Christopher A. Bradfield, Ph.D.
University of Wisconsin Medical School
Background: Recent NIEHS-supported research has shown that the aryl hydrocarbon receptor plays a role in the closure of a fetal blood vessel known as the ductus venosus. The ductus venosus is a vessel that functions during development to shunt blood from the umbilical vein to the heart, bypassing the fetal liver. Its role during development is to direct highly oxygenated and nutrient rich blood to the brain and heart bypassing the liver where it is less needed. In humans, the ductus venosus is usually closed within a month of birth and normal blood flow to the liver is established.
Research in the same laboratory has expanded the body of knowledge of the role of the Ah receptor in xenobiotic metabolism. The receptor is known to up-regulate a variety of xenobiotic metabolizing enzymes including the cytochromes P450 and glutathione transferase. In response to exposure to dioxins, Ah receptor activation leads to a bevy of toxic responses including liver cell damage, involution of the thymus, over growth of epithelial cells, birth defects, and cancer. A great deal is known about the structure, activation, and biology of the receptor; however, how it accomplishes its varied functions with a similar signal transduction mechanism is unclear.
Advance: Expanding on their past work, these investigators hypothesized that receptor signaling in different cell types is responsible for the varied functions of the Ah receptor. To test their theory, they employed Cre-lox technology to determine what effect Ah receptor activation in either hepatocytes or endothelial cells has on the varied pathways of Ah receptor signaling in the liver. Cre-lox technology is a means to efficiently edit and manipulate the genome of a variety of organisms. It permits the controlled expression of certain genes and can streamline research systems and reduce the laborious traditional procedures of developing individual transgenic models. Results from these studies confirm that Ah receptor activation in endothelial cells is responsible for the closure of the ductus venosus. However Ah receptor signaling in hepatocytes is responsible for the adaptive and toxic responses of the liver in response to dioxin exposure.
Implications: These data demonstrate that receptor signaling in specific cells is responsible for the generation of distinct Ah receptor-dependent physiological outcomes. These findings aid in the understanding of Ah receptor function and could have implications in the treatment of dioxin toxicity and the rare condition of a patent ductus venosus.
Citation: Walisser JA, Glover E, Pande K, Liss AL, Bradfield CA. Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17858-63.