Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Abstract

A physiological examination of mice harboring a null allele at the aryl hydrocarbon (Ah) locus revealed that the encoded aryl hydrocarbon receptor plays a role in the resolution of fetal vascular structures during development. Although the aryl hydrocarbon receptor is more commonly studied for its role in regulating xenobiotic metabolism and dioxin toxicity, a developmental role of this protein is supported by the observation that Ah null mice display smaller livers, reduced fecundity, and decreased body weights. Upon investigating the liver phenotype, we found that the decrease in liver size is directly related to a reduction in hepatocyte size. We also found that smaller hepatocyte size is the result of massive portosystemic shunting in null animals. Colloidal carbon uptake and microsphere perfusion studies indicated that 56% of portal blood flow bypasses the liver sinusoids. Latex corrosion casts and angiography demonstrated that shunting is consistent with the existence of a patent ductus venosus in adult animals. Importantly, fetal vascular structures were also observed at other sites. Intravital microscopy demonstrated an immature sinusoidal architecture in the liver and persistent hyaloid arteries in the eyes of adult Ah null mice, whereas corrosion casting experiments described aberrations in kidney vascular patterns.T he aryl hydrocarbon receptor (AHR) is a member of the per-arnt-sim (PAS) superfamily of proteins. The AHR regulates biological responses to a variety of environmental contaminants, such as the polycyclic aromatic hydrocarbons found in cigarette smoke, the polychlorinated dioxins that contaminate industrial chemicals, and the wartime defoliant Agent Orange (1-5). These chemical ligands bind to the AHR, leading to receptor dimerization with another PAS protein known as the aryl hydrocarbon nuclear translocator (ARNT). This heterocomplex interacts with genomic enhancer elements upstream of a battery of target genes that encode xenobiotic metabolizing enzymes (1, 6, 7). The observation that the up-regulated enzymes often have metabolic activity toward AHR agonists has led to the idea that this pathway represents an adaptive metabolic response that protects an organism from exposure to certain classes of toxic environmental contaminants. Although this adaptive role has considerable experimental support, this pathway is not always protective. Exposure to high-affinity AHR agonists, like the chlorinated dioxins, can result in cancer (8), immunosuppression (9), liver damage (10), and birth defects (11). The mechanisms underlying these toxic effects are unknown but appear to be AHR mediated.Because of its role in mediating responses to environmental contaminants, the biology of the AHR has been extensively characterized from a toxicological viewpoint. However, several observations suggest an additional role for the AHR in vertebrate development. First, a phylogenetic survey indicates that the AHR arose over 450 million years ago, with functional orthologs found in species that have evolved in vario...

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

“…In the mammalian fetus and in fish larvae, the AHR plays prominent roles in both resolving vascular structures and mediating cardiovascular toxicities of TCDD (Lahvis et al, 2000;Bello et al, 2004). In mammals, the importance of functional AHR is demonstrated in AHR-null mice by a failure of a fetal vascular structure, the ductus venosus, to close, thus permitting blood from the portal vein to bypass the liver by shunting to the inferior vena cava.…”

“…In mammals, the importance of functional AHR is demonstrated in AHR-null mice by a failure of a fetal vascular structure, the ductus venosus, to close, thus permitting blood from the portal vein to bypass the liver by shunting to the inferior vena cava. Functional AHR is also required for normal vascular "pruning" during fetal development, the absence of which results in the propagation into maturity the highly anastomotic vasculature architecture of the liver, eye and kidney that that are characteristically neonatal (Lahvis et al, 2000).…”

“…It has been hypothesized that the AHR/ARNT transcriptional complex evolved for defense against an increasingly diverse array of plant toxins and as a result it is unlikely to serve endogenous physiological functions (Gonzalez et al, 1990). More recently however, the AHR has emerged as an important regulator of physiologic and developmental processes in the absence of an apparent exogenous (xenobiotic) ligand (Fernandez-Salguero et al, 1997;Lahvis et al, 2000). The AHR represents a pivotal upstream event in the apoptosis cascade (Nebert et al, 2000;Slim et al, 2000;Dong et al, 2004), exerts an important level of influence on reproductive success (Abbott et al, 1999) and participates in cell cycle regulation (Puga et al, 2002;Marlowe et al, 2004).…”

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

“…The wide range of toxic effects induced by these compounds, including birth defects, impaired reproductive capacity and altered immune responses, have encouraged research on the interaction of AhR with sex steroid receptors and the immune system (Ohtake et al, 2008;Quintana et al, 2008;Veldhoen et al, 2008). AhR regulates cellular differentiation during development (Huang et al, 2004;Lahvis et al, 2000) and may promote cell cycle progression in the absence of exogenous ligand (Chang et al, 2007;Marlowe and Puga, 2005). There is also an emerging evidence for a prominent role of AhR in tumorigenesis.…”

Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor levels in murine and human liver

“…AhR is also known to affect vascular development, as demonstrated by persistent ductus venosus and microvasculature abnormalities in the livers of AhRnull mice. 14 Recently, it has been demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure severely impairs the regenerative ability of partially excised mouse livers, 15 an effect most likely mediated through AhR. On the other hand, TCDD is also known to be a potent tumor promoter in mouse liver.…”