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Liver in humanized-liver mice: Control vs 4,4'-Methylenebis(2-chlorobenzenamine) treatment

ABSTRACT: The gene expression profiling between Control and 4,4'-Methylenebis(2-chlorobenzenamine) exposure for 4 weeks in liver of F1-TKm30 female mice transplanted with commercially available human hepatocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253614 | GEO | 2024/11/11

REPOSITORIES: GEO

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Liver in humanized-liver mice: Control vs ortho-toluidine treatment

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Liver in F1-TKm30 mice: Control vs 4,4'-Methylenebis(2-chlorobenzenamine) treatment

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Liver in F1-TKm30 mice: Control vs 4,4'-Methylenebis(2-chlorobenzenamine) treatment

Project description:Liver in F1-TKm30 mice: Control vs 4,4'-Methylenebis(2-chlorobenzenamine) treatment

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Project description:Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, since rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling, and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/ß-catenin signaling when compared to those of hCAR/hPXR mice, wild type mice and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators, whereas the hCAR/hPXR mouse is not.

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