Effects of low-dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

Objectives: Exposure to chlorpyrifos (CPF), a neurotoxic insecticide, is implicated with adverse neurodevelopmental effects in children through noncholinergic mechanisms.

Methods: This review presents qualitative and quantitative evidence in three animal models (rodent, zebrafish, and Caenorhabditis elegans), for neurodevelopmental and behavioral effects occurring at CPF doses lower than those inhibiting acetylcholinesterase (AChE).

Results: CPF treatment in rodents at low noncholinergic doses during neurodevelopment showed behavioral effects, including locomotor activity, neuromotor function (NMF), cognition, anxiety, social behavior, and maternal care. Zebrafish and C. elegans, which are transparent during development, allow for detailed analysis of specific systems; further, they exhibit neurotoxic effects closely emulating those observed in mammalian pathways. Qualitative results showed concordance among rodents, zebrafish and C. elegans for adverse effects on locomotor activity, NMF, and AChE inhibition. Male rodents had greater sensitivity for effects on locomotor activity than females and exposure during the gestation day 10-14 window showed consistent increases in locomotor activity at low CPF doses (≤1.0 mg kg^-1 day^-1 ). Zebrafish had cognitive and anxiety deficits after CPF treatment at low doses and young adult C. elegans had reproductive dysfunction associated NMF and disruption of the serotonergic pathway. Quantitative data for all three species showed neurobehavioral effects after exposure to CPF doses approximately 2-10-fold below the threshold for AChE inhibition.

Conclusions: Taken together, these findings provided a weight-of-evidence for low-dose CPF neurotoxicity and noncholinergic mechanisms. Variability in laboratories, exposure methods, tests, sex, and animal species/strain might have contributed to the inconsistent results. The detrimental CPF effects during early development are relevant to human populations.

C. elegans; acetylcholinesterase; chlorpyrifos; neurobehavior; neurodevelopment; zebrafish.