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

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.

Androgens regulate the binding of endogenous HuR to the AU-rich 3'UTRs of HIF-1alpha and EGF mRNA.

The 3'UTRs of mammalian HIF-1alpha and EGF mRNA contain several highly conserved AU-rich elements (ARE) known to control the turnover of labile mRNAs by binding ARE-binding proteins that regulate nucleocytoplasmic shuttling, translation, and degradation. Androgens regulate the level and subcellular shuttling of HuR, a major ARE-binding protein that stabilizes many ARE-mRNAs. Pull down of biotinylated 3'UTRs of HIF-1alpha or EGF enriches HuR on blots from Jurkat cell lysates 5-fold, and enriches the amount of RNase-protected biotinylated RNA that comigrates with HuR approximately 10-fold. Dihydrotestosterone treatment decreases the HuR-protected riboprobe pulled down from total Jurkat cell lysates by 30-40%, apparently reflecting shifts in HuR from the nucleus to the cytoplasm. Androgen treatment also changes the amount of HuR-protected riboprobe pulled down from a PC-3 clone expressing a functional androgen receptor. The shift in the amount of riboprobe bound by HuR suggests that androgen is up-regulating endogenous ARE-mRNAs that can compete for binding endogenous HuR. These changes in the shuttling and ARE-binding of endogenous HuR indicate that androgen can act posttranscriptionally to regulate ARE-mRNAs, including HIF-1alpha and EGF.