Long-term effects of subchronic exposure to sarin, alone and with stress or other chemicals

Abstract

Abstract : The major objective of this proposal is to investigate the consequences of long-term, low- level exposure to sarin, alone, and in combination with pyridostigmine bromide (PB) and stress on the development of chronic and neurologic deficits. An important finding from our studies is that brain AChE and plasma BChE inhibition might be used as a biomarker for exposure, not for sarin-induced neurologic deficits. Rats treated with toxic doses of sarin showed inhibition of brain and plasma cholinesterases, that subsequently recovered. On the other hand, these animals exhibited sensorimotor deficit that persisted throughout the six-month observation period. Another significant result from our studies is that a brief insult from a single lethal or sub-lethal dose of sarin, can generate a series of events to result in a diffuse neuronal cell death. Neuronal degeneration was exhibited in the cerebral cortex, the hippocampus, and Purkinje cell neurons in the cerebellum. Stress, caused by immobilization or heat also exacerbated sarin-induced neurotoxicity. The results show that prophylactic treatment with PB offered some protection of peripheral AChE against sarin inhibition. On the other hand, PB exacerbated the toxicity of high doses of sarin. Furthermore, the results showed that treatment with either sarin or PB alone resulted in sensorimotor impairments that persisted throughout the six-month observation period. Neuronal cell death of the motor cortex and Purkinje cells of the cerebellum following exposure to sarin could lead to weakness and loss of strength as well as problems with gait and coordination of movement. Further, disruption of hippocampal circuitry due to degeneration of neurons in different subfields can lead to learning and memory deficits.