Elsevier

Neuroscience Letters

Volume 730, 21 June 2020, 135032
Neuroscience Letters

Research article
Glyphosate exposure exacerbates the dopaminergic neurotoxicity in the mouse brain after repeated administration of MPTP

https://doi.org/10.1016/j.neulet.2020.135032Get rights and content

Highlights

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    The herbicide glyphosate has been used widely in the world.

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    Exposure of glyphosate potentiated MPTP-induced dopaminergic neurotoxicity in the mouse brain.

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    Glyphosate exposure may be an environmental risk factor for Parkinson’s disease.

Abstract

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder. Epidemiological studies suggest that the exposure of the herbicide glyphosate may influence the development of PD in humans. In this study, we examined whether the exposure of glyphosate can affect the reduction of dopamine transporter (DAT) in the striatum and tyrosine hydroxylase (TH) in the substantial nigra (SNr) of mouse brain after repeated administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Repeated injections of MPTP (10 mg/kg × 3, 2-h interval) significantly decreased the density of DAT-immunoreactivity in the striatum and the number of TH-immunoreactivity in the SNr. Glyphosate exposure for 14 days significantly potentiated MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of mouse brain. This study suggests that glyphosate exposure might exacerbate MPTP-induced dopaminergic neurotoxicity in the striatum and SNr of adult mice. It is likely that exposure of glyphosate may be an environmental risk factor for PD since glyphosate has been used widely in the world.

Introduction

Parkinson’s disease (PD) is the common neurodegenerative disorder that affects predominately dopaminergic neurons in the substantial nigra (SNr) [1,11]. Although the molecular mechanisms underlying PD pathology are unclear, the agrochemicals such as the pesticide rotenone and the herbicide paraquat may be involved in the pathology of PD [12]. For example, a meta-analysis showed a high association between paraquat exposure and PD (odd ratio = 1.64) [20].

Glyphosate [N-(phosphonomethyl)glycine], the world’s most heavily applied herbicide, is an active ingredient in RoundupⓇ. It is reported that people exposed to glyphosate had 33% higher odds (odd ratio = 1.33) of premature mortality from PD than those that were not exposed [3]. In contrast, exposure to other agonochemicals such as paraquat, atrazine, or diazinon was not associated with premature mortality from PD [3]. Furthermore, there are some cases who developed PD after ingesting glyphosate [2,6,24]. However, there are no reports investigating the effects of glyphosate exposure in the animal models of PD.

This study was undertaken to investigate whether the exposure of glyphosate could affect the dopaminergic neurotoxicity in the striatum and SNr of mouse brain after the repeated administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) since MPTP-induced dopaminergic neurotoxicity has been widely used as animal model of PD [10].

Section snippets

Animals

Male adult C57BL/6 mice (10 weeks old, body weight 20–25 g, Japan SLC, Inc., Hamamatsu, Japan) were used. Mice were housed in room temperature (23 ± 1 °C), humidity (55 ± 5%) and 12-h light/dark cycles (lights on between 07:00–19:00) with ad libitum food and water. The experimental protocol of this study was approved by the Chiba University Institutional Animal Care and Use Committee (permission number: 2-314).

Exposure of glyphosate

In this study, we used commercially available RoundupⓇ Maxload [48% (w/v) glyphosate (

Results

There were no changes in body weight among the four groups (Fig. 1B). Repeated administration of MPTP (10 mg/kg × 3, 2-h interval) significantly decreased the density of DAT-immunoreactivity in the mouse striatum (Fig. 2A). Two-way ANOVA revealed statistical differences among the four groups [MPTP: F1,30 = 70.88, P < 0.001, glyphosate: F1,30 = 6.407, P = 0.017, interaction (MPTP × glyphosate), F1,30 = 3.596, P = 0.068] (Fig. 2A). Post-hoc test revealed that MPTP significantly (P < 0.001)

Discussion

Here, we found that drinking water of glyphosate for 14 days exacerbated the reduction of DAT-immunoreactivity in the mouse striatum and the reduced number of TH-positive cells in the SNr after repeated MPTP administration. We recently reported that maternal glyphosate exposure caused autism-like behavioral abnormalities in offspring through inflammation [15]. Therefore, it is possible that glyphosate exposure may increase the risk for PD in adulthood.

Glyphosate is the most commonly and

CRediT authorship contribution statement

Yaoyu Pu: Investigation, Writing - original draft. Lijia Chang: Investigation. Youge Qu: Investigation. Siming Wang: . Yunfei Tan: Investigation. Xingming Wang: Investigation. Jiancheng Zhang: Investigation. Kenji Hashimoto: Conceptualization, Funding acquisition, Supervision, Writing - original draft, Writing - review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This study was partly supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (to K.H., 17H04243). Dr. Lijia Chang was supported by the NIPPON Foundation, The Japan China Medical Association (Tokyo, Japan). Ms. Siming Wang was supported by TAKASE Scholarship Foundation (Tokyo, Japan).

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