Gadolinium (Gd)-based contrast agents are extensively used for magnetic resonance imaging (MRI). Liposomes are potential nanocarrier-based biocompatible platforms for development of new generations of MRI diagnostics. Liposomes with Gd-complexes (Gd-lip) co-encapsulated with thrombolytic agents can serve both for imaging and treatment of various pathological states including stroke. In this study, we evaluated nanosafety of Gd-lip containing PE-DTPA chelating Gd+3 prepared by lipid film hydration method. We detected no cytotoxicity of Gd-lip in human liver cells including cancer HepG2, progenitor (non-differentiated) HepaRG, and differentiated HepaRG cells. Furthermore, no potential side effects of Gd-lip were found using a complex system including general biomarkers of toxicity, such as induction of early response genes, oxidative, heat shock and endoplasmic reticulum stress, DNA damage responses, induction of xenobiotic metabolizing enzymes, and changes in sphingolipid metabolism in differentiated HepaRG. Moreover, Gd-lip did not show pro-inflammatory effects, as assessed in an assay based on activation of inflammasome NLRP3 in a model of human macrophages, and release of eicosanoids from HepaRG cells. In conclusion, this in vitro study indicates potential in vivo safety of Gd-lip with respect to hepatotoxicity and immunopathology caused by inflammation.

• MeSH
• Gadolinium DTPA * adverse effects   toxicity   MeSH
• Fibrinolytic Agents MeSH
• Phosphatidylethanolamines * adverse effects   toxicity   MeSH
• Hepatocytes drug effects   MeSH
• Inflammasomes MeSH
• Contrast Media * MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Liposomes * MeSH
• Magnetic Resonance Imaging * MeSH
• Macrophages drug effects   MeSH
• Nanoparticles MeSH
• Drug Carriers * MeSH
• NLR Family, Pyrin Domain-Containing 3 Protein MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Gadolinium DTPA * MeSH
• Fibrinolytic Agents MeSH
• Phosphatidylethanolamines * MeSH
• gadolinium phosphatidylethanolamine-DTPA MeSH Browser
• Inflammasomes MeSH
• Contrast Media * MeSH
• Liposomes * MeSH
• NLRP3 protein, human MeSH Browser
• Drug Carriers * MeSH
• NLR Family, Pyrin Domain-Containing 3 Protein MeSH

The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.

• Keywords
• Airborne polychlorinated biphenyls, Endocrine disruption, HydroxyLated PCBs, Metabolism of xenobiotics, Tumor promotion,
• MeSH
• Cell Line MeSH
• Endocrine Disruptors metabolism   toxicity   MeSH
• Epithelial Cells drug effects   MeSH
• Hydroxylation MeSH
• Constitutive Androstane Receptor MeSH
• Air Pollutants toxicity   MeSH
• Humans MeSH
• Neoplasms metabolism   MeSH
• Polychlorinated Biphenyls metabolism   toxicity   MeSH
• Pregnane X Receptor MeSH
• Receptors, Cytoplasmic and Nuclear metabolism   MeSH
• Signal Transduction drug effects   MeSH
• Receptors, Steroid metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Endocrine Disruptors MeSH
• Constitutive Androstane Receptor MeSH
• Air Pollutants MeSH
• Polychlorinated Biphenyls MeSH
• Pregnane X Receptor MeSH
• Receptors, Cytoplasmic and Nuclear MeSH
• Receptors, Steroid MeSH