Organophosphate Neurotoxicity

Pictorial summary of the literature concerning the neurotoxic response to OP compounds.

Organophosphate (OP) compounds (insecticides, pesticides, and military nerve agents) can rapidly induce neurotoxicity in humans, with long term exposure to sublethal levels producing irreversible neurological damage. OP compounds are widely used by civilians as pesticides for crop protection in the agricultural industry. Considerable increase in the annual use of OP compounds in agriculture has led to increased concern of chronic occupational exposure, widespread distribution in food and available drinking water, and local environmental impact. The standard (civilian and military) post-exposure treatment consists of atropine combined with an oxime. However, neither treatment acts against all OP compounds, and oximes themselves neurotoxic. Therefore, there is a clear need to develop alternative treatment options for both civilian and military applications. The challenge of discovering alternative, efficacious targets and countermeasures demands a comprehensive solution based on an understanding of the fundamental mechanistic action of the toxin and the neural countermeasure as well as their relations with other biological processes. CFDRC has successfully implemented a methodology that uses validated systems biology models of cellular processes as the basis for a rational identification, validation and prioritization of potential therapeutic targets.

Noise and Noise Induced Hearing Loss (Ototoxicity)

Potential pathological pathways through reactive oxygen specie formation associated with noise-induced hearing loss.

Military personnel are at a higher risk for sensorineural, or noise-induced hearing loss (NIHL), due to the magnitude and duration of noise levels associated with military service (e.g. weapons systems, artillery, jet engines, helicopters, and even communication systems). The sense of hearing is considered the most important survival sense for both the dismounted soldier as well as for the armored warfighter. Moreover, the monetary cost of NIHL is a tremendous burden to the overall military budget, with the total disability pension payments for hearing damage to all veterans reaching approximately $1 billion per year. NIHL primarily results in the death or damage of the ear hair cells in the cochlea, and can be accelerated by recognized risk factors such as solvents, cigarette smoke, exposure to vibration, elevated body temperature, or extreme physical exertion. Developing an understanding of NIHL for the purposes of control and prevention is critical to the readiness of military personnel. Current methods of NIHL prevention focus on the development of hearing conservation and prevention programs, which include modification of the noise source, use of protective devices, and, recently, pharmaceutical treatments. However, many of these conventional conservation and prevention programs are not adequate for military purposes as they may hinder communication. Recently, NIHL prevention research has shifted to cellular mechanisms and new avenues for protection through the use of prophylactic otoprotective drugs. CFDRC is working to provide a more detailed mechanistic biological understanding of the effects of noise exposure in order to provide a more intelligent design to drug therapy development.

Quantifying Changes in Neuron Action Potential upon Toxin Exposure
The development of assays specifically for arrays of cells can provide functional cues at the cellular level for a compound’s or gene’s action, immediately providing valuable information as to the action of a particular toxin. However, in studies to date, single neurons have not been integrated with electronic components except in expensive patch-clamp methodology, which can be tedious and kills the cells within 4-8 hours. The drug development and toxicology community would benefit from a system to assay the effect of a compound or protein (or its gene) as it interacts with a cell over a period of time. A promising technology that has been under investigation is the use of neurons for discriminating pathogens and toxins. Neurons exhibit an action potential that can be recorded electronically and integrated with electronic platforms. Action potentials give complex information about the internal / external environment of excitable cells enabling not only detection of an active compound but also the potential to discriminate between compounds with different mechanisms of action. It also allows methods of system science and kinetic analysis, which are important in defining metabolic systems, to be applied to a compound’s toxicity and drug capability as well as gene function that are not available with other methods. CFDRC’s contribution to this effort is to develop computational algorithms and tools to analyze electrophysiological measurements and other signals to infer modulation of cellular processes, given a set of cellular functional categories for classification of unknown toxins.