Neurotoxicity in acute and repeated organophosphate exposure

Abstract

The term organophosphate (OP) refers to a diverse group of chemicals that are found in hundreds of products worldwide. As pesticides, their most common use, OPs are clearly beneficial for agricultural productivity and the control of deadly vector-borne illnesses. However, as a consequence of their widespread use, OPs are now among the most common synthetic chemicals detected in the environment as well as in animal and human tissues. This is an increasing environmental concern because many OPs are highly toxic and both accidental and intentional exposures to OPs resulting in deleterious health effects have been documented for decades. Some of these deleterious health effects include a variety of long-term neurological and psychiatric disturbances including impairments in attention, memory, and other domains of cognition. Moreover, some chronic illnesses that manifest these symptoms such as Gulf War Illness and Aerotoxic Syndrome have (at least in part) been attributed to OP exposure. In addition to acute acetylcholinesterase inhibition, OPs may affect a number of additional targets that lead to oxidative stress, axonal transport deficits, neuroinflammation, and autoimmunity. Some of these targets could be exploited for therapeutic purposes. The purpose of this review is thus to: 1) describe the important uses of organophosphate (OP)-based compounds worldwide, 2) provide an overview of the various risks and toxicology associated with OP exposure, particularly long-term neurologic and psychiatric symptoms, 3) discuss mechanisms of OP toxicity beyond cholinesterase inhibition, 4) review potential therapeutic strategies to reverse the acute toxicity and long term deleterious effects of OPs.

Keywords: Aerotoxic syndrome; Agriculture; Cholinesterase inhibitor; Gulf war illness; Memory; Pesticide.

Fig 1.

Illustration of several representative sources of toxic exposures to OPs by humans and other non-target species. A. OP exposures in the agricultural setting, which may come from insecticides, anthelmintics, fungicides, and herbicides. B. OP exposures from terrorist attacks and chemical warfare assaults by rogue governments. C. Exposures as a result of “fume events” where the cabin air of an airplane can be contaminated with heated engine oil fumes that contain OPs. D. Exposures from insecticides used by public health officials to combat vector borne illnesses.

Fig 2.

Illustration of several representative physiological processes that may be affected by OPs to result in long-term deleterious health effects. A. OPs may impair axonal transport by altering the function of motor proteins such as kinesin and/or components of the neuronal cytoskeleton (e.g., microtubules). B. OPs can increase free radical formation and oxidative stress, which can lead to mitochondrial dysfunction and DNA damage to cells. C. OPs can lead to microglia activation and an increase in proinflammatory cytokines, which in turn may lead to neuroinflammation. D. OP exposure may lead to the generation of autoantibodies that target multiple proteins known to play important roles in both the structure and function of neurons including myelination and axonal transport.