The aryl hydrocarbon (Ah) receptor has occupied the attention of toxicologists for over two decades. Interest arose from the early observation that this soluble protein played key roles in the adaptive metabolic response to polycyclic aromatic hydrocarbons and in the toxic mechanism of halogenated dioxins and dibenzofurans. More recent investigations have provided a fairly clear picture of the primary adaptive signaling pathway, from agonist binding to the transcriptional activation of genes involved in the metabolism of xenobiotics. Structure-activity studies have provided an understanding of the pharmacology of this receptor; recombinant DNA approaches have identified the enhancer sequences through which this factor regulates gene expression; and functional analysis of cloned cDNAs has allowed the characterization of the major signaling components in this pathway. Our objective is to review the Ah receptor's role in regulation of xenobiotic metabolism and use this model as a framework for understanding the less well-characterized mechanism of dioxin toxicity. In addition, it is hoped that this information can serve as a model for future efforts to understand an emerging superfamily of related signaling pathways that control biological responses to an array of environmental stimuli.

Ah receptor signaling pathways

A review of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced changes in immunocompetence: 1991 update.

Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and structurally similar halogenated aromatic hydrocarbons cause a broad range of immunologic effects in experimental animals including decreased host resistance to infectious disease and suppressed humoral and cell-mediated immune responses. In the mouse, TCDD immunotoxicity has been shown to be an aryl hydrocarbon (Ah) receptor-dependent process. However, despite considerable research, the biochemical and molecular alterations that occur subsequent to Ah receptor activation that lead to altered immune reactivity remain to be elucidated. In addition to immune suppression, TCDD promotes inflammatory responses. This effect may result from an upregulation of the production of inflammatory cytokines such as interleukin-1 and tumor necrosis factor. Nonhuman primates exposed to TCDD show suppressed antibody responses and changes in lymphocyte subsets in the peripheral blood. The immunotoxic effects of TCDD in humans are poorly characterized, and few studies have examined the immune status of individuals with known, documented exposure to TCDD. It is important for laboratory research to focus on defining TCDD-sensitive immunologic biomarkers in animal models that can also be used in human subjects. Understanding the mechanisms that underlie species differences in TCDD immunotoxicity is also of critical importance for extrapolation of effects seen in laboratory animals to man.

Robert K. Dooley

Papers

Direct suppression of antibody responses by chlorinated dibenzodioxins in cultured spleen cells from (C57BL/6 × C3H)F1 and DBA/2 mice