Premature aging and neuropathic behaviours induced by an acute low-dose exposure to a sarin surrogate

Abstract

Acute poisoning from organophosphorus (OP) compounds induced a cholinergic toxidrome. Neurological complications may manifest weeks after the initial exposure, including muscle weakness and progressive loss of sensitivity. These symptoms may be analogous to those observed in elderly individuals. However, the delayed neurological impact of OP exposure has received limited attention and remains an under-explored area of research. The present study investigated the long-term effects of OP exposure on the sensorimotor system using a mouse model exposed to a sublethal dose of a sarin surrogate. The mice received a 0.5 LD50 dose of 4-nitrophenyl isopropylmethylphosphonate (NIMP), and were observed for a period of six months. Our results demonstrate that NIMP exposure induced a mild intoxication severity in mice, without affecting weight evolution. Behavioral evaluation, using locomotor and sensory tests, revealed that mice exhibited persistent muscle weakness and an increase in mechanical sensitivity. Six months after NIMP exposure, acetylcholinesterase activity remained inhibited in specific regions of the cerebral cortex, while the spinal cord exhibited a return to normal values. Positron emission tomography scans and microcomputed tomography imaging revealed alterations in cerebral glucose metabolism and bone density. Luminex multiplex immunoassay analyses revealed an increase in specific biomarkers of aging. The present study demonstrates that a sublethal dose of NIMP triggered premature aging phenotype, resulting in long-term sensorimotor impairments, neurometabolic and cellular disturbances. These findings underscore the importance of identifying intoxication hallmarks, even in cases of asymptomatic OP exposure.

Keywords: Aging; Behavior; Bone density; Inflammation; Organophosphorus; PET; Signaling pathways.