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Neurotoxicological Profiling of Paraquat in Zebrafish Model

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Abstract

Paraquat is a polar herbicide protecting plant products against invasive species, it requires careful manipulation and restricted usage because of its harmful potentials. Exposure to paraquat triggers oxidative damage in dopaminergic neurons and subsequently causes a behavioral defect in vivo. Thereby, persistent exposure to paraquat is known to increase Parkinson’s disease risk by dysregulating dopaminergic systems in humans. Therefore, most studies have focused on the dopaminergic systems to elucidate the neurotoxicological mechanism of paraquat poisoning, and more comprehensive neurochemistry including histaminergic, serotonergic, cholinergic, and GABAergic systems has remained unclear. Therefore, in this study, we investigated the toxicological potential of paraquat poisoning using a variety of approaches such as toxicokinetic profiles, behavioral effects, neural activity, and broad-spectrum neurochemistry in zebrafish larvae after short-term exposure to paraquat and we performed the molecular modeling approach. Our results showed that paraquat was slowly absorbed in the brain of zebrafish after oral administration of paraquat. In addition, paraquat toxicity resulted in behavioral impairments, namely, reduced motor activity and led to abnormal neural activities in zebrafish larvae. This locomotor deficit came with a dysregulation of dopamine synthesis induced by the inhibition of tyrosine hydroxylase activity, which was also indirectly confirmed by molecular modeling studies. Furthermore, short-term exposure to paraquat also caused simultaneous dysregulation of other neurochemistry including cholinergic and serotonergic systems in zebrafish larvae. The present study suggests that this neurotoxicological profiling could be a useful tool for understanding the brain neurochemistry of neurotoxic agents that might be a potential risk to human and environmental health.

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Data Availability

Enquiries about data availability should be directed to the authors.

Abbreviations

3-HAA:

3-Hydroxyanthranilic acid

3-HK:

3-Hydroxykynurenine

3-MT:

3-Methoxytyramine

5-HIAA:

5-Hydroxyindoleacetic acid

5-HT:

5-Hydroxytryptamine (serotonin)

5-HTP:

5-Hydroxytryptophan

AA:

Anthranilic acid

ACHO:

Acetylcholine

BBB:

Blood–brain barrier

BET:

Betaine

CHO:

Choline

CNS:

Central nervous system

DA:

Dopamine

E:

Epinephrine

GABA:

Gamma-aminobutyric acid

GLN:

Glutamine

GLU:

Glutamic acid

HA:

Histamine

HIS:

Histidine

KYN:

Kynurenine

KYNA:

Kynurenic acid

LC–MS/MS:

Liquid chromatography triple quadruple mass spectrometry

L-DOPA:

3,4-Dihydroxy-L-phenylalanine

LDT:

Light dark transition

LEU:

Leucine

LYS:

Lysine

ME:

Melatonin

NE:

Norepinephrine

NM:

Normetanephrine

OA:

Octopamine

PD:

Parkinson’s disease

PHE:

Phenylalanine

PQ:

Paraquat

SE:

Serine

TA:

Tyramine

TH:

Tyrosine hydroxylase

TRYP:

Tryptophan

TYR:

Tyrosine

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Funding

This work was supported by Korea Environment Industry & Technology Institute (KEITI) through Technology Development Project for Safety Management of Household Chemical Products, funded by Korea Ministry of Environment (MOE) (2020002960007, NTIS-1485017544), Republic of Korea. This work was also partially supported by project of Korea Research Institute of Chemical Technology (SI2131-50), Republic of Korea.

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Author notes

  1. Seong Soon Kim and Kyu-Seok Hwang both contributed equally on this work.

Authors and Affiliations

  1. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea

    Seong Soon Kim, Kyu-Seok Hwang, Hyemin Kan, Jung Yoon Yang, Yuji Son, Dae-Seop Shin, Byung Hoi Lee, Chong Hak Chae & Myung Ae Bae

  2. Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon, Republic of Korea

    Myung Ae Bae

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  1. Seong Soon Kim
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Contributions

SSK and KSH: Conceptualization, Methodology, Formal analysis, Investigation, and Writing–original draft; HMK, JYY, YS, DSS, and BHL: Methodology, Investigation, Formal analysis. CHC: Methodology, Investigation, and Writing–original draft, MAB: Conceptualization, Writing–review & editing, Funding acquisition, Supervision, and Project administration.

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Correspondence to Myung Ae Bae.

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Kim, S.S., Hwang, KS., Kan, H. et al. Neurotoxicological Profiling of Paraquat in Zebrafish Model. Neurochem Res 47, 2294–2306 (2022). https://doi.org/10.1007/s11064-022-03615-y

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