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Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity
Umeå University, Faculty of Science and Technology, Department of Chemistry. University of Texas at Arlington, Department of Chemistry and Biochemistry, Arlington, TX, USA.
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2018 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 354, p. 94-100Article in journal (Refereed) Published
Abstract [en]

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 (grs(357)) 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.

Place, publisher, year, edition, pages
Academic Press, 2018. Vol. 354, p. 94-100
Keywords [en]
Developmental neurotoxicity, Methylmercury, Glucocorticoid receptor, Endocrine disruptor, alternative methods
National Category
Pharmacology and Toxicology Developmental Biology
Identifiers
URN: urn:nbn:se:umu:diva-151549DOI: 10.1016/j.taap.2018.02.021ISI: 000442335500010PubMedID: 29499248OAI: oai:DiVA.org:umu-151549DiVA, id: diva2:1247104
Funder
Swedish Research Council, 2015-04114Swedish Research Council, 10815-20-4
Note

Special Issue: Alternative Approaches to Developmental Neurotoxicity Evaluation

Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2018-09-11Bibliographically approved

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Nam, Kwangho

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