Comparative in vitro and in vivo effects of chlorpyrifos oxon in the outbred CD-1 mouse (Mus musculus) and great plains toad (Anaxyrus cognatus).

We compared biochemical, functional, and behavioral responses to the organophosphorus anticholinesterase chlorpyrifos oxon (CPO) in mice (Mus musculus, CD-1) and toads (Anaxyrus cognatus, Great Plains toad). Toads were substantially less sensitive to acute lethality of CPO based on the maximum tolerated (nonlethal) dose (toads, 77 mg/kg; mice, 5.9 mg/kg). Sublethal exposures led to classical signs of toxicity (increased involuntary movements, autonomic secretions) in mice but hypoactivity in toads. Motor performance in an inclined plane test was not affected by CPO in mice but was altered at the highest dosage in toads. Acetylcholinesterase (AChE), butyrylcholinesterase, monoacylglycerol lipase, and fatty acid amide hydrolase activities in brain were inhibited in mice but not in toads, and fatty acid amide hydrolase activity in the liver was inhibited in both species. Toad brain AChE was less sensitive to in vitro inhibition by CPO (50% inhibitory concentration [IC50; 20 min, 37 °C], 101 vs 7.8 nM; IC50 [20 min, 26 °C], 149 vs 6.2 nM), and studies of inhibitor kinetics indicated substantially lower anticholinesterase potency of CPO against the toad brain enzyme. Using an in vitro indirect inhibition assay, preincubation of CPO with toad brain homogenate was more effective than an equivalent mouse brain homogenate at reducing CPO potency. These data suggest that the relatively low sensitivity of toads to cholinergic toxicity is based on the low sensitivity of brain AChE, which in turn may be attributable to more effective target-site detoxification. Environ Toxicol Chem 2018;37:1898-1906.