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.

A variety of ‘-omic’ technologies are being increasingly applied in preclinical safety assessments. Such approaches, however, have not been implemented in neurotoxicity safety evaluations. Current regulatory guidelines for assessing neurotoxicity emphasise reliance on traditional histopathological stains and behavioural testing batteries. Although these methods may be sufficient to detect some neurotoxic effects, they lack both the sensitivity and specificity required for broad-scale neurotoxicity screening. The glial reaction to nervous system damage, often termed gliosis, represents a hallmark of all types of nervous system injury. As such, the development and implementation of gliosis biomarkers represents a broadly applicable approach for neurotoxicity safety assessment. Using a panel of known neurotoxic agents, the authors have shown that the astroglial protein, glial fibrillary acidic protein (GFAP), can serve as one such biomarker of neurotoxicity. Qualitative and quantitative analysis of GFAP has ...

Enhanced expression of tumor necrosis factor (TNF) ‐α, is associated with the neuropathological effects underlying disease‐, trauma‐and chemically induced neurodegeneration. Previously, we have shown that deficiency of TNF receptors protects against MPTP‐induced striatal dopaminergic neurotoxicity, findings suggestive of a role for TNF‐α in neurodegeneration. Here, we demonstrate that deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP. MPTP‐induced expression of microglia‐derived factors, TNF‐α, MCP‐1, and IL‐1α, preceded the degeneration of striatal dopaminergic nerve terminals and astrogliosis, as assessed by loss of striatal dopamine and TH, and an increase in striatal GFAP. Pharmacological neuroprotection with the dopamine reuptake inhibitor, nomifensine, abolished striatal dopaminergic neurotoxicity and associated microglial activation. Similarly, in mice lacking TNF receptors, microglial activation was suppressed, findings consistent with a role for TNF‐α in striatal MPTP neurotoxicity. In the hippocampus, however, TNF receptor‐deficient mice showed exacerbated neuronal damage after MPTP, as evidenced by Fluoro Jade‐B staining (to identify degenerating neurons) and decreased microtubule‐associated protein‐2 (MAP‐2) immunoreactivity. These effects were not accompanied by microglial activation, but were associated with increased oxidative stress (nitrosylation of tyrosine residues). These findings suggest that TNF‐α exerts a neurotrophic/neuroprotective effect in hippocampus. The marked differences we observed in the regional density, distribution and/or activity of microglia and microglia‐derived factors may influence the region‐specific role for this cell type. Taken together, our results are indicative of a region‐specific and dual role for TNF‐α in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus.‐Sriram, K., Matheson, J. M., Benkovic, S. A., Miller, D. B., Luster, M. I., O'Callaghan, J. P. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP‐induced neurotoxicity: role of TNF‐α. FASEB J. 20, 670–682 (2006)