Neurotoxicity and behavioral disorders induced in mice by acute exposure to the diamide insecticide chlorantraniliprole

Diamide insecticides activate ryanodine receptors expressed in lepidopteran skeletal muscle and promote Ca²⁺ release in the sarcoplasmic reticulum, causing abnormal contractions and paralysis, leading to death of the pest. Although they had been thought not to act on nontarget organisms, including mammals, adverse effects on vertebrates were recently reported, raising concerns about their safety in humans. We investigated the neurotoxicity of the acute no-observed-adverse-effect level of chlorantraniliprole (CAP), a diamide insecticide, in mice using clothianidin (CLO), a neonicotinoid insecticide, as a positive control. The CLO-administered group showed decreased locomotor activities, increased anxiety-like behaviors, and abnormal human-audible vocalizations, while the CAP-administered group showed anxiety-like behaviors but no change in locomotor activities. The CAP-administered group had greater numbers of c-fos–immunoreactive cells in the hippocampal dentate gyrus, and similar to the results in a CLO-administered group in our previous study. Blood corticosterone levels increased in the CLO-administered group but did not change in the CAP-administered group. Additionally, CAP was found to decreased 3-Methoxytyramine and histamine in mice at the time to maximum concentration. These results suggest that CAP-administered mice are less vulnerable to stress than CLO-administered mice, and the first evidence that CAP exposure increases neuronal activity and induces anxiety-like behavior as well as neurotransmitter disturbances in mammals.