Developmental synapse pathology triggered by maternal exposure to the herbicide glufosinate ammonium

Hironori Izumi; Maina Demura; Ayako Imai; Ryohei Ogawa; Mamoru Fukuchi; Taisaku Okubo; Toshihide Tabata; Hisashi Mori; Tomoyuki Yoshida

doi:10.3389/fnmol.2023.1298238

Developmental synapse pathology triggered by maternal exposure to the herbicide glufosinate ammonium

Front Mol Neurosci. 2023 Nov 30:16:1298238. doi: 10.3389/fnmol.2023.1298238. eCollection 2023.

Authors

Hironori Izumi^{1

2}, Maina Demura¹, Ayako Imai^{1

2}, Ryohei Ogawa³, Mamoru Fukuchi⁴, Taisaku Okubo⁵, Toshihide Tabata⁵, Hisashi Mori^{1

2

6}, Tomoyuki Yoshida^{1

2}

Affiliations

¹ Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama, Japan.
² Research Center for Idling Brain Science, University of Toyama, Toyama, Japan.
³ Department of Radiology, Faculty of Medicine, University of Toyama, Toyama, Japan.
⁴ Laboratory of Molecular Neuroscience, Faculty of Pharmacy, Takasaki University of Health and Welfare, Gunma, Japan.
⁵ Laboratory for Biological Information Processing, Faculty of Engineering, University of Toyama, Toyama, Japan.
⁶ Research Center for Pre-Disease Science, University of Toyama, Toyama, Japan.

Abstract

Environmental and genetic factors influence synapse formation. Numerous animal experiments have revealed that pesticides, including herbicides, can disturb normal intracellular signals, gene expression, and individual animal behaviors. However, the mechanism underlying the adverse outcomes of pesticide exposure remains elusive. Herein, we investigated the effect of maternal exposure to the herbicide glufosinate ammonium (GLA) on offspring neuronal synapse formation in vitro. Cultured cerebral cortical neurons prepared from mouse embryos with maternal GLA exposure demonstrated impaired synapse formation induced by synaptic organizer neuroligin 1 (NLGN1)-coated beads. Conversely, the direct administration of GLA to the neuronal cultures exhibited negligible effect on the NLGN1-induced synapse formation. The comparison of the transcriptomes of cultured neurons from embryos treated with maternal GLA or vehicle and a subsequent bioinformatics analysis of differentially expressed genes (DEGs) identified "nervous system development," including "synapse," as the top-ranking process for downregulated DEGs in the GLA group. In addition, we detected lower densities of parvalbumin (Pvalb)-positive neurons at the postnatal developmental stage in the medial prefrontal cortex (mPFC) of offspring born to GLA-exposed dams. These results suggest that maternal GLA exposure induces synapse pathology, with alterations in the expression of genes that regulate synaptic development via an indirect pathway distinct from the effect of direct GLA action on neurons.

Keywords: developmental neurotoxicity; glufosinate ammonium; maternal pesticide exposure; synapse formation; synaptic organizers.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by JSPS KAKENHI Grant Numbers JP19K19407, JP20H03350, JP21H00190, JP23H02585, and JP23K09644, Toyama University President’s Discretionary Fund 2018 and 2022, and the FIRSTBANK of Toyama Scholarship Foundation Research Grant.