Sex-specific behavioral effects of acute exposure to the neonicotinoid clothianidin in mice

Shizuka Kubo; Tetsushi Hirano; Yuka Miyata; Shuji Ohno; Kanoko Onaru; Yoshinori Ikenaka; Shouta M M Nakayama; Mayumi Ishizuka; Youhei Mantani; Toshifumi Yokoyama; Nobuhiko Hoshi

doi:10.1016/j.taap.2022.116283

Sex-specific behavioral effects of acute exposure to the neonicotinoid clothianidin in mice

Toxicol Appl Pharmacol. 2022 Dec 1:456:116283. doi: 10.1016/j.taap.2022.116283. Epub 2022 Oct 14.

Authors

Affiliations

¹ Laboratory of Animal Molecular Morphology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai, Nada, Kobe, Hyogo 657-8501, Japan.
² Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: thirano@cts.u-toyama.ac.jp.
³ Translational Research Unit, Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan; Water Research Group, Unit for Environmental Sciences and Management, North-West University, Potchefstroom, South Africa; One Health Research Center, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan; Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan.
⁴ Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan; School of Veterinary Medicine, The University of Zambia, Zambia.
⁵ Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan.
⁶ Laboratory of Histophysiology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai, Nada, Kobe, Hyogo 657-8501, Japan.

PMID: 36252886
DOI: 10.1016/j.taap.2022.116283

Abstract

Although neonicotinoids are among the major classes of pesticides that affect mammalian nervous systems, little is known about sex differences in their effects. This study aimed to examine whether the neurobehavioral effects of a neonicotinoid, clothianidin (CLO), differed between sexes. Male and female C57BL/6N mice were orally administered CLO (5 or 50 mg/kg) at or below the chronic no-observed-adverse-effect-level (NOAEL) and subjected to behavioral tests of emotional and learning functions. Changes in neuroactivity in several brain regions and the concentrations of CLO and its metabolites in blood and urine were measured. Acute CLO exposure caused sex-related behavioral effects; decreases in locomotor activities and elevation of anxiety-like behaviors were more apparent in males than in females. In addition, male-specific impairment of short- and long-term learning memory by CLO exposure was observed in both the novel recognition test and the Barnes maze test. Male-dominant increases in the number of c-fos positive cells were observed in the paraventricular thalamic nucleus in the thalamus and in the dentate gyrus in the hippocampus, which are related to the stress response and learning function, respectively. The concentrations of CLO and most metabolites in blood and urine were higher in males. These results support the notion that male mice are more vulnerable than females to the neurobehavioral effects of CLO and provide novel insights into the risk assessment of neonicotinoids in mammalian neuronal function.

Keywords: Behavior; Clothianidin; Learning Memory; Neonicotinoid; Sex Difference.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Guanidines / toxicity
Insecticides* / toxicity
Male
Mammals
Mice
Mice, Inbred C57BL
Neonicotinoids / toxicity

Substances

clothianidin
Insecticides
Neonicotinoids
Guanidines