Table 8.

Studies using animal and in Vitro models of Gulf War illness and related diseases.

Study	Model	Parameter(s) evaluated exposure	Key findings
Abdullah et al., 2011	Mouse	PB, PER	Exposed mice demonstrated significantly increased anxiety behavior, memory impairment and psychomotor dysfunction. After 150 days of exposure, significant increases in astrogliosis were seen in exposed mice. Proteomic analysis showed significant expression alterations for proteins that regulate lipid metabolism, molecular transport, and endocrine and immune function.
Abdullah et al., 2012	Mouse	PB, PER, DEET, stress	Significant increases in ether-containing PC, diacyl, PC and SM lipids, indicating altered transport, uptake, storage and synthesis in ACh pathways in the brain. Anxiety-like behavior was increased in exposed mice, especially in females. Sensorimotor deficits were also significantly associated with exposure, as was astrogliosis.
Abdullah et al., 2013	Mouse	PB, PER	Exposed mice had elevated brain levels of PC and SM phospholipid species, particularly those containing ether PC. Brain catalase staining was higher in exposed than control mice. Lyso-platelet activating factors (precursors of inflammatory lipid mediators) were decreased in the brain and blood from exposed compared to control mice.
Bozkurt et al., 2010	Rat	CPF	Single CPF dose led to significant short term (12 h) changes in glial and neuronal markers in serum. Immediate significant changes in body weight and temperature persisted for approximately 168 h.
Cardona et al., 2006	Rat	CPF	CPF significantly inhibited AChE and APF enzymatic activity even when signs of acute toxicity were absent. Striatum and brainstem areas showed slowed AChE recovery after CPF exposure.
Corbel et al., 2009	Insect and mouse cultured tissue	DEET	DEET application to insect CNS neuronal preparation produced significant initial increase in neuronal electrophysiological activation, followed by a significant decrease, indicating changes in synaptic transmission and inhibition of cholinesterase activity.
Grigoryan et al., 2008	Bovine protein isolate	Sarin, soman, CPO, DFP, FP-biotin	Pesticide agents bind covalently to tubulin, a protein required for neuronal transport, putatively creating axonal transport deficits.
Grigoryan et al., 2009	Bovine, human, porcine and murine protein isolate	FP-biotin	OP esters bind to tyrosine in proteins across different species. OP-reactive proteins include enzymes with and without active serine sites.
Grigoryan et al., 2009	Bovine, human, porcine, murine protein isolate	DFP, CPO	OP esters covalently bind to lysine in albumin, keratin, actin, tubulin and transferrin in a number of mammalian species.
Jiang et al., 2010	Mouse	CPF, CPO	Microtubules isolated from brain tissue from exposed mice showed fewer associated proteins than control mice, and microtubules from exposed mice were significantly smaller in comparison to controls. Mice brains show CPO-labeled tubulin after injections of nontoxic doses of CPF or CPO.
Middlemore-Risher et al., 2011	Rat	CPF, CPO	Mitochondrial length, number and axonal movement were decreased in central nervous system neurons in rats exposed to CPF or CPO when compared to controls.
Nutter et al., 2013	Rat	CPF, PER, PB	After exposure, K+ channel kinetics were altered in vascular pain receptors, with significant increases in electrophysiological excitability. No behavioral differences were noted between exposed and control animals, nor were significant effects seen in Na+ channel activity.
O’Callaghan et al., 2015	Mouse	DFP, DEET, CORT	Pretreatment with CORT greatly increased neuroinflammatory responses to DFP. Minocycline (anti-inflammatory) suppressed DFP + CORT neuroinflammation.
Ojo et al., 2013	Mouse	CPF, PB, PER	Exposure to CPF alone or in combination with PB and PER reduced synaptic function by reducing hippocampal synaptophysin and impairing cell differentiation in the dentate gyrus, with altered basal ACh levels throughout the brain.
Parihar et al., 2013	Rat	DEET, PER, PB, stress	Exposure to low doses of DEET, PER and PB increased disordered mood and cognitive behaviors. Rats exposed to pesticides and stress showed significantly reduced hippocampal volume and neuron growth, and increased CNS inflammation.
Speed et al., 2012	Mouse	CPF	Mice injected with CPF showed a short term increase in synaptic transmission in the CA3–CA1 hippocampal region. After three months, decreased spine density in the hippocampus and reduced synaptic activity was seen in exposed versus control mice.
Torres-Altoro et al., 2011	Mouse	CPF, sarin, PB, DEET, DFP	CPF and PB altered dopaminergic and glutamatergic synaptic transmission in vivo and slice preparations. Combined PB/DEET/DFP exposure stimulated aberrant brain specific protein expression in the striatum and hippocampus.

Abbreviations: PB = pyridostigmine bromide; PER = permethrin; DEET = N,N-diethyl-meta-toluamide; PC = phosphatidylcholine; SM = sphingomyelin; ACh = acetylcholine; DU = depleted uranium; CPF = chlorpyrifos; CNS = central nervous system; CPO = chlorpyrifos oxon; DFP = diisopropylfluorophosphate; FP-biotin = 10-fluoroethoxyphosphinyl-N-biotinamidopentyldecanamide; OP = organophosphorus; AChE = acetylcholinesterase; APF = acylpeptide hydrolase; LV = left ventricular; TH = tyrosine hydroxylase; PC = phosphatidylcholine; SM = sphingomyelin; DU = depleted uranium; ROS = reactive oxygen species; CORT = corticosterone.

(Table adapted from RACGWVI, 2014).