulf War illness (GWI) is a currently untreatable multi-symptom disorder experienced by 1990-1991 Persian Gulf War (GW) veterans. The characteristic hallmarks of GWI include cognitive dysfunction, tremors, migraine, and psychological disturbances such as depression and anxiety. Meta-analyses of epidemiological studies have consistently linked these symptomatic profiles to the combined exposure of GW agents such as organophosphate-based and pyrethroid-based pesticides (e.g. chlorpyrifos (CPF) and permethrin (PER) respectively) and the prophylactic use of pyridostigmine bromide (PB) as a treatment against neurotoxins. Due to the multi-symptomatic presentation of this illness and the lack of available autopsy tissue from GWI patients, very little is currently known about the distinct early pathological profile implicated in GWI (including its influence on synaptic function and aspects of neurogenesis). In this study, we used preclinical models of GW agent exposure to investigate whether 6-month-old mice exposed to CPF alone, or a combined dose of CPF, PB and PER daily for 10 days, demonstrate any notable pathological changes in hippocampal, cortical (motor, piriform) or amygdalar morphometry. We report that at an acute post-exposure time point (after 3 days), both exposures resulted in the impairment of synaptic integrity (reducing synaptophysin levels) in the CA3 hippocampal region and altered neuronal differentiation in the dentate gyrus (DG), demonstrated by a significant reduction in doublecortin positive cells. Both exposures also significantly increased astrocytic GFAP immunoreactivity in the piriform cortex, motor cortex and the basolateral amygdala and this was accompanied by an increase in (basal) brain acetylcholine (ACh) levels. There was no evidence of microglial activation or structural deterioration of principal neurons in these regions following exposure to CPF alone or in combination with PB and PER. Evidence of subtle microvascular injury was demonstrated by the reduction of platelet endothelial cell adhesion molecule (PECAM)-1 levels in CPF+PB+PER exposed group compared to control. These data support early (subtle) neurotoxic effects on the brain following exposure to GW agents.

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Microbial Inoculant: Modern Era of Fertilizers and Pesticides

Patil

Solanki

2016

Microbial Inoculants in Sustainable Agricultural Productivity

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Examining Possible Causes of Gulf War Illness: RAND Policy Investigations and Reviews of the Scientific Literature

Cited by 8 publications

References 0 publications

Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness

Exposure to an organophosphate pesticide, individually or in combination with other Gulf War agents, impairs synaptic integrity and neuronal differentiation, and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure

Microbial Inoculant: Modern Era of Fertilizers and Pesticides

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