Liver Deformation in Ahr-Null Mice: Evidence for Aberrant Hepatic Perfusion In Early Development

Abstract

Mice harboring mutations in the Ahr locus display a patent ductus venosus and smaller livers throughout life. We tested the hypothesis that these hepatic aberrations are secondary to a developmental defect in hepatovascular blood flow by performing a detailed analysis of hepatic development in wild-type and Ahr Ϫ/Ϫ mice. This study revealed necrotic lesions in the peripheries of Ahr Ϫ/Ϫ fetal livers as early as embryonic day 15.5, with an increasing incidence up to postnatal day 1 and resolution by 2 weeks post partum. To visualize perfusion of fetal livers, we injected fluorescein isothiocyanate-labeled dextran into the cranial artery and monitored hepatic fluorescence by microscopy. The peripheries of the median and left lobes displayed decreased perfusion in regions corresponding to those regions that displayed necrosis at later developmental times. An examination of adult Ahr Ϫ/Ϫ animals revealed that smaller livers are predominantly due to decreased sizes of the left and right lobes, corresponding to regions of decreased perfusion and hepatic necrosis observed in fetal livers. Histological aberrations in the portal vein also support a model in which perfusion is compromised in the Ahr Ϫ/Ϫ liver. Taken in sum, these results indicate that the Ahr locus is required for normal perfusion of the developing liver and that disruption of the AHR signaling pathway gives rise to fetal hepatic necrosis and consequent liver deformation which persists through adulthood.

Dioxin-Produced Alteration in the Profiles of Fecal and Urinary Metabolomes: A Change in Bile Acids and Its Relevance to Toxicity

“…Although it has been established that dioxin-produced hepatotoxicity occurs via an AhR-governed mechanism, [3][4][5] knocking-out of AhR results in atrophy and dysfunction of the liver even in the absence of dioxin treatment. [3][4][5]37) Thus, it is likely that the endogenous activation of AhR is important for the maintenance of hepatic function and morphology. [3][4][5]37) This study suggests that restricting food intake alters the levels of tryptophan metabolites including a reduction in urinary excretion of L-kynurenine which is a candidate endogenous AhR ligand.…”

“…[3][4][5]37) Thus, it is likely that the endogenous activation of AhR is important for the maintenance of hepatic function and morphology. [3][4][5]37) This study suggests that restricting food intake alters the levels of tryptophan metabolites including a reduction in urinary excretion of L-kynurenine which is a candidate endogenous AhR ligand. 38) Such attenuation in AhR ligand possibly produces a rise in abnormal morphology and liver function.…”

Omeprazole Stimulates the Induction of Human Insulin-Like Growth Factor Binding Protein-1 through Aryl Hydrocarbon Receptor Activation

“…ahr (Ϫ/Ϫ) mice, although viable, exhibit multiple organ dysfunction (Schmidt et al, 1996), abnormal vasculature (Harstad et al, 2006), compromised immune system (Rodríguez-Sosa et al, 2005), and reduced life span and limited fertility (Abbott et al, 1999). In line with these phenotypic abnormalities, the repertoire of AhR-regulated genes, the "AhR battery" now incorporates targets not directly involved in detoxification.…”

Development and characterization of monoclonal antibodies against human aryl hydrocarbon receptor

“…In the immune system, AhR was involved in regulating the antigen responses in Th17 cells, dendritic cells, and other adaptive immune cells (Esser, 2009;Esser et al, 2009;Tian et al, 2015). In addition, smaller liver size and hepatic deformation were observed in adult AhR KO mice (Harstad et al, 2006), and the animals were more likely to develop liver tumors after exposure to diethylnitrosamine (Fan et al, 2010). Besides, a recent investigation demonstrated that AhR KO mice had a higher risk of developing bladder stones (Butler et al, 2012).…”