scholarly journals More than additive effects on liver triglyceride accumulation by combinations of steatotic and non-steatotic pesticides in HepaRG cells

2021 ◽  
Author(s):  
Alexandra Lasch ◽  
Philip Marx-Stoelting ◽  
Albert Braeuning ◽  
Dajana Lichtenstein
Keyword(s):  
Fatty Acid ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Adverse Outcome Pathway ◽  
Additive Effects ◽  
Liver Triglyceride ◽  
Combination Effects ◽  
Hepatic Fatty Acid ◽  
Triglyceride Accumulation

AbstractThe liver is constantly exposed to mixtures of hepatotoxic compounds, such as food contaminants and pesticides. Dose addition is regularly assumed for mixtures in risk assessment, which however might not be sufficiently protective in case of synergistic effects. Especially the prediction of combination effects of substances which do not share a common adverse outcome (AO) might be problematic. In this study, the focus was on the endpoint liver triglyceride accumulation in vitro, an indicator of hepatic fatty acid changes. The hepatotoxic compounds difenoconazole, propiconazole and tebuconazole were chosen which cause hepatic fatty acid changes in vivo, whereas fludioxonil was chosen as a hepatotoxic substance not causing fatty acid changes. Triglyceride accumulation was analyzed for combinations of steatotic and non-steatotic pesticides in human HepaRG hepatocarcinoma cells. Investigations revealed a potentiation of triglyceride accumulation by mixtures of the steatotic compounds with the non-steatotic fludioxonil, as compared to the single compounds. Mathematical modeling of combination effects indicated more than additive effects for the tested combinations if the method by Chou was applied, and a decrease in EC50 values of the steatotic compounds when applied in mixtures. Use of an adverse outcome pathway (AOP)-driven testing strategy for liver steatosis showed interactions of the test compounds with the nuclear receptors AHR, CAR and PXR, as well as a downregulation of ACOX2. An ACOX2-dependent mechanism underlying the observed mixture effect could not be verified using a siRNA approach. By contrast, a toxicokinetic interaction was identified including an inhibition of the metabolic enzyme CYP3A4 by fludioxonil and a decreased metabolic conversion of the CYP3A4 substrate difenoconazole when used in mixture experiments. In conclusion, an interaction by a steatotic and a non-steatotic compound at the toxicokinetic level on the endpoint triglyceride accumulation in vitro was described.

scholarly journals Investigating the in vitro steatotic mixture effects of similarly and dissimilarly acting test compounds using an adverse outcome pathway-based approach

2021 ◽  
Author(s):  
Jimmy Alarcan ◽  
Georges de Sousa ◽  
Efrosini S. Katsanou ◽  
Anastasia Spyropoulou ◽  
Petros Batakis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Receptor Activation ◽  
Adverse Outcome Pathway ◽  
Vitro Assay ◽  
Mixture Effects ◽  
Triglyceride Accumulation

AbstractWithin the EuroMix project, we have previously developed an adverse outcome pathway (AOP)-based in vitro assay toolbox to investigate the combined effects of liver steatosis-inducing compounds in human HepaRG hepatocarcinoma cells. In this study, we applied the toolbox to further investigate mixture effects of combinations, featuring either similarly acting or dissimilarly acting substances. The valproic acid structural analogs 2-propylheptanoic acid (PHP) and 2-propylhexanoic acid (PHX) were chosen for establishing mixtures of similarly acting substances, while a combination with the pesticidal active substance clothianidin (CTD) was chosen for establishing mixtures of dissimilarly acting compounds. We first determined relative potency factors (RPFs) for each compound based on triglyceride accumulation results. Thereafter, equipotent mixtures were tested for nuclear receptor activation in transfected HepG2 cells, while gene expression and triglyceride accumulation were investigated in HepaRG cells, following the proposed AOP for liver steatosis. Dose addition was observed for all combinations and endpoints tested, indicating the validity of the additivity assumption also in the case of the tested mixtures of dissimilarly acting substances. Gene expression results indicate that the existing steatosis AOP can still be refined with respect to the early key event (KE) of gene expression, in order to reflect the diversity of molecular mechanisms underlying the adverse outcome.

scholarly journals Adverse Outcome Pathway-Driven Analysis of Liver Steatosis in Vitro: A Case Study with Cyproconazole

2018 ◽  
Vol 31 (8) ◽  
pp. 784-798 ◽  
Author(s):  
Claudia Luckert ◽  
Albert Braeuning ◽  
Georges de Sousa ◽  
Sigrid Durinck ◽  
Efrosini S. Katsanou ◽  
...  
Keyword(s):  
Adverse Outcome ◽  
Liver Steatosis ◽  
Adverse Outcome Pathway

scholarly journals Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 180
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Luc Lebeau ◽  
Françoise Pons ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Lung Inflammation ◽  
Adverse Outcome ◽  
Cellular Responses ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Adverse Outcome Pathway ◽  
Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

scholarly journals Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

2014 ◽  
Vol 15 (5) ◽  
pp. 7651-7666 ◽  
Author(s):  
Ivanka Tsakovska ◽  
Merilin Al Sharif ◽  
Petko Alov ◽  
Antonia Diukendjieva ◽  
Elena Fioravanzo ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Mode Of Action ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Adverse Outcome Pathway ◽  
Modelling Study

Application of an adverse outcome pathway-based in vitro testing battery for neurotoxicity evaluation

2021 ◽  
Vol 350 ◽  
pp. S51
Author(s):  
K. Koch ◽  
M. Elgamal ◽  
S. Masjosthusmann ◽  
I. Lauria ◽  
R Hartmann ◽  
...  
Keyword(s):  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
In Vitro Testing

Inhibition of matrix metalloproteinases increases PPAR-α and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model

2006 ◽  
Vol 291 (6) ◽  
pp. G1011-G1019 ◽  
Author(s):  
Ian P. J. Alwayn ◽  
Charlotte Andersson ◽  
Sang Lee ◽  
Danielle A. Arsenault ◽  
Bruce R. Bistrian ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Essential Fatty Acid ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Resonance Spectroscopy ◽  
Liver Triglyceride ◽  
Triglyceride Accumulation ◽  
Tnf Α

Steatosis is a prominent feature of nonalcoholic fatty liver disease and a potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF-α induced liver injury. We hypothesized that Marimastat, a broad-spectrum MMP and TNF-α converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for hepatic steatosis. Mice receiving a fat-free, high-carbohydrate diet (HCD) for 19 days developed severe fatty liver infiltration, demonstrated by histology, magnetic resonance spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat (HCD+MAR) were comparable to control animals. Increased tissue levels of peroxisome proliferator activated receptor-α (PPAR-α), higher levels of serum IL-6, and decreased levels of serum TNF-α receptor II were also seen in the HCD+MAR group compared with HCD-only. In addition, there was increased phosphorylation, and likely activation, of PPAR-α in the HCD+MAR group. PPAR-α is a transcription factor involved in β-oxidation of fatty acids, and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only but improved with Marimastat treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides. This may be related to increased expression and activation of PPAR-α or IL-6, respectively.

Fibrates modify rat hepatic fatty acid chain elongation and desaturation in vitro

1993 ◽  
Vol 46 (10) ◽  
pp. 1791-1796 ◽  
Author(s):  
Rosa M. Sánchez ◽  
Marisa Viñals ◽  
Marta Alegret ◽  
Manuel Vázquez ◽  
Tomás Adzet ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Chain Elongation ◽  
Hepatic Fatty Acid ◽  
Fatty Acid Chain

scholarly journals Metformin Ameliorates Ethanol-Induced Liver Triglyceride Accumulation by LKB1/AMPK/ACC Pathway

2021 ◽  
Author(s):  
Fotian Xie ◽  
Dongmei Wang ◽  
Kwok Fai So ◽  
Jia Xiao ◽  
Yi Lv
Keyword(s):  
Lipid Accumulation ◽  
Therapeutic Potential ◽  
Lipid Lowering ◽  
Liver Triglyceride ◽  
Hepatic Lipid Accumulation ◽  
Triglyceride Accumulation ◽  
Lipid Formation

Abstract Background: Hepatic lipid accumulation is one of the main pathological features of alcoholic liver disease. Metformin is an AMPK activator that has been shown to have lipid lowering effects. The purpose of this study was to investigate whether metformin had a beneficial effect on lipid accumulation in the pathogenesis of ALD.Methods: AML12 cells and male C57BL/6 mice were used to establish ALD models in vitro and in vivo, respectively. The effects of metformin on hepatocyte lipid accumulation and ALD progression in mice were detected. The role of LKB1/AMPK/ACC axis in metformin against ethanol-induced lipid accumulation was evaluated by siRNA and AAV-shRNA interference.Results: Metformin reduced the ethanol-induced lipid accumulation in AML12 cells through activating AMPK/ACC and SREBP1c and inhibiting PPARα. In addition, compared with control mice, metformin treatment inhibited ethanol-induced liver adipose accumulation and the increase of ALT and AST in serum. Interference with LKB1 attenuated the effect of metformin on ethanol-induced lipid accumulation both in vitro and in vivo.Conclusion: Metformin protects against lipid formation in ALD by activating LKB1/AMPK/ACC axis. Thus, metformin has therapeutic potential for the prevention of ALD.

Sign in / Sign up

Export Citation Format

Share Document