Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

Abstract

Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.

Sex-Specific Neurotoxic Effects of Organophosphate Pesticides Across the Life Course

“…Sexually dimorphic outcomes in experimental studies of occupational exposure have been virtually ignored (for review see [19]). One study in male and female Wistar rats treated with a single dose of malathion (250 mg/kg) in early adulthood (3 months of age) found decreased hippocampal AChE activity more pronounced in males [114].…”

“…Neurotoxicity resulting from low-dose exposure is thought to occur mainly through non-cholinergic processes that remain unclear, yet proposed mechanisms include cytotoxicity, abnormal neuronal cytoarchitecture, aberrant energy homeostasis and neurotransmission, neuroinflammation, and blood-brain barrier impairment; reviewed in [19]. Such low-dose exposure can begin as early as gestation; OPs can pass through the placenta and amniotic fluid to the fetus [20].…”

Understanding environmental contributions to autism: Causal concepts and the state of science

“…Organophosphates, currently among the most abundantly used insecticides, are acutely toxic due to inhibition of the enzyme acetylcholinesterase (AChE), which breaks down neurotransmitters at the post-synaptic membrane. However, neurodevelopmental and neurologic dysfunction occur at subacute levels, when AChE inhibition is absent, [Voorhees, Rohlman, Lein, & Pieper, 2016]. Hence other toxic mechanisms are at play and potentially relevant for gestational exposures in early brain development, including inflammation, GABA signaling, thyroid disruption, oxidative stress and mitochondrial dysregulation [Banks & Lein, 2012;Schuh, Lein, Beckles, & Jett, 2002;Shelton, Hertz-Picciotto, & Pessah, 2012;Voorhees et al, 2016].…”

Malathion Neurotoxic Effects on Dopaminergic System in Mice: Role of Inflammation

“…It is worthy-mentioning that prolonged low level OPs exposure is not only limited to occupational settings, but also includes living with those occupationally exposed, living near OPs manufacturing and application sites or ingesting contaminated food [4].…”

“…The exact clinical phenotyping of OPs-induced chronic neurotoxicity has been an area of debate with different suggested mechanisms [9,10]. increased risk of cognitive deficits and neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease, and amyotrophic lateral sclerosis [4,11,12]. …”