Acetylcholinesterase Inhibition Leading to Neurodegeneration

Kendra Conrow (a)

Dennis Sinitsyn (a)

Natalia Garcia-Reyero (c)

Karen H. Watanabe (a)

(a) Arizona State University

(b) IDAEA-CSIC

(c) US Army Corps of Engineers, Engineering Research and Development Center

The enzyme acetylcholinesterase (AChE) hydrolyzes acetylcholine (ACh) in order to eliminate it from the body.  When AChE is inhibited ACh levels increase. An excess of ACh at cholinergic synapses overstimulates both muscarinic- and nicotinic- receptors (1,2). These receptors are found in most organs in the body, thus the effects of AChE inhibition can result in multiple adverse outcomes affecting a wide variety of functions (1). This AOP focuses upon an acute outcome of neurodegeneration due to AChE inhibition specifically through calcium dysregulation as that has been identified as central to the development of the most severe phenotype caused by acute organophosphate poisoning (3).

1. United States., Environmental Protection Agency., Office of Pesticide Programs. (2000). The Use of Data on Cholinesterase Inhibition for Risk Assessments of Organophosphorous and Carbamate Pesticides. https://www.epa.gov/sites/production/files/2015-07/documents/cholin.pdf accessed Nov. 2018.

2. Quick, M. W., & Lester, R. A. J. (2002). Journal of Neurobiology, 53(4), 457-478. doi:10.1002/neu.10109.

3. Faria et al. (2015). Scientific Reports, 5. doi:10.1038/srep15591.

Epidemiological studies concerning OP pesticides estimated approximately 3 million cases of acute severe poisoning, as well as 300,000 deaths annually. Most of those deaths occur in developing countries of the Asia-Pacific region (Bertolote et al., 2006). These OP compounds can also be used as chemical warfare nerve agents. The improper use of OP chemicals has tragic consequences such as neurodegeneration, brain damage, and death underscoring the need for safety measures that protect both human health and the environment.

Bertolote, J. M., Fleischmann, A., Eddleston, M. & Gunnell, D. 2006. Deaths from pesticide poisoning: A global response. British Journal of Psychiatry, 189, 201-203. DOI: 10.1192/bjp.bp.105.020834.

Construction of AOP 281 started from the bottom up, and involved searching the literature and consultation with experts in neuroscience.  Extensive literature searches were conducted in Scopus and Pubmed using keywords such as, “acetylcholinesterase inhibition”, “muscarinic acetylcholine receptor”, “calcium dysregulation”, “organophosphate”, “glutamate”, and “cell death” with an initial focus on zebrafish data.  Over 300 papers were reviewed and categorized by whether they contained data to support one or more parts of the AOP.  An Excel spreadsheet was used to record reviewed papers and which part(s) of the AOP they supported.

AOP 281 was developed primarily by the authors and experts in this publication, except when existing KEs or KERs are used in the AOP.  These existing KEs and KERs have additional authors who are not explicitly cited herein. Three KEs of the 10 in AOP 281 (including the MIE and AO as key events), and eight KERs of eleven were developed specifically for this AOP.  The remaining KEs and KERs were modified accordingly to include additional data specific for AOP 281.