An Evaluation of the Human Relevance of the Liver Tumors Observed in Female Mice Treated With Permethrin Based on Mode of Action

2020 ◽  
Vol 175 (1) ◽  
pp. 50-63 ◽  
Author(s):  
Miwa Kondo ◽  
Hiroko Kikumoto ◽  
Thomas G Osimitz ◽  
Samuel M Cohen ◽  
Brian G Lake ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Liver Tumor ◽  
Mode Of Action ◽  
Mouse Liver ◽  
Liver Tumors ◽  
Tumor Formation ◽  
Human Hepatocytes ◽  
Mrna Levels ◽  
Mouse Hepatocytes

Abstract In 2-year studies, the nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, we demonstrated that the mode of action (MOA) for mouse liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), resulting in a mitogenic effect. In the present study, the effects of permethrin and 2 major permethrin metabolites, namely 3-phenoxybenzoic acid and trans-dichlorochrysanthemic acid, on cytochrome P450 mRNA levels and cell proliferation (determined as replicative DNA synthesis) were evaluated in cultured CD-1 mouse, Wistar rat, and human hepatocytes. Permethrin and 3-phenoxybenzoic acid induced CYP4A mRNA levels in both mouse and human hepatocytes, with trans-dichlorochrysanthemic acid also increasing CYP4A mRNA levels in mouse hepatocytes. 3-Phenoxybenzoic acid induced CYP4A mRNA levels in rat hepatocytes, with trans-dichlorochrysanthemic acid increasing both CYP4A mRNA levels and replicative DNA synthesis. Permethrin, 3-phenoxybenzoic acid, and trans-dichlorochrysanthemic acid stimulated replicative DNA synthesis in mouse hepatocytes but not in human hepatocytes, demonstrating that human hepatocytes are refractory to the mitogenic effects of permethrin and these 2 metabolites. Thus, although some of the key (eg, PPARα activation) and associative (eg, CYP4A induction) events in the established MOA for permethrin-induced mouse liver tumor formation could occur in human hepatocytes at high doses of permethrin, 3-phenoxybenzoic acid, and/or trans-dichlorochrysanthemic acid, increased cell proliferation (an essential step in carcinogenesis by nongenotoxic PPARα activators) was not observed. These results provide additional evidence that the established MOA for permethrin-induced mouse liver tumor formation is not plausible for humans.

Plasma mannose-binding lectin is stimulated by PPARα in humans

2012 ◽  
Vol 302 (5) ◽  
pp. E595-E602 ◽  
Author(s):  
Maryam Rakhshandehroo ◽  
Rinke Stienstra ◽  
Nicole J. de Wit ◽  
Marjolijn C. E. Bragt ◽  
Martin Haluzik ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Lipid Metabolism ◽  
Mouse Liver ◽  
Human Hepatocytes ◽  
Primary Mouse Hepatocytes ◽  
Primary Mouse ◽  
Mannose Binding ◽  
Mouse Hepatocytes ◽  
Binding Lectin ◽  
Pparα Agonist

The peroxisome proliferator activated receptor-α (PPARα) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARα on lipid metabolism are partially mediated by circulating proteins such as FGF21 and ANGPTL4. The present study was undertaken to screen for and identify circulating proteins produced by human liver that are under the control of PPARα. Toward that aim, primary human hepatocytes were treated with the synthetic PPARα agonist Wy-14643 and whole genome expression data selected for secreted proteins. Expression of FGF21, ANGPTL4, and mannose-binding lectin (MBL), a soluble mediator of innate immunity and primary component of the lectin branch of the complement system, was markedly upregulated by Wy-14643 in primary human hepatocytes. Mice express two MBL isomers, Mbl1 and Mbl2. Mbl1 mRNA was weakly induced by Wy-14643 in primary mouse hepatocytes and remained unaltered by Wy-14643 in mouse liver. Mbl2 mRNA was unchanged by Wy-14643 in primary mouse hepatocytes and was strongly reduced by Wy-14643 in mouse liver. Remarkably, plasma Mbl1 levels were increased by chronic PPARα activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARα agonist fenofibrate at 200 mg/day for 6 wk and 3 mo increased plasma MBL levels by 73 ( P = 0.0016) and 86% ( P = 0.017), respectively. It is concluded that hepatocyte gene expression and plasma levels of MBL are stimulated by PPARα and fenofibrate in humans, linking PPARα to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.

scholarly journals Effects of Combination of Anti-CTLA-4 and Anti-PD-1 on Gastric Cancer Cells Proliferation, Apoptosis and Metastasis

2018 ◽  
Vol 49 (1) ◽  
pp. 260-270 ◽  
Author(s):  
Bin Wang ◽  
Lei Qin ◽  
Mei Ren ◽  
Hao Sun
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Combination Therapy ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
Mrna Levels ◽  
Mesenchymal Transition ◽  
Induced Apoptosis

Background/Aims: Gastric cancer (GC) is one of the most common and lethal varieties of cancers. Anticancer activities of anti-CTLA-4 and anti-PD-1 antibodies have been explored in different cancers, including GC. The study aimed to explore the role of combination therapy with anti-CTLA-4 and anti-PD-1 antibodies in GC cells, and understand the possible underlying molecular mechanism. Methods: MKN-45 and MGC-803 cells were divided into four groups, namely control, CTLA-4, PD-1, and CTLA-4&PD-1. Cell viability, cell cycle, apoptosis, migration and invasion were measured by MTT, flow cytometry, and transwell assays, respectively. Expression levels of different mRNAs and proteins associated with apoptosis, epithelial mesenchymal transition (EMT), β-catenin, MAPK, and PI3K/AKT pathways were assessed by RT-qPCR and western blot analysis, respectively. The tumor formation in vivo was examined by tumor Xenograft model assay. Results: Combination with anti-CTLA-4 and anti-PD-1 antibodies significantly suppressed cell proliferation, induced apoptosis, as well as inhibited migration, invasion, and EMT in MKN-45 and MGC-803 cells. Western blotting revealed that combination with anti-CTLA-4 and anti-PD-1 antibodies declined the activation of β-catenin, MAPK and PI3K/AKT signal pathways. Moreover, combination of anti-CTLA-4 and anti-PD-1 antibodies inhibited tumor formation in vivo. Furthermore, the mRNA levels of CTLA-4 and PD-1 were significantly decreased in si-CTLA and si-PD-1 transfected cells, and combination with si-CTLA and si-PD-1 also suppressed cell proliferation, migration, invasion, EMT and induced apoptosis in MKN-45 cells. Conclusion: Combination therapy with anti-CTLA-4 and anti-PD-1 antibodies presented the promising outcomes in GC, although further investigations are warranted.

scholarly journals Mice with hepatocyte-specific FXR deficiency are resistant to spontaneous but susceptible to cholic acid-induced hepatocarcinogenesis

2016 ◽  
Vol 310 (5) ◽  
pp. G295-G302 ◽  
Author(s):  
Bo Kong ◽  
Yan Zhu ◽  
Guodong Li ◽  
Jessica A. Williams ◽  
Kyle Buckley ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Bile Acids ◽  
Cholic Acid ◽  
Liver Tumor ◽  
Liver Tumors ◽  
Tumor Formation ◽  
Farnesoid X Receptor ◽  
Whole Body ◽  
Wild Type ◽  
Depth Analysis

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXRhep−/−) in liver tumor formation. The results showed that FXRhep−/− mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXRhep−/− mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXRhep−/− mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXRhep−/− mice presented with severe liver injury and tumors. Interestingly, FXRhep−/− mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXRhep−/− mice. However, cholic acid feeding reversed these effects in FXRhep−/− mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation.

Induction of hepatic cell proliferation and unscheduled DNA synthesis in mouse hepatocytes following in vivo treatment

1985 ◽  
Vol 6 (10) ◽  
pp. 1521-1524 ◽  
Author(s):  
Jon C. Mirsalis ◽  
C. Kimerly Tyson ◽  
Erica N. Loh ◽  
Karen L. Steinmetz ◽  
James P. Bakke ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Hepatic Cell ◽  
Unscheduled Dna Synthesis ◽  
Mouse Hepatocytes ◽  
In Vivo Treatment

scholarly journals Mode of action and human relevance of THF-induced mouse liver tumors

2017 ◽  
Vol 276 ◽  
pp. 138-143 ◽  
Author(s):  
Christopher J. Choi ◽  
Erik K. Rushton ◽  
Audrey Vardy ◽  
Larry Higgins ◽  
Andrea Augello ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Mouse Liver ◽  
Liver Tumors

scholarly journals Bridging Sex-Specific Differences in the CAR-Mediated Hepatocarcinogenesis of Nitrapyrin Using Molecular and Apical Endpoints

2021 ◽  
Vol 3 ◽  
Author(s):  
Lynea Murphy ◽  
Matthew J. LeBaron ◽  
Kamin Johnson ◽  
Reza J. Rasoulpour ◽  
Xiujuan Wang ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Liver Tumors ◽  
Constitutive Androstane Receptor ◽  
Nitrification Inhibitor ◽  
Tumor Formation ◽  
Male Mice ◽  
Female Mice ◽  
Increased Sensitivity ◽  
Males And Females ◽  
Related Increase

Nitrapyrin, a nitrification inhibitor, produces liver tumors in B6C3F1 mice. In a 2-year oncogenicity study, increased incidence of mice with hepatocellular tumors was observed following exposure to 125 (females only) or 250 mg/kg/day (males and females) nitrapyrin in the diet. Previous data was generated in male mice to support a mode-of-action (MoA) characterized by constitutive androstane receptor (CAR) nuclear receptor (NR) activation, increased hepatocellular proliferation, and subsequent hepatocellular foci and tumor formation. Uncertainty as to the relevance of this MoA for females remained given the increased sensitivity to tumor formation in female mice. A targeted MoA study was conducted to evaluate CAR activation and hepatic responses in female mice treated with the female carcinogenic dose of nitrapyrin for 4 days. Nitrapyrin induced a treatment-related increase in hepatocellular hypertrophy and hepatocellular proliferation. Nitrapyrin also induced a dose-related increase in the Cyp2b10/CAR-associated transcript and liver weights. Nitrapyrin-induced liver weights and Cyp2b10 gene expression for both males and females were compared to data generated from three other established CAR activators; methyl isobutyl ketone, phenobarbital, and sulfoxaflor. The response observed in female mice following exposure to nitrapyrin was within range of the degree of change observed in mice following exposure to tumorigenic doses of other CAR activators. Consistent with the liver MoA in male mice, these data support a CAR-mediated mode of action for nitrapyrin-induced liver tumors in female mice, with the understanding that a focused approach minimizing animal use can bridge male and female datasets when sex-specific carcinogenic differences are observed.

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