TY - JOUR
T1 - Therapeutic Efficacy of the N,N′ Bis-(2-Mercaptoethyl) Isophthalamide Chelator for Methylmercury Intoxication in Caenorhabditis elegans
AU - Ke, Tao
AU - Bornhorst, Julia
AU - Schwerdtle, Tanja
AU - Santamaría, Abel
AU - Soare, Félix Alexandre Antunes
AU - Rocha, João B.T.
AU - Farina, Marcelo
AU - Bowman, Aaron B.
AU - Aschner, Michael
N1 - Funding Information:
This work was supported by the National Institutes of Health to MA (NIEHS R01ES007331). The authors thank the Analytical Imaging Facility (AIF) at Albert Einstein College of Medicine, which is sponsored by NCI cancer center support grant P30CA013330 and Shared Instrumentation Grant (SIG) 1S10OD023591-01. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). NBMI was kindly provided by Mr. Ragnar Klingberg.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Methylmercury (MeHg) is a global pollutant and potent neurotoxin. In humans, MeHg damages the central nervous system (CNS), causing irreversible neuronal shrinkage, and neuronal loss. Most chelators for clinical mercury detoxification are thiol-containing agents. N,N ‘bis-(2-mercaptoethyl) isophthalamide (NBMI) is a lipophilic thiol agent synthesized from natural chemicals. NBMI has high affinity for mercury, cadmium and lead, and can decrease their concentrations in polluted water. However, the efficacy of NBMI for MeHg toxicity has yet to be evaluated in intact animals. Here we used the nematode Caenorhabditis elegans (C. elegans) to test the efficacy of NBMI in attenuating MeHg toxicity in vivo in the whole organism. The results showed that NBMI reduced both the acute toxicity (125 μM MeHg, 1 h) and chronic (5 μM MeHg, 24 h) MeHg toxicity. Co-treatment with NBMI achieved maximal efficacy against MeHg toxicity, however delayed treatment 6 days after initiation of exposure was also effective at reducing neurotoxicity. Co-treatment of NBMI reduced the worms’ death rate, structural damage in DAergic neurons, and restored antioxidant response levels. While this study provides proof of principle for the therapeutic value of NBMI in MeHg toxicity, future studies are needed to address the cellular and molecular mechanisms and translatability of these effects to humans and other animals.
AB - Methylmercury (MeHg) is a global pollutant and potent neurotoxin. In humans, MeHg damages the central nervous system (CNS), causing irreversible neuronal shrinkage, and neuronal loss. Most chelators for clinical mercury detoxification are thiol-containing agents. N,N ‘bis-(2-mercaptoethyl) isophthalamide (NBMI) is a lipophilic thiol agent synthesized from natural chemicals. NBMI has high affinity for mercury, cadmium and lead, and can decrease their concentrations in polluted water. However, the efficacy of NBMI for MeHg toxicity has yet to be evaluated in intact animals. Here we used the nematode Caenorhabditis elegans (C. elegans) to test the efficacy of NBMI in attenuating MeHg toxicity in vivo in the whole organism. The results showed that NBMI reduced both the acute toxicity (125 μM MeHg, 1 h) and chronic (5 μM MeHg, 24 h) MeHg toxicity. Co-treatment with NBMI achieved maximal efficacy against MeHg toxicity, however delayed treatment 6 days after initiation of exposure was also effective at reducing neurotoxicity. Co-treatment of NBMI reduced the worms’ death rate, structural damage in DAergic neurons, and restored antioxidant response levels. While this study provides proof of principle for the therapeutic value of NBMI in MeHg toxicity, future studies are needed to address the cellular and molecular mechanisms and translatability of these effects to humans and other animals.
KW - Chelation
KW - DAergic neuron
KW - Methylmercury
KW - Oxidative stress
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U2 - 10.1007/s12640-020-00194-0
DO - 10.1007/s12640-020-00194-0
M3 - Article
C2 - 32236898
AN - SCOPUS:85082568652
VL - 38
SP - 133
EP - 144
JO - Neurotoxicity Research
JF - Neurotoxicity Research
SN - 1029-8428
IS - 1
ER -