Brain acetylcholinesterase

Following acute oral toxicity from dosages ranging from 14 to 80 mg/kg, laboratory rats had earlier recovery of brain acetylcholinesterase levels than did feral cotton rats. Similar results were seen in a comparison of laboratory mice to feral mice (Roberts et al. 1988). 

Pope et al. (1991) found that 7-day-old Sprague-Dawley rat pups were approximately twice as sensitive as 80-100-day-old adults to single subcutaneous doses of methyl parathion the highest nonlethal dose 7.8 mg/kg for the neonates and 18.0 mg/kg for adults. Initially, both neonates and adults exhibited similarly reduced brain acetylcholinesterase activity levels (approximately 10% that of controls) ... 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Roberts DK, Silvey NJ, Bailey EM Jr. 1988. Brain acetylcholinesterase activity recovery following acute methyl parathion intoxication in two feral rodent species comparison to laboratory rodents. Bull Environ Contam Toxicol 41 26-35. 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

Morgan, M.J., Fancey, L.L., and Kiceniuk, J.W. (1990). Response and Recovery of Brain Acetylcholinesterase Activity in Atlantic Salmon (Sahno-Salar). Exposed to Fenitrothion. Canadian Journal of Fisheries and Aquatic Sciences 47, 1652-1654. 

Sancho, E., Ferrando, M.D., and Andreu, E. (1997). Response and recovery of brain acetylcholinesterase activity in the European eel, Anguilla anguilla, exposed to fenitrothion. Ecotoxicology and Environmental Safety 38, 205-209. 

Similar results were also observed in a two-generation reproductive study using brown Ranch Wild mink that ingested 0, 16, 45, or 262 mg/kg/day (males) or 0, 20, 57, or 330 mg/kg/day (females) (Bucci et al. 1997). No changes in brain acetylcholinesterase were observed in either the Fj or F2 offspring. 

Consistent decreases in plasma cholinesterase may not have been observed in rats and dogs because they were treated with lower doses of diisopropyl methylphosphonate. In general, depression of plasma cholinesterase, also known as pseudocholinesterase or butyrylcholinesterase, is considered a marker of exposure rather than an adverse effect. Depression of cholinesterase activity in red blood cells (acetylcholinesterase) is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity. It is considered an adverse effect. Acetylcholinesterase is found mainly in nervous tissue and erythrocytes. Diisopropyl methylphosphonate was not found to inhibit RBC... 

Although this study (Hart 1980) did not identify an effect level, the NOAEL is below the LOEL found in all studies examining the toxicity of diisopropyl methylphosphonate. The LOEL for diisopropyl methylphosphonate is 262 mg/kg/day for male mink and 330 mg/kg/day for female mink (Bucci et al. 1997), doses at which statistically significant decreases in plasma cholinesterase (butyrylcholinesterase) but not RBC cholinesterase (acetylcholinesterase) activity were observed (Bucci et al. 1997). In general, a decrease in plasma cholinesterase activity is considered to be a marker of exposure rather than a marker of adverse effect, while a decrease in RBC acetylcholinesterase activity is a neurological effect thought to parallel the inhibition of brain acetylcholinesterase activity and is thus considered an adverse effect. Diisopropyl methylphosphonate was not found to inhibit red blood cell cholinesterase at doses at which plasma cholinesterase was significantly inhibited. No effects were observed in males at 45 mg/kg/day (Bucci et al. 1997) or at 63 mg/kg/day (Bucci et al. 1994), and no effects were observed in females at 82 mg/kg/day (Bucci et al. 1994), or at 57 mg/kg/day (Bucci et al. 1997). 

Richardson RJ, Moore TB, Kayyali US, et al. 1993. Chlorpyrifos Assessment of potential for delayed neurotoxicity by repeated dosing in adult hens with monitoring of brain acetylcholinesterase, brain and lymphocyte neurotoxic esterase, and plasma butyrylcholinesterase activities. Fundam Appl Toxicol 21 89-96. 

Thakkar, M. Mallick, B. N. (1991). Effect of REM sleep deprivation on rat brain acetylcholinesterase. Pharmacol Biochem. Behav. 39, 211-14. 

A decrease in brain acetylcholinesterase activity in rats (Gietzen and Wooley 1984). 

Solar-Rodriguez, F., M-P. Miguez-Santiyan, A. Reja-Sanchez, V. Roncero-Cordero, and J.-P. Garcia-Cambero. 1998. Recovery of brain acetylcholinesterase and plasma cholinesterase activities in quail (Cotumix cotumix) after chlorpyrifos administration and effect of prahdoxime treatment. Environ. Toxicol. Chem. 17 1835-1839. 

Goodman, L.R., D.J. Hansen, D.L. Coppage, J.C. Moore, and E. Matthews. 1979. Diazinon chronic toxicity to, and brain acetylcholinesterase inhibition in, the sheepshead minnow, Cyprinodon variegatus. Trans. Amer. Fish. Soc. 108 479-488. 

Di Marzio, W.D. and M.C. Tortorelli. 1993. Acute toxicity of paraquat and no-inhibitory chronic effect on brain acetylcholinesterase activity of freshwater fish Bryconamericus iheringii (Pisces, Characidae). Jour. Environ. Sci. Health 28B 701-709. 

Disulfoton has also been studied for behavioral effects. Rats fed >0.5 mg/kg/day disulfoton for 90 days had significantly depressed brain acetylcholinesterase levels (59-74% below control), but the treated rats had shorter maze running times and made fewer mistakes than the controls (Clark and... 

Because cholinesterase inhibition is a very sensitive biomarker for other chemicals, it is not always conclusive evidence of disulfoton exposure. However, depression of cholinesterase activity can alert a physician to the possibility of more serious neurological effects. Erythrocyte acetylcholinesterase activity more accurately reflects the degree of synaptic cholinesterase inhibition in nervous tissue, while serum cholinesterase activity may be associated with other sites (Goldfrank et al. 1990). In addition, a recent study showed that after rats received oral doses of disulfoton for 14 days, acetylcholinesterase levels in circulating lymphocytes correlated better with brain acetylcholinesterase activity than did erythrocyte cell cholinesterase activities during exposure (Fitzgerald and Costa 1993). However, recovery of the activity in lymphocytes was faster than the recovery of activity in the brain, which correlated better with the activity in erythrocytes. Animal studies have also demonstrated that brain acetylcholinesterase depression is a sensitive indicator of neurological effects (Carpy et al. 1975 Costa et al. 1984 Schwab and Murphy 1981 Schwab et al. 1981, 1983) however, the measurement of brain acetylcholinesterase in humans is too invasive to be practical. 

Pan, G. and Dutta, H.M. The inhibition of brain acetylcholinesterase activity of juvenile largemouth bass Micropterus salmoideshy sublethal concentrations of diazinon. Environ. Res., 79(2) 133-137, 1998. 

J.O. Rinne, V. Kaasinen, T. Jarvenpaa, K. Nagren, A. Roivainen, M. Yu, V. Oikonen, T. Kurki, Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer s disease, J. Neurol. Neurosurg. Psychiatry 74 (2003) 113-115. 

In dogs poisoned with soman (Intravenously at 30 pg/kg) and treated with I at 104 mg/kg (Intravenously 31/2 min after soman), the large dose of I stopped aging of Inhibited cholinesterase and reactivated 24.0% and 35.6% of the red-cell and diaphragm cholinesterase activities, respectively. It failed to reactivate brain cholinesterase. Indeed, the brain acetylcholinesterase activity after the treatment with 1 was lower than that just before the injection of I. The last finding indicates the inability of I to cross the blood-brain barrier in significant quantities. 

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