Liver deformation in Ahr-null mice: evidence for aberrant hepatic perfusion in early development.
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-/- mice. This study revealed necrotic lesions in the peripheries of Ahr-/- 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-/- 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-/- 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 adult-hood.
Harstad
Eric B
EB
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53711, USA.
Guite
Christopher A
CA
Thomae
Tami L
TL
Bradfield
Christopher A
CA
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D003433:Crosses, Genetic; D047108:Embryonic Development; D005260:Female; D008099:Liver / Q000002:abnormalities* / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D008102:Liver Circulation / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010477:Perfusion; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse