The possible roles of environmental factors and the aryl hydrocarbon receptor in the prevalence of thyroid diseases in Vietnam era veterans

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) profoundly affects the immune system in experimental animals. TCDD was a contaminant in defoliants used in the Vietnam War, and is known to cause prolonged activation of the aryl hydrocarbon receptor (AhR) in humans. Chronic exposure to TCDD is associated with an increased prevalence of certain chronic diseases, lymphomas and leukemias. The AhR is a transcription factor that responds to cellular metabolites as well as to environmental substances. We review how TCDD and the AhR alter thyroid metabolism directly, and how recent experimental and clinical findings on TCDD and immunity are related to autoimmune thyroid diseases. TCDD exaggerates the normal responses of the AhR to endogenous activators, affecting dendritic cells, regulatory T cells (T(reg)), T(helper)17 (T(h)17) and T(helper)22 (T(h)22) cells. A recent study on approximately 225 000 veterans of the Vietnam era found that those who served in Vietnam or were otherwise exposed to defoliants had a 2.5-fold to three-fold higher prevalence of the diagnosis of Graves' disease, compared to Veterans who served elsewhere. The balance between T(reg), T(h)17 and T(h)22 cells is disrupted by TCDD, resembling what has been found clinically in Graves' disease and Hashimoto's thyroiditis, and in animal models of these diseases. By altering the immune balance in susceptible individuals, chronic TCDD exposure may influence the prevalence of autoimmune thyroid diseases.