Dioxin Receptor Important for Vascular Development

Christopher A. Bradfield, Ph.D.
University of Wisconsin Medical School
R01ES06883

Background: The aryl hydrocarbon receptor is a transcription factor that is involved in three biological pathways. First, it is involved in initiating biological processes designed to detoxify various polycyclic aromatic hydrocarbons, which are common environmental pollutants. Second, upon exposure to the environmental toxicant, dioxin, activity of the aryl hydrocarbon receptor results in a variety of toxic responses that include abnormal skin growth, birth defects and liver toxicity/cancer. Third, the aryl hydrocarbon receptor has a role in the development of the fetus and particularly during the few days surrounding birth. 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 very important because it directs highly oxygenated and nutrient rich blood to the brain and heart and away from 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. This closure is important for the development of the adult circulation in the liver. But, on rare occasions, the ductus venosus fails to close appropriately. The consequences of having an open ductus venosus as an adult include glaucoma, difficulty breathing and central nervous system toxicity.

Advance: Previous research by this NIEHS-supported researcher has shown that genetically modified laboratory mice lacking the gene coding for the aryl hydrocarbon receptor have smaller than normal livers. Further investigation in this laboratory identified the cause of the small liver size as a failure of the ductus venosus to close resulting in disrupted blood flow to the liver, similar to that seen in the abnormal condition in humans. Furthering this line of inquiry, these researchers have gone on to make other genetically modified mice that produce only small quantities of the aryl hydrocarbon receptor or its partner ARNT. These mice are called hypomorphs. The fetal blood vessel also fails to close in these hypomorphs, similar to that seen in mice that completely lack the aryl hydrocarbon receptor. However, when the researchers exposed the hypomorphs to small amounts of dioxin during gestation, the ductus venosus closed appropriately, as in normal mice. The research demonstrates that activation of the aryl hydrocarbon receptor is necessary for normal closure of the ductus venosus.

Implications: This finding represents one of the first reports of a possible therapeutic use of dioxin, which is the polar opposite of the more common reported harmful effects of the substance. The authors have begun investigations with clinicians to determine if children with unclosed ductus venosae have disruptions in the aryl hydrocarbon receptor signal transduction pathways. The current findings could lead to new treatments for this condition, which presumably would be less invasive than the currently used surgical procedure. The new mouse model developed for this work will also enable these researchers to make further discoveries regarding the biological roles of the aryl hydrocarbon receptor.

Citation: Walisser JA, Bunger MK, Glover E, Bradfield CA. Gestational exposure of Ahr and Arnt hypomorphs to dioxin rescues vascular development. Proc Natl Acad Sci 101(47):16677-16682.