A review of chemical warfare agents linked to respiratory and neurological effects experienced in Gulf War Illness.

Over 40% of veterans from the Persian Gulf War (GW) (1990-1991) suffer from Gulf War Illness (GWI). Thirty years since the GW, the exposure and mechanism contributing to GWI remain unclear. One possible exposure that has been attributed to GWI are chemical warfare agents (CWAs). While there are treatments for isolated symptoms of GWI, the number of respiratory and cognitive/neurological issues continues to rise with minimum treatment options. This issue does not only affect veterans of the GW, importantly these chronic multisymptom illnesses (CMIs) are also growing amongst veterans who have served in the Afghanistan-Iraq war. What both wars have in common are their regions and inhaled exposures. In this review, we will describe the CWA exposures, such as sarin, cyclosarin, and mustard gas in both wars and discuss the various respiratory and neurocognitive issues experienced by veterans. We will bridge the respiratory and neurological symptoms experienced to the various potential mechanisms described for each CWA provided with the most up-to-date models and hypotheses.

A Quantitative Method for Determining Uptake of Silica Nanoparticles in Macrophages by Single Particle Inductively Coupled Plasma-Mass Spectrometry.

Engineered nanomaterials are becoming increasingly ubiquitous in our society, with numerous applications in medicine, consumer products, bioremediation, and advanced materials. As these nanomaterials increase in variety, analyzing their characteristics is of great importance. Single particle inductively coupled plasma-mass spectrometry (SP-ICP-MS) is a high-throughput, sensitive, and robust instrumental analysis method used to simultaneously characterize and quantify nanoparticles in a variety of matrices. One such type of nanoparticle of interest is amorphous silica nanoparticles (SiNPs). SiNPs have widespread use in consumer products such as food and cosmetics and are prime candidates for novel medical applications and uses in environmental bioremediation. Despite their increased use, SiNPs have been shown to have toxicological properties in vitro and in vivo, particularly with regard to the immune system. Because of the potential for increased SiNP exposure in the general public and in occupational settings, examining the relationship that SiNPs have with immune cells such as macrophages to elucidate mechanisms of toxicity is vital. To effectively determine the toxicity of nanoparticles, it is critical to examine dosimetry and the amount of nanoparticles taken up by the cell of interest. Different cell types have different uptake profiles, and varying physicochemical properties govern nanoparticle dosimetry and uptake in cells. Here, we describe a protocol using SP-ICP-MS to quantify and characterize the size, size distribution, and amount of SiNPs present in a cell and medium sample. We use a single-step digestion, which allows for the digestion of biological matrices while simultaneously keeping the SiNPs intact for SP-ICP-MS analysis. Clinically, this approach has the potential to be used as a method for analyzing SiNPs in other biological matrices, potentially as a way of defining SiNP uptake as a biomarker in immune-mediated diseases. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Treatment of cells with silica nanoparticles (SiNPs) and digestion of biological matrices Support Protocol 1: Culturing RAW 264.7 cells for SiNP uptake assay Support Protocol 2: Determination of SiNP size via dynamic light scattering Support Protocol 3: Optimization of sample and ICP-MS parameters for SP-ICP-MS analysis of cells and medium Basic Protocol 2: Analysis and quantification of SiNP uptake in macrophages with SP-ICP-MS.

Mast Cells Promote Nitrogen Mustard-Mediated Toxicity in the Lung Associated With Proinflammatory Cytokine and Bioactive Lipid Mediator Production.

Sulfur mustard (SM) has been widely used as a chemical warfare agent including most recently in Syria. Mice exposed to SM exhibit an increase in pro-inflammatory cytokines followed by immune cell infiltration in the lung, however, the mechanisms leading to these inflammatory responses has not been completely elucidated. Mast cells are one of the first responding innate immune cells found at the mucosal surfaces of the lung and have been reported to be activated by SM in the skin. Therefore, we hypothesized that nitrogen mustard (NM: a surrogate for SM) exposure promotes activation of mast cells causing chronic respiratory inflammation. To assess the role of mast cells in NM-mediated pulmonary toxicity, we compared the effects of NM exposure between C57BL/6 and B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh; mast cell deficient) mice. Lung injury was observed in C57BL/6J mice following NM exposure (0.125 mg/kg) at 72 h, which was significantly abrogated in KitW-sh mice. Although both strains exhibited damage from NM, C57BL/6J mice had higher inflammatory cell infiltration and more elevated prostaglandin D2 (PGD2) present in bronchoalveolar lavage fluid compared with KitW-sh mice. Additionally, we utilized murine bone marrow-derived mast cells to assess NM-induced early and late activation. Although NM exposure did not result in mast cell degranulation, we observed an upregulation in PGD2 and IL-6 levels following exposure to NM. Results suggest that mast cells play a prominent role in lung injury induced by NM and may contribute to the acute and potentially long-term lung injury observed caused by SM.

Selective dopaminergic neurotoxicity of three heterocyclic amine subclasses in primary rat midbrain neurons.

Heterocyclic amines (HCAs) are primarily produced during high temperature meat cooking. These compounds have been intensively investigated as mutagens and carcinogens. However, converging data suggest that HCAs may also be neurotoxic and potentially relevant to neurodegenerative diseases such as Parkinson's disease (PD). The identification of new potential etiological factors is important because most PD cases are sporadic. Our group previously showed that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was selectively neurotoxic to dopaminergic neurons. However, PhIP is one of many HCAs, a class of compounds that exhibits wide structural variability. The goal of this study was to determine the neurotoxicity of the most prevalent and best studied HCAs from three subclasses: aminoimidazoaazarenes (AIA), α-carbolines, and ß-carbolines. Using E17 rat primary midbrain cultures, we tested dopaminergic and non-dopaminergic neurotoxicity elicited by the following compounds: 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), PhIP, 1-methyl-9H-pyrido[3,4-b]indole (harmane), 9H-pyrido[3,4-b]indole (norharmane) and 2-amino-9H-pyrido[2,3-b]indole (AαC) at concentrations ranging from 100 nM-5 µM. All tested HCAs were selectively neurotoxic, though the dose required to elicit selective loss of dopaminergic neurons or decreases in dopaminergic neurite length was compound specific. Non-dopaminergic neurons were unaffected at all tested doses. The sensitivity (determined by threshold dose required to elicit selective neurotoxicity) appears to be unrelated to published mutagenic potency. Both AIA and α/ß-carbolines produced oxidative damage, which was magnified in dopaminergic neurons vs. non-dopaminergic neurons as further evidence of selective neurotoxicity. These studies are expected to prompt clinical and mechanistic studies on the potential role of HCA exposure in PD.