Despite a global ban on their production, polychlorinated biphenyls (PCBs) remain widespread environmental contaminants and pose considerable risks to human health. Experimental findings demonstrate that PCBs have profound neurotoxic effects, with individual congeners varying in degrees of cytotoxicity and carcinogenicity. Exposure to PCBs is regarded as a probable risk factor for several neurological and psychiatric conditions of unknown etiology. Though more often investigated from a neurodevelopmental standpoint, PCB-induced neurotoxicity likely also has implications for adolescent- and adult-onset disease states. This review outlines significant findings of epidemiological studies that examined risks for neurodegenerative diseases and affective disorders in cases of adult PCB exposure. The biological plausibility of the observed associations between PCB exposure and increased risk for Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and major depressive disorder (MDD) are discussed in the context of preclinical evidence supporting potential pathological mechanisms by which PCBs confer risk of neurodegenerative disease. Specifically, we focus on oxidative stress, altered neural connectivity, disrupted monoamine neurotransmitter homeostasis, and aggregated protein pathology. Lastly, key data gaps in the existing epidemiological literature are identified.

Current therapeutic strategies for organophosphate (OP)-induced status epilepticus (SE) prevent mortality, but not chronic neurotoxic outcomes, which may be mediated in part by neuroinflammation. The plasminogen activation system (PAS) is implicated in diverse models of neuroinflammation but has yet to be evaluated after acute OP intoxication. Here, we characterized the PAS in a rat model of acute intoxication with diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats exposed to DFP (4 mg/kg, sc) followed 1 min later by atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) exhibited prolonged SE as determined using behavioral criteria. Electron microscopy of the hippocampus and piriform cortex at 1 day post-exposure (DPE) was consistent with metabolic stress and acute neurodegeneration. At 1 DPE, concentrations of plasminogen activator inhibitor-1 (PAI-1) were significantly increased in serum from DFP rats. Protein levels of the plasminogen activators (PA), tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), as determined by ELISA, were elevated in the cerebellum, cortex and hippocampus in a time- and region-dependent manner after DFP exposure. Similarly, normalized protein levels of the primary PA inhibitor, PAI-1, was also elevated in the same brain regions. At 1 DPE, tPA, uPA and PAI-1 were significantly increased in the cortex and hippocampus. Normalized concentrations of uPA and PAI-1 returned to control values by 3-7 DPE, whereas tPA concentrations remained persistently elevated in the cortex and hippocampus up to 28 DPE. Immunohistochemistry confirmed increased PAI-1 immunoreactivity in multiple regions of the DFP brain up to 28 DPE. Co-localization of PAI-1 with neuronal, microglial and astrocytic biomarkers indicated that PAI-1 predominantly localized to astrocytic subsets, with intense immunofluorescence in astrocytic endfeet associated with endothelial cells. Collectively, these data indicate that acute DFP intoxication activates the PAS, identifying this enzymatic cascade as a potential therapeutic target for mitigating the long-term neurologic consequences of acute OP intoxication.

Organophosphate (OP) cholinesterase inhibitors and GABA receptor antagonists represent mechanistically diverse classes of chemicals that can cause seizures and death following acute intoxication at relatively low doses. OPs inhibit acetylcholinesterase (AChE), which results in the over accumulation of acetylcholine (ACh) in the nervous system. Rapid inhibition of > 60-80% of brain AChE triggers seizures that rapidly progress to life-threatening status epilepticus (SE). GABA receptor antagonists, exemplified by tetramethylenedisulfotetramine (TETS), induce seizures and death by reducing the inhibitory tone in the nervous system, which results in neuronal hyperexcitability. The standard first-line therapy for the treatment of TETS- or OP-induced SE, high-dose benzodiazepines, are effective at terminating seizure behavior and reducing mortality if administered within minutes after exposure. However, even with timely treatment, benzodiazepines often fail to adequately protect against subsequent brain damage and neurologic deficits. Preclinical rodent models are essential to elucidating the cellular and molecular mechanisms driving acute seizurogenic events and the spatiotemporal progression of brain damage following SE. The major objective of this dissertation was to characterize acute and chronic neurotoxic outcomes in novel mouse models of TETS- and OP-induced SE to gain a better understanding of the pathogenic mechanisms contributing to SE and the consequential neuropathology. In Chapter 2, in vivo imaging is used to compare the spatiotemporal progression of neuropathology after TETS-SE in two different mouse strains commonly used to study chemical-induced SE. The findings in this study demonstrate that the extent of brain damage observed in the mouse brain after TETS-induced SE varies according to strain and the duration of SE. Chapter 3 focuses on the development and characterization of a mouse model of acute intoxication with diisopropylfluorophosphate (DFP). Specifically, this chapter describes the spatiotemporal progression of AChE inhibition, neuropathology, and behavioral deficits up to 28 days post-exposure. The findings in this chapter demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening. The mouse model of acute DFP intoxication was leveraged in Chapter 4 to investigate the role of nicotinic cholinergic receptors (nAChR) in the initiation and propagation of OP-induced SE. The findings described in Chapter 4 identify a role for α4-containing nAChR in the initiation and/or progression of seizures following acute OP intoxication, and support further investigation of nicotinic antagonists as prophylactics for OP-induced SE. The studies presented in this dissertation support the use of mouse models to investigate the mechanisms contributing to the initiation and consequences of SE caused by chemical threat agents. The findings of this work have important mechanistic and therapeutic implications regarding the pathophysiology and treatment of chemical-induced SE. The observation that genetic background and duration of SE influence the neuropathologic consequences of TETS-SE suggests that humans who do not respond to antiseizure medication after acute TETS intoxication are at increased risk for brain injury, and this susceptibility may vary genetically. The observation that nicotinic receptors play a necessary role in the initiation of OP-induced SE highlights a novel therapeutic target, and supports the strategy of using a nicotinic antagonist as a preventative antidote against OP-induced seizures.