Genetics of the human placenta: implications for toxicokinetics

Gundacker, Claudia; Neesen, Jürgen; Straka, Elisabeth; Ellinger, Isabella; Dolznig, Helmut; Hengstschläger, Markus

doi:10.1007/s00204-016-1816-6

Cited by 40 publications

(28 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Different types of efflux and influx proteins have been detected in the placenta at the apical (maternal facing brush border membrane) or basolateral (fetal facing basal membrane) sides of the syncytiotrophoblast cell layer [30]. For instance, some ATP-binding cassette (ABC) transporters (including the multidrug resistance protein 1, P-gp, and the multidrug resistance-associated proteins) are located at the apical surface of the syncytiotrophoblast ensuring the efflux of substances back to maternal circulation [31].…”

Section: Placental Transfer Of Xenobioticsmentioning

confidence: 99%

Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data

Codaccioni

Brochot

2019

Computational Toxicology

View full text Add to dashboard Cite

Section: Placental Transfer Of Xenobioticsmentioning

confidence: 99%

Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data

Codaccioni

Brochot

2019

Computational Toxicology

View full text Add to dashboard Cite

“…In the body, defense systems against xenobiotics such as BPDE include the activation of detoxifying phase II and III enzymes to prevent further cellular damage; specifically, glutathione S-transferases (GSTs) [14], nicotinamide adenine dinucleotide phosphate (NAD(P)H): quinone oxidoreductase 1 (NQO1), sulfotransferases (SULTs), and multidrug resistance-associated proteins (ABCCs) [15][16][17]. Previous studies showed that the genotoxicity of B[a]P was reduced by phase II enzymes conjugated with B[a]P metabolites and that B[a]P was excreted by ABCCs before BPDE-DNA adducts could form [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

Jee

Kim

Sung

2020

IJMS

View full text Add to dashboard Cite

Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon, is a group 1 carcinogen that introduces mutagenic DNA adducts into the genome. In this study, we investigated the molecular mechanisms underlying the involvement of silymarin in the reduction of DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), induced by B[a]P. B[a]P exhibited toxicity in HepG2 cells, whereas co-treatment of the cells with B[a]P and silymarin reduced the formation of BPDE-DNA adducts, thereby increasing cell viability. Determination of the level of major B[a]P metabolites in the treated cells showed that BPDE levels were reduced by silymarin. Nuclear factor erythroid 2-related factor 2 (Nrf2) and pregnane X receptor (PXR) were found to be involved in the activation of detoxifying genes against B[a]P-mediated toxicity. Silymarin did not increase the expression of these major transcription factors, but greatly facilitated their nuclear translocation. In this manner, treatment of HepG2 cells with silymarin modulated detoxification enzymes through NRF2 and PXR to eliminate B[a]P metabolites. Knockdown of Nrf2 abolished the preventive effect of silymarin on BPDE-DNA adduct formation, indicating that activation of the Nrf2 pathway plays a key role in preventing B[a]P-induced genotoxicity. Our results suggest that silymarin has anti-genotoxic effects, as it prevents BPDE-DNA adduct formation by modulating the Nrf2 and PXR signaling pathways.

show abstract

“…As the CTB layer becomes discontinuous during pregnancy, in the late placenta there are only two cell layers (STB and pFEC) that a substance must cross. Slightly modified from Gundacker et al ( 2016 ). d siRNA-mediated gene knockdown was performed in HTR-8/SVneo cells using MRP1-specific siRNA (siMRP1).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Genetics of the human placenta: implications for toxicokinetics

Cited by 40 publications

References 132 publications

Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data

Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data

Modulatory Effects of Silymarin on Benzo[a]pyrene-Induced Hepatotoxicity

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

Contact Info

Product

Resources

About