Table 2.
Non-Cholinesterase Targets of OPs and Downstream Effects
| Target | Description/Function | Reference(s) |
|---|---|---|
| Neuroinflammation | Cytokines mediate a variety of inflammatory processes (IL-6, IL-1β, CCL2). |
Koo et al., 2018, Mohammadzadeh et al., 2018 |
| Oxidative Stress | Process by which reactive oxygen species are generated in excess or improperly cleared to cause widespread cell damage. | Eftekhari et al., 2018, Abolaji et al., 2017 |
| Gene Expression | Changes in gene expression can occur throughout all biological systems in virtually all cell types. Pathological changes in gene expression have been associated with a wide array of disorders. | Moyano et al., 2017, Savy et al., 2018, Lee et al., 2016 |
| Autoimmunity | Formation of autoantibodies that target proteins, especially those known to play important roles in the structure and function of neurons including myelination and axonal transport (e.g., MBP, NFP, Tau, MAP-2) |
Abou-Donia et al., 2013; AbouDonia et al., 2017; El-Rahman et al., 2018 |
| Mitochondria | Organelle responsible for ATP production. Changes in transport and morphology can affect function. Also associated with the release of apoptotic factors. | Middlemore-Risher et al 2011, Eftekhari et al., 2018 |
| Gut Microbiome | Large group of bacteria found in the gut existing in symbiosis with the host. Implicated in a wide range of functions and downstream effects ranging from immune function to cognitive development. | Gao et al., 2017 |
| DNA | DNA Damage (i.e. fragmentation, single and double strand breaks) is associated with carcinogenic and reproductive toxicity | Li et al., 2015 |
| Dynactin | Modulates the binding of cargoes to molecular motor proteins (dynein and kinesin-2) | Song et al., 2012 |
| Dynein | Motor protein responsible for retrograde axonal transport. | Song et al., 2012 |
| Tubulin | Globular proteins that polymerize into microtubules (i.e., α- and β-tubulin assemblies which serve structural roles in the cytoskeleton, support intracellular transport, mitosis, etc.). | Jiang et al., 2010 |
| Transferrin | Plasma glycoprotein that regulates iron levels. | Grigoryan et al., 2009 |
| Kinesin | Motor protein responsible for anterograde axonal transport in neurons as well as other cellular functions such as mitosis, meiosis, etc. | Grigoryan et al., 2009 |
| ATP Synthase | Enzyme responsible for ATP synthesis in mitochondria. | Grigoryan et al., 2009 |
| Nerve Growth Factor (NGF) and its receptors TrkA and P-75NTR |
NGF-Neurotrophin associated with survival, growth, and proliferation in neurons. TrkA-high affinity NGF receptor responsible for mediating neurotrophic effects of NGF. P-75NTR-low affinity neurotrophin receptor, which mediates apoptosis and cell death. | Terry et al., 2011 |
| Choline acetyltransferase (ChAt) |
Enzyme important for the synthesis of acetylcholine. | Terry et al., 2007, 2011 |
| α7-nicotinic acetylcholine receptors (nAChRs) | Acetylcholine receptor with known role in learning and memory. | Terry et al., 2007, 2011 |
| Butyrylcholinesterase | Serine hydrolase which nonspecifically hydrolyzes choline-based esters. | Li et al., 2007 |
| Monoacylglycerol lipase | Responsible for 2-AG hydrolysis in endocannabinoid inactivation. | Quistad et al, 2006, Reviewed Casida et al.,2008 |
| Serine Hydrolase KIAA 1363 |
Regulates lipid metabolism, involved with the invasiveness of tumors. | Nomura et al., 2006, Reviewed Casida et al.,2008 |
| Albumin | Globular protein responsible for transport | Peeples et al., 2005 |
| Cannabinoid CB1 receptors | G protein-coupled receptors, which mediate endocannabinoid signaling. | Quistad et al., 2002 |
| Fatty acid amide hydrolase | Serine hydrolase enzyme that catabolizes a class of bioactive lipids called the fatty acid amides, traditionally associated with endocannabinoid catabolism. | Quistad et al., 2001 |
| M2 muscarinic acetylcholine receptors | Second messenger coupled autoreceptor, modulates acetylcholine signaling. | Bomser and Casida 2001* |
| Acylpeptide hydrolase | Serine protease enzyme that catalyzes the removal of N-acylated amino acids from acetylated peptides, this plays a role in the coordinated protein-degradation | Richards et al., 2000 |
| Adenylyl cyclase | Enzyme that is required for the conversion of ATP to cyclic AMP/Important in the G protein signaling cascade |
Huff et al., 1994; Song et al., 1997; Auman et al., 2000 |
| Neuropathy target esterase | Phospholipase enzyme with known role in phospholipid metabolism, neurite outgrowth and process elongation during neuronal differentiation. | Lush et al., 1998 |
| Papain | Lysozomal cysteine protease. | Chaiken and Smith, 1969 |
*
OP-phosphorylation of M2 receptors was initially reported by Bomser and Casida 2001 (using chlorpyrifos oxon), but was not observed in experiments where paraoxon or a biotinlabeled fluorophosphonate were evaluated (Proskocil et al., 2010)