ToxSci Advance Access originally published online on November 17, 2007
Toxicological Sciences 2008 102(1):160-170; doi:10.1093/toxsci/kfm283
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The Aryl Hydrocarbon Receptor Affects Distinct Tissue Compartments during Ontogeny of the Immune System
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* Department of Pharmaceutical Sciences, Center for Reproductive Biology and Biotechnology Training Program, Washington State University, Pullman, Washington 99164
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
1 To whom correspondence should be addressed at Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 575 Elmwood Ave, Box 850, Rochester, NY 14642. Tel: (585) 275-1974. Fax: (585) 276-0239. E-mail: paige_lawrence{at}urmc.rochester.edu.
Received September 21, 2007; accepted November 12, 2007
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Abstract |
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There is growing evidence that prenatal and early postnatal environmental factors influence the development and programming of the immune system, causing long-lasting negative health consequences. The aryl hydrocarbon receptor (AhR) is an important modulator of the development and function of the immune system; however, the mechanism is poorly understood. Exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin throughout gestation and during lactation yields adult offspring with persistent defects in their immune response to influenza virus. These functional alterations include suppressed lymphocyte responses and increased inflammation in the infected lung despite normal cellularity and anatomical development of lymphoid organs. The studies presented here were conducted to determine the critical period during immune ontogeny that is particularly sensitive to inappropriate AhR activation. We also investigated the contribution of AhR-mediated events within and extrinsic to hematopoietic cells. Our findings show that AhR activation alters different elements of the immune system at different times during development by affecting different tissue targets. In particular, diminished T-cell responses arise due to deregulated events within bone marrow–derived cells. In contrast, increased interferon gamma levels in the infected lung result from AhR-regulated events extrinsic to bone marrow–derived cells, and require AhR agonist exposure during early gestation. The persistence of AhR activation induced immune modulation was also compared, revealing that AhR activation causes long-lasting functional alterations in the developing immune system, whereas the impact on the mature immune system is transient.
Key Words: developmental immunotoxicity; hematopoietic cells; infection; influenza virus; dioxin.
Jason P. Hogaboam and Amanda J. Moore contributed equally to the experimental work presented.