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Researcher Presents Strategy for Studying Environmental AhR Modulation

By Brian Chorley
January 2009

Coauthors Jennifer Head, left, and Paige Lawrence are shown in their lab at the University of Rochester (UR). Head is a third-year graduate student at UR, supported by an NIEHS-funded Institutional Research Training Grant. (Photo courtesy of Paige Lawrence)

In the wake of her 2008 study of dioxin's effects on the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) and influenza A infection in mice, NIEHS grantee B. Paige Lawrence, Ph.D., has published a review of research on AhR modulation of anti-viral immunity that translates mechanistic research by her and others into a proposed research agenda based on a unified hypothesis - "that environmental signals delivered via the AhR influence anti-viral immune defenses." The review is part of a special issue of the journal Biochemical Pharmacology devoted to "Biological Functions of the Ah Receptor: Beyond Induction of Cytochrome P450s."

Lawrence is an associate professor of Environmental Medicine and Microbiology and Immunology at the University of Rochester School of Medicine and Dentistry. She and coauthor Jennifer L. Head argue in the review ( Exit NIEHS that more research could be useful in preparing for "the global health threat posed by viruses" and "stimulate new therapies to aid in the treatment of other diseases." According to the review, better understanding of how pollutants deregulate anti-viral immunity could yield "new information regarding specific aspects of the disease process that are susceptible to modulation." They propose that in addition to the canonical pathway of AhR-mediated transcriptional regulation, AhR modulation may work through interaction with signaling pathways, including non-genomic pathways, to influence immunity.

Much of the review focuses on the experimental mouse model of infection with human influenza A virus - the one Lawrence and colleagues used in their 2008 study ( Exit NIEHS of epigenetic alterations related to AhR activation. In those experiments, Lawrence's research team exposed pregnant and lactating mice to low doses of a common form of dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), thereby indirectly exposing fetuses and early postnatal pups during different periods of gestation and lactation. Depending on when the pups were exposed to TCDD, differential elements of the immune system were affected, purportedly through AhR modulation.

Specifically, after TCDD-exposed pups had matured, their ability to mount an immune response to influenza virus had diminished due to two separate mechanisms. It was observed that CD8+ T-cells decreased when pups were exposed to dioxin while nursing, and neutrophils increased if pups had been exposed during late gestation and nursing. These events were attributed to a diminished viral clearance and enhanced inflammation, respectively. Of note, the adult mother mice directly exposed to TCDD did not exhibit persistent defects in their immune response to viral infection, supporting the theory that these detrimental effects in the offspring were due to alteration during immune development.

In their review, Head and Lawrence point to several additional areas of AhR modulation that have not received the attention they merit. They observe that "specific effects of AhR activation on the immune response to other viruses have not been specifically examined in vivo." They also propose more research into the mechanisms that control excessive neutrophil recruitment during viral infection and into how AhR affects epithelial and endothelial cells, which are often overlooked as critical elements of innate host defenses.

Head JL, Lawrence BP ( Exit NIEHS. 2009. The aryl hydrocarbon receptor is a modulator of anti-viral immunity. Biochem Pharmacol 77(4):642-653.

Hogaboam JP, Moore AJ, Lawrence BP ( Exit NIEHS. 2008. The aryl hydrocarbon receptor affects distinct tissue compartments during ontogeny of the immune system. Toxicol Sci 102(1):160-170.

Dioxin as a Model AhR Trigger

Dioxins directly affect biological systems via binding to cellular environmental sensors known as Per-Arnt-Sim proteins. One well-studied member of this family of proteins is the aryl hydrocarbon receptor (AhR), which readily binds many environmental contaminants, including dioxins, making AhR an important mediator of immune development and function.

Dioxins are a group of chemically related chemicals that are produced from the combustion of chlorine containing substances. Low levels of dioxin naturally result from volcanic and forest fire activity, but the advent of industrial processes in the mid-18th century has exponentially increased dioxin release into the atmosphere. Today, dioxin production has considerably lessened due to restrictions on industrial emissions. However, combustion of coal, municipal waste, treated wood, and other chlorine-containing substances still contribute substantially to environmental dioxin pollution.

Diet is the main source of dioxin exposure in humans. Dioxins are highly lipophilic in nature and bioaccumulate in the fats of animals over time, due to their slow rate of elimination. Red meats, dairy, and chicken products are common reservoirs. Once consumed, the ingested dioxins can remain in human fat storage for an estimated 8 years or even longer, resulting in long-term exposure. Because of their persistence in tissues and the environment, dioxins' effects on physiology and health are of keen interest to researchers. Certain dioxins are known carcinogens, and a number of studies have found effects on reproduction, sexual development, and interrupted homeostasis of the epidermal, neurological and immune systems.

Because dioxin is quickly eliminated in about eight days from mice after exposure, study results are not directly translatable to humans; however, this physiologic aspect makes the mouse an excellent model to test for acute effects of dioxin exposure. Lawrence's own results support the conclusion that permanent detrimental effects to the immune system can occur through dioxin-mediated AhR activation during development.

Since dioxin exposure can occur through consumption of a high fat diet, avoidance of these foods may offer one of the several ways that changing environmental exposures may modulate disease processes.

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