PUBLICATION
Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity
- Authors
- Spulber, S., Raciti, M., Dulko-Smith, B., Lupu, D., Rüegg, J., Nam, K., Ceccatelli, S.
- ID
- ZDB-PUB-180303-13
- Date
- 2018
- Source
- Toxicology and applied pharmacology 354: 94-100 (Journal)
- Registered Authors
- Keywords
- Alternative methods, Developmental neurotoxicity, Endocrine disruptor, Glucocorticoid receptor, Methylmercury
- MeSH Terms
-
- Humans
- Molecular Dynamics Simulation
- Binding Sites
- Receptors, Glucocorticoid/chemistry
- Receptors, Glucocorticoid/drug effects*
- Receptors, Glucocorticoid/genetics
- Receptors, Glucocorticoid/metabolism
- Signal Transduction/drug effects
- Gene Expression Regulation, Developmental/drug effects
- Risk Assessment
- Nervous System/drug effects*
- Nervous System/embryology
- Nervous System/metabolism
- Embryonic Development/drug effects
- Animals
- Mercury Poisoning, Nervous System/embryology
- Mercury Poisoning, Nervous System/etiology*
- Mercury Poisoning, Nervous System/genetics
- Mercury Poisoning, Nervous System/metabolism
- Toxicity Tests
- HeLa Cells
- Toxicology/methods
- Animals, Genetically Modified
- Protein Binding
- Zebrafish
- Ligands
- Methylmercury Compounds/chemistry
- Methylmercury Compounds/metabolism
- Methylmercury Compounds/toxicity*
- PubMed
- 29499248 Full text @ Tox. App. Pharmacol.
- CTD
- 29499248
Citation
Spulber, S., Raciti, M., Dulko-Smith, B., Lupu, D., Rüegg, J., Nam, K., Ceccatelli, S. (2018) Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity. Toxicology and applied pharmacology. 354:94-100.
Abstract
Methylmercury (MeHg) is a widespread environmental contaminant with established developmental neurotoxic effects. Computational models have identified glucocorticoid receptor (GR) signaling to be a key mediator behind the birth defects induced by Hg, but the mechanisms were not elucidated. Using molecular dynamics simulations, we found that MeHg can bind to the GR protein at Cys736 (located close to the ligand binding site) and distort the conformation of the ligand binging site. To assess the functional consequences of MeHg interaction with GR, we used a human cell line expressing a luciferase reporter system (HeLa AZ-GR). We found that 100 nM MeHg does not have any significant effect on GR activity alone, but the transactivation of gene expression by GR upon Dex (a synthetic GR agonist) administration was reduced in cells pre-treated with MeHg. Similar effects were found in transgenic zebrafish larvae expressing a GR reporter system (SR4G). Next we asked whether the effects of developmental exposure to MeHg are mediated by the effects on GR. Using a mutant zebrafish line carrying a loss-of-function mutation in the GR (grS357) we could show that the effects of developmental exposure to 2.5 nM MeHg are mitigated in absence of functional GR signaling. Taken together, our data indicate that inhibition of GR signaling may have a role in the developmental neurotoxic effects of MeHg.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping