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

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.

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p53 mutations are absent from carcinogen-induced mouse liver tumors but occur in cell lines established from these tumors

Molecular Carcinogenesis ◽

10.1002/mc.2940060210 ◽

1992 ◽

Vol 6 (2) ◽

pp. 148-158 ◽

Cited By ~ 54

Author(s):

Stefan Kress ◽

Jorg König ◽

Jürgen Schweizer ◽

Heinz Löhrke ◽

Richard Bauer-Hofmann ◽

...

Keyword(s):

Cell Lines ◽

Mouse Liver ◽

Liver Tumors ◽

P53 Mutations

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Growth hormone upregulates the pro-tumorigenic galectin 1 in mouse liver

Endocrine Connections ◽

10.1530/ec-19-0292 ◽

2019 ◽

Vol 8 (8) ◽

pp. 1108-1117 ◽

Cited By ~ 2

Author(s):

María L Bacigalupo ◽

Verónica G Piazza ◽

Nadia S Cicconi ◽

Pablo Carabias ◽

Andrzej Bartke ◽

...

Keyword(s):

Growth Hormone ◽

Transgenic Mice ◽

Mouse Liver ◽

Liver Tumors ◽

Tumor Development ◽

Hepatic Cancer ◽

Liver Pathology ◽

Liver Carcinogenesis ◽

Short Period ◽

Hcc Cells

Transgenic mice overexpressing growth hormone (GH) spontaneously develop liver tumors, including hepatocellular carcinoma (HCC), within a year. The preneoplastic liver pathology in these mice recapitulates that observed in humans at high risk of developing hepatic cancer. Although increased expression of galectin 1 (GAL1) in liver tissue is associated with HCC aggressiveness, a link between this glycan-binding protein and hormone-related tumor development has not yet been explored. In this study, we investigated GAL1 expression during liver tumor progression in mice continuously exposed to high levels of GH. GAL1 expression was determined by Western blotting, RT-qPCR and immunohistochemistry in the liver of transgenic mice overexpressing GH. Animals of representative ages at different stages of liver pathology were studied. GAL1 expression was upregulated in the liver of GH-transgenic mice. This effect was observed at early ages, when animals displayed no signs of liver disease or minimal histopathological alterations and was also detected in young adults with preneoplastic liver pathology. Remarkably, GAL1 upregulation was sustained during aging and its expression was particularly enhanced in liver tumors. GH also induced hepatic GAL1 expression in mice that were treated with this hormone for a short period. Moreover, GH triggered a rapid increment in GAL1 protein expression in human HCC cells, denoting a direct effect of the hormone on hepatocytes. Therefore, our results indicate that GH upregulates GAL1 expression in mouse liver, which may have critical implications in tumorigenesis. These findings suggest that this lectin could be implicated in hormone-driven liver carcinogenesis.

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