Recently, it has been reported that neonicotinoid pesticides (NNs) are transferred from mother to child and are assumed to affect the next generation, but the behavioral effects of NN exposure at different developmental stages have not been investigated. We exposed mice to no-observed-adverse-effect level (NOAEL) doses of clothianidin (CLO) during the fetal and lactational period, and then evaluated the neurobehavioral effects in juvenile and adult mice. Significant increases in anxiety-like behavior and locomotor activity were observed in juveniles and adults, respectively, and neuronal activity and neurogenesis in the hippocampal dentate gyrus were affected in both stages. These results suggest that fetal and lactational exposure to CLO may inhibit neurogenesis and cause different behavioral abnormalities at different developmental stages.

Recently, developmental exposure to clothianidin (CLO) has been shown to cause reproductive toxicity in male mice, but the effects in female mice remain to be clarified. Pregnant C57BL/6N mice were given a no-observed-adverse-effect-level (NOAEL) dose of CLO until weaning. We then examined ovaries of 3-or 10-week-old female offspring. In the CLO-administered group, morphological changes, a decrease in the immunoreactivity of the antioxidant enzyme glutathione peroxidase 4 (GPx4), and activation of genes in the steroid hormone biosynthesis pathway were observed in 3-week-old mice, and decreases of GPx4 immunoreactivity, 17OH-progesterone and corticosterone levels were observed in 10-week-old mice, along with high rates of infanticide and severe neglect, providing new evidence that developmental exposure to CLO affects juvenile and adult mice differently.

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Recently, the effects of exposure to clothianidin (CLO) on the thymus and gut microbiota have become clear, but no report has examined its next-generation impacts. Pregnant C57BL/6N mice were administered a no-observed-adverse-effect-level dose of CLO until weaning. We examined CLO's effects on the gut microbiota and immune organs of dams and their 3-and 10-week-old male offspring. CLO administration led to several alterations of the top 30 bacterial genera in the gut microbiota in dams and 3-week-old mice. Compared to controls, 10-week-old mice had more thymic Hassall's corpuscles, and both dams and 10-week-old mice had fewer macrophages. These results suggest that fetal and lactational CLO exposure may affect the immune system and gut microbiota of the next generation.

Neonicotinoid pesticides (NNs) cause behavioral abnormalities in mammals, raising concerns about their effects on neural circuit activity. We herein examined the neurological effects of the NN clothianidin (CLO) by in vivo Ca 2+ imaging using two-photon microscopy. Mice were fed the no-observed-adverse-effect-level (NOAEL) dose of CLO for 2 weeks and their neuronal activity in the primary somatosensory cortex (S1) was observed weekly for 2 weeks. CLO exposure caused a sustained influx of Ca 2+ in neurons in the S1 2/3 layers, indicating hyperactivation of neurons. In addition, microarray gene expression analysis suggested the induction of neuroinflammation and changes in synaptic activity. These results demonstrate that exposure to the NOAEL dose of CLO can overactivate neurons and disrupt neuronal homeostasis.