New Trends in Aryl Hydrocarbon Receptor Biology

Abstract

Traditionally considered as a critical intermediate in the toxic and carcinogenic response to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), the Aryl hydrocarbon/Dioxin receptor (AhR) has proven to be also an important regulator of cell physiology and organ homeostasis. AhR has become an interesting and actual area of research mainly boosted by a significant number of recent studies analyzing its contribution to the proper functioning of the immune, hepatic, cardiovascular, vascular and reproductive systems. At the cellular level, AhR establishes functional interactions with signaling pathways governing cell proliferation and cell cycle, cell morphology, cell adhesion and cell migration. Two exciting new aspects in AhR biology deal with its implication in the control of cell differentiation and its more than likely involvement in cell pluripotency and stemness. In fact, it is possible that AhR could help modulate the balance between differentiation and pluripotency in normal and transformed tumor cells. At the molecular level, AhR regulates an increasingly large array of physiologically relevant genes either by traditional transcription-dependent mechanisms or by unforeseen processes involving genomic insulators, chromatin dynamics and the transcription of mobile genetic elements. AhR is also closely related to epigenetics, not only from the point of view of target gene expression but also with respect to its own regulation by promoter methylation. It is reasonable to consider that deregulation of these many functions could have a causative role, or at least contribute to, human disease. Consequently, several laboratories have proposed that AhR could be a valuable tool as diagnostic marker and/or therapeutic target in human pathologies. An additional point of interest is the possibility of regulating AhR activity by endogenous non-toxic low weight molecules agonist or antagonist molecules that could be present or included in the diet. In this review, we will address these molecular and functional features of AhR biology within physiological and pathological contexts.

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells

“…The AhR is a ubiquitous nuclear factor that mediates toxic and/or adaptive responses in a cell-type and ligand-specific manner. 40 In a chronic pancreatitis model, AhR activation in T cells elicited IL-22 secretion associated with promotion of the fibrotic pancreatic stellate cell phenotype. 29 Given the robust activation of AhR by smoking compounds in acinar as well as immune cells, the specific role of AhR on adaptive/inflammatory responses in different cell types participating in smoking-related pancreatic disorders deserves further investigation.…”

Diversity as opportunity: Insights from 600 million years of AHR evolution

“…However, early on it was recognized by some investigators that study of this receptor and its high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) offered potential insights into fundamental biological processes, in the same way that other potent toxins and toxicants have been used to understand cellular functions [6]. Now, it is widely acknowledged that the AHR has multiple functions beyond toxicology [7–10], and the past decade has ushered in a new and exciting era in AHR biology as experts from a variety of fields in biomedicine have turned their attention to elucidate the roles of this pleiotropic protein in cell and developmental biology, immunology, and human disease.…”

Spermatogenesis disruption by dioxins: Epigenetic reprograming and windows of susceptibility

“…Upon entering the cell, TCDD binds to the cytosolic AhR and is then translocated to the nucleus where it forms another complex with the AhR nuclear translocator (ARNT) protein. Ligand/AhR/ARNT complex bind to dioxin response elements (DRE) on DNA, enhancing the transcription of specific genes [20–22] responsible for breakdown of toxic compounds [23]. While this mechanism is thought to confer protection from toxin exposure, TCDD-dependent AhR dysregulation of gene expression activates Phase I xenobiotic-metabolizing enzymes, which may be deleterious.…”