Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans

Abstract

Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and gastrointestinal problems, that is experienced by approximately one-third of 1991 Gulf War veterans. Over the nearly three decades since the end of the war, investigators have worked to elucidate the initiating factors and underlying causes of GWI. A significant portion of this research has indicated a strong correlation between GWI and exposure to a number of different acetycholinesterase inhibitors (AChEIs) in theater, such as sarin and cyclosarin nerve agents, chlorpyrifos and dichlorvos pesticides, and the anti-nerve agent prophylactic pyridostigmine bromide. Through studying these exposures and their relationship to the symptoms presented by ill veterans, it has become increasingly apparent that GWI is the likely result of an underlying neuroimmune disorder. While evidence indicates that AChEIs are a key exposure in the development of GWI, particularly organophosphate AChEIs, the mechanism(s) by which these chemicals instigate illness appears to be related to “off-target”, non-cholinergic effects. In this review, we will discuss the role of AChEI exposure in the development and persistence of GWI; in particular, how these chemicals, combined with other exposures, have led to a chronic neuroimmune disorder. This article is part of the special issue entitled ‘Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield’.

Resolving whether inhalation of depleted uranium contributed to Gulf War Illness using high-sensitivity mass spectrometry

“…From our negative results, we conclude that inhalation of DU during the Gulf War was not an important contributor to the GWI. Now scientific attention must be focused even more intensely on the remaining likely causes, particularly the widespread exposure to cholinesterase-inhibiting toxicants including low-level sarin nerve gas known to have been widely dispersed during destruction of chemical weapons stores by Allied bombing of Iraqi chemical weapons storage depots 32 , 33 , as well as pesticides and pyridostigmine, for which considerable evidence exists 31 .…”

Sex-Based Differences in Plasma Autoantibodies to Central Nervous System Proteins in Gulf War Veterans versus Healthy and Symptomatic Controls

“…Currently, the only consistent risk factors for GWI are chemical exposures and a history of mTBI [ 30 , 36 , 37 , 48 , 49 , 50 , 51 ]. These chemicals include: pyridostigmine bromide, pesticides including the insecticides permethrin and lindane as well as the insect repellant, DEET ( N , N -diethyl- m -toluamide), and organophosphate (OP) insecticides and nerve gases, sarin and cyclosarin, which are now known to adversely affect the CNS in significant or combined dosages [ 3 , 14 , 15 , 48 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ].…”

Resolving Whether Inhalation of Depleted Uranium Contributed to Gulf War Illness Using High-Sensitivity Mass Spectrometry

“…From our negative results, we conclude that inhalation of DU during the Gulf War was not an important contributor to the GWI. Now scienti c attention must be focused even more intensely on the remaining likely causes, particularly the widespread exposure to cholinesterase-inhibiting toxicants including low-level sarin nerve gas known to have been widely dispersed during destruction of chemical weapons stores by Allied bombing of Iraqi chemical weapons storage depots [35][36], as well as pesticides and pyridostigmine, for which considerable evidence exists [34]. showing fractional uranium excretion predicted by the combined dissolution-storage-excretion function of the HRTM for uranium oxide particulates are shown; these represent "Low" and "High" absorption curves during dissolution and metabolism of compounds of uranium oxide with contrasting chemical form and solubilities.…”

“…During his wartime deployment to the war theatre, however, he was also exposed to low-level sarin nerve agent, took pyridostigmine tablets, and has moderately low PON1 type Q isoenzyme level, which are typical risk factors for GWI [33][34][35]. The veteran had symptoms satisfying the case de nitions of GWI, subclassi ed as variant syndrome 1 ("cognitive impairment"), but his urine showed a total [U] of 1.35 ng/g creatinine, a 238 U/ 235 U ratio of 137.8, and a 236 U/ 238 U ratio below detection limit (< 0.000001)-all typical of natural U with no DU.…”