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In vitro function and in situ localization of Multidrug Resistance-associated Protein (MRP)1 (ABCC1) suggest a protective role against methyl mercury-induced oxidative stress in the human placenta
S. Granitzer, I. Ellinger, R. Khan, K. Gelles, R. Widhalm, M. Hengstschläger, H. Zeisler, G. Desoye, L. Tupova, M. Ceckova, H. Salzer, C. Gundacker
Language English Country Germany
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
ProQuest Central
from 2002-01-01 to 1 year ago
Medline Complete (EBSCOhost)
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2002-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2002-01-01 to 1 year ago
- MeSH
- ATP-Binding Cassette Transporters metabolism MeSH
- Apoptosis drug effects MeSH
- Cell Line MeSH
- Madin Darby Canine Kidney Cells MeSH
- Endothelial Cells MeSH
- Gene Knockdown Techniques MeSH
- Glutathione metabolism MeSH
- Immunohistochemistry MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Methylmercury Compounds adverse effects metabolism MeSH
- Oxidative Stress * MeSH
- Placenta metabolism MeSH
- Multidrug Resistance-Associated Proteins physiology MeSH
- Dogs MeSH
- Pregnancy MeSH
- Amino Acid Transport Systems metabolism MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Dogs MeSH
- Pregnancy MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium.
Clinic for Pediatrics and Adolescent Medicine University Hospital Tulln Tulln Austria
Department of Obstetrics and Gynecology Medical University of Graz Graz Austria
Department of Obstetrics and Gynecology Medical University Vienna Vienna Austria
Department of Pharmacology and Toxicology Charles University Hradec Kralove Czech Republic
Institute of Medical Genetics Medical University of Vienna Vienna Austria
Institute of Pathophysiology and Allergy Research Medical University of Vienna Vienna Austria
Karl Landsteiner Private University for Health Sciences Krems Austria
References provided by Crossref.org
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- $a Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium.
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