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.
ATP-Binding Cassette Transporters
/ metabolism
Amino Acid Transport Systems
/ metabolism
Animals
Apoptosis
/ drug effects
Cell Line
Cell Survival
/ drug effects
Cells, Cultured
Dogs
Endothelial Cells
Female
Gene Knockdown Techniques
Glutathione
/ metabolism
Humans
Immunohistochemistry
Madin Darby Canine Kidney Cells
Methylmercury Compounds
/ adverse effects
Multidrug Resistance-Associated Proteins
/ physiology
Oxidative Stress
Placenta
/ metabolism
Pregnancy
HTR-8/SVneo
Human placenta
MDCKII
Methyl mercury
Multidrug resistance-associated protein 1
Oxidative stress
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
10
06
2020
accepted:
02
09
2020
pubmed:
12
9
2020
medline:
7
8
2021
entrez:
11
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32915249
doi: 10.1007/s00204-020-02900-5
pii: 10.1007/s00204-020-02900-5
pmc: PMC7603445
doi:
Substances chimiques
ATP-Binding Cassette Transporters
0
Amino Acid Transport Systems
0
Methylmercury Compounds
0
Multidrug Resistance-Associated Proteins
0
dimethyl mercury
C60TQU15XY
Glutathione
GAN16C9B8O
multidrug resistance-associated protein 1
Y49M64GZ4Q
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3799-3817Références
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