Neurotoxicity of the Parkinson Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos.
BACKGROUND
Exposure to the commonly used dithiocarbamate (DTC) pesticides is associated with an increased risk of developing Parkinson disease (PD), although the mechanisms by which they exert their toxicity are not completely understood.


OBJECTIVE
We studied the mechanisms of ziram's (a DTC fungicide) neurotoxicity in vivo.


METHODS
Zebrafish (ZF) embryos were utilized to determine ziram's effects on behavior, neuronal toxicity, and the role of synuclein in its toxicity.


RESULTS
Nanomolar-range concentrations of ziram caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior. Because ziram increases α-synuclein (α-syn) concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms, and ZF γ1 appears to be the closest functional homologue to α-syn. We found that recombinant ZF γ1 formed fibrils in vitro, and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity in a manner similar to that of α-syn. Importantly, knockdown of ZF γ1 with morpholinos and disruption of oligomers with the molecular tweezer CLR01 prevented ziram's DA toxicity.


CONCLUSIONS
These data show that ziram is selectively toxic to DA neurons in vivo, and this toxicity is synuclein-dependent. These findings have important implications for understanding the mechanisms by which pesticides may cause PD. Citation: Lulla A, Barnhill L, Bitan G, Ivanova MI, Nguyen B, O'Donnell K, Stahl MC, Yamashiro C, Klärner FG, Schrader T, Sagasti A, Bronstein JM. 2016. Neurotoxicity of the Parkinson disease-associated pesticide ziram is synuclein-dependent in zebrafish embryos. Environ Health Perspect 124:1766-1775; http://dx.doi.org/10.1289/EHP141.
Department of Neurology, University of Los Angeles (UCLA), Los Angeles, California, USA.
Aaron
A
Lulla
Lisa
L
Barnhill
Gal
G
Bitan
Magdalena I
MI
Ivanova
Binh
B
Nguyen
Kelley
K
O'Donnell
Mark C
MC
Stahl
Chase
C
Yamashiro
Frank-Gerrit
FG
Klärner
Thomas
T
Schrader
Alvaro
A
Sagasti
Jeff M
JM
Bronstein
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D010300:Parkinson Disease / Q000209:etiology*; D051843:Synucleins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology*; D015039:Ziram / Q000633:toxicity*
D009498:Neurotoxins; D051843:Synucleins; D015039:Ziram