Combined exposure to dinotefuran and chronic mild stress counteracts the change of the emotional and monoaminergic neuronal activity induced by either exposure singly despite corticosterone elevation in mice

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  • TAKADA Tadashi
    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
  • YONEDA Naoki
    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
  • HIRANO Tetsushi
    Division of Drug and Structural Research, Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
  • ONARU Kanoko
    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
  • MANTANI Youhei
    Laboratory of Histophysiology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai, Nada, Kobe, Hyogo 657-8501, Japan
  • YOKOYAMA Toshifumi
    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
  • KITAGAWA Hiroshi
    Laboratory of Histophysiology, Department of Animal Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai, Nada, Kobe, Hyogo 657-8501, Japan
  • TABUCHI Yoshiaki
    Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
  • NIMAKO Collins
    Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
  • ISHIZUKA Mayumi
    Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
  • IKENAKA Yoshinori
    Laboratory of Toxicology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita 18, Nishi 9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
  • HOSHI Nobuhiko
    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

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Abstract

<p>Dinotefuran (DIN) belongs to the neonicotinoids (NNs), a class of globally applied pesticides originally developed to exhibit selective toxicity in insects. However, several reports have suggested that NNs also exert neurotoxic effects in mammals. We previously demonstrated neurobehavioral effects of DIN on mice under non-stressful conditions. For further toxicity assessments in the present study, we investigated the effects of DIN on mice exposed to stressful conditions. After subacutely administering a no-observed-effect-level (NOEL) dose of DIN and/or chronic unpredictable mild stress (CUMS) to mice, we conducted three behavioral tests (i.e., open field test [OFT], tail suspension test [TST] and forced swimming test [FST]). In addition, serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) of the dorsal raphe nuclei (DRN) and median raphe nuclei (MRN) and tyrosine hydroxylase (TH) of the ventral tegmental area and substantia nigra (SN) were evaluated immunohistochemically. A NOEL dose of DIN or CUMS alone increased of the total distance in OFT, decreased or increased the immobility time in TST or FST, respectively, and increased the positive intensity of 5-HT and TPH2 in the DRN/MRN, and TH in the SN. These changes were suppressed under the conditions of combined exposure to DIN and CUMS, though the blood corticosterone level was increased depending on the blood DIN values and the presence of CUMS. The present study suggests the multifaceted toxicity of the neurotoxin DIN.</p>

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