Delayed Reduction of Hippocampal Synaptic Transmission and Spines Following Exposure to Repeated Subclinical Doses of Organophosphorus Pesticide in Adult Mice

Abstract

Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2-7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2-7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo.

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

“…It was concluded that CPF and CPO decrease axonal growth by interfering with the morphogenic activity of AChE. In support of these findings, Speed et al (2012) demonstrated that CPF decreased dendritic spine density in vivo following 5 days of exposure at 5 mg/kg/d, levels that inhibited hippocampal AChE by <10% after a single injection and by approximately 40% after 5 injections. Spine density was unaffected by CPF exposure when examined 1 week later.…”

“…Changes in length, number, or branching patterns of axons or dendrites have been linked to psychiatric manifestations in patients, including depression, anxiety, AD, and PD (Marsden, 2013; Rubia et al, 2014; Canu et al, 2015; Negrón-Oyarzo et al, 2016). Axonal length, neurite length, neurite number, and dendritic branching in neuronal culture systems have also been shown to be altered following exposure to a variety of OPs, including CPF (Howard et al, 2005; Yang et al, 2008; Speed et al, 2012), DZ (Pizzurro et al, 2014a,b), parathion (Yousefpour et al, 2006; Berríos et al, 2015), and T O CP (Chen et al, 2013; Duarte et al, 2016; Hausherr et al, 2016). For example, in primary cultures of sympathetic neurons, CPF inhibited axon outgrowth but promoted dendritic arborization (Howard et al, 2005).…”

Trends in brain cancer mortality among U.S. Gulf War veterans: 21 year follow-up

“…Both human (Gulf War veteran populations) and animal studies have reported neurological outcomes associated with the exposures present during Gulf War deployment, including neuro-inflammation [16], changes in brain volume [17], hippocampal dysfunction [18,19], decreased white matter [7,9,20] and alterations in executive function and cognition [21,22]. …”

Impact of Exposure to Fenitrothion on Vital Organs in Rats

“…In addition, symptoms of chronic OPs toxicity vary between headache, sweating, Parkinson's, alterations in memory, and psychiatric or neuropsychological dysfunction [15, 16]. In addition, the key findings of OPs toxicity in respiratory system include shortness of breath and rapidly progressive bradypnea leading to apnea due to loss of central inspiratory drive causing central failure of breathing [17].…”