TY - JOUR
T1 - Lead (Pb) exposure induces dopaminergic neurotoxicity in Caenorhabditis elegans
T2 - Involvement of the dopamine transporter
AU - Akinyemi, Ayodele Jacob
AU - Miah, Mahfuzur R.
AU - Ijomone, Omamuyovwi M.
AU - Tsatsakis, Aristidis
AU - Soares, Félix Alexandre Antunes
AU - Tinkov, Alexey A.
AU - Skalny, Anatoly V.
AU - Venkataramani, Vivek
AU - Aschner, Michael
N1 - Funding Information:
The first author and OMI are a recipient of IBRO/ISN postdoctoral fellowship and wish to thank the organization for their support. Also, dopamine analysis was performed in the Neurochemistry Core at Vanderbilt University. The Core receives support from the EKS NICHD of the NIH under Award #U54HD083211
Publisher Copyright:
© 2019
PY - 2019
Y1 - 2019
N2 - Lead (Pb) is an environmental neurotoxicant, and has been implicated in several neurological disorders of dopaminergic dysfunction; however, the molecular mechanism of its toxicity has yet to be fully understood. This study investigated the effect of Pb exposure on dopaminergic neurodegeneration and function, as well as expression level of several dopaminergic signaling genes in wild type (N2) and protein kinase C (pkc) mutant Caenorhabditis elegans. Both N2 and pkc mutant worms were exposed to Pb2+ for 1 h. Thereafter, dopaminergic (DAergic) neurodegeneration, behavior and gene expression levels were assessed. The results revealed that Pb2+ treatment affects dopaminergic cell morphology and structure in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. Also, there was a significant impairment in dopaminergic neuronal function as tested by basal slowing response (BSR) in wild-type, N2 worms, but no effect was observed in pkc mutant worms. Furthermore, Pb2+ exposure increased dat-1 gene expression level when compared with N2 worms, but no alteration was observed in the pkc mutant strains. LC–MS analysis revealed a significant decrease in dopamine content in worms treated with Pb2+ when compared with controls. In summary, our results revealed that Pb2+ exposure induced dopaminergic dysfunction in C. elegans by altering dat-1 gene levels, but pkc mutants showed significant resistance to Pb2+ toxicity. We conclude that PKC activation is directly involved in the neurotoxicity of Pb.
AB - Lead (Pb) is an environmental neurotoxicant, and has been implicated in several neurological disorders of dopaminergic dysfunction; however, the molecular mechanism of its toxicity has yet to be fully understood. This study investigated the effect of Pb exposure on dopaminergic neurodegeneration and function, as well as expression level of several dopaminergic signaling genes in wild type (N2) and protein kinase C (pkc) mutant Caenorhabditis elegans. Both N2 and pkc mutant worms were exposed to Pb2+ for 1 h. Thereafter, dopaminergic (DAergic) neurodegeneration, behavior and gene expression levels were assessed. The results revealed that Pb2+ treatment affects dopaminergic cell morphology and structure in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. Also, there was a significant impairment in dopaminergic neuronal function as tested by basal slowing response (BSR) in wild-type, N2 worms, but no effect was observed in pkc mutant worms. Furthermore, Pb2+ exposure increased dat-1 gene expression level when compared with N2 worms, but no alteration was observed in the pkc mutant strains. LC–MS analysis revealed a significant decrease in dopamine content in worms treated with Pb2+ when compared with controls. In summary, our results revealed that Pb2+ exposure induced dopaminergic dysfunction in C. elegans by altering dat-1 gene levels, but pkc mutants showed significant resistance to Pb2+ toxicity. We conclude that PKC activation is directly involved in the neurotoxicity of Pb.
KW - Dopaminergic neuron
KW - Neurotoxicant
KW - PKC
KW - Pb
KW - dat-1
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U2 - 10.1016/j.toxrep.2019.08.001
DO - 10.1016/j.toxrep.2019.08.001
M3 - Article
AN - SCOPUS:85070819311
SN - 2214-7500
VL - 6
SP - 833
EP - 840
JO - Toxicology Reports
JF - Toxicology Reports
ER -