Aryl hydrocarbon receptors: diversity and evolution1
Introduction
Most animals, including humans, are exposed daily to a multitude of chemicals in the air, water, or food. Some of these chemicals are signaling molecules that carry valuable information about the animal's environment (e.g. the presence of food, predators, or members of the opposite sex), while others are toxic, and must be avoided or eliminated. Animals have evolved a variety of mechanisms to detect and respond to these chemicals. Like the adaptive immune system, which is capable of recognizing and responding to a wide variety of antigens, chemical surveillance systems have evolved as mechanisms for recognizing a broad range of chemical structures and initiating appropriate responses.
One component of this chemical surveillance system consists of large families of olfactory/chemosensory receptors that in both vertebrate and invertebrate animals serve to detect volatile and soluble chemicals in their environment [1]. Stimulation of these receptors initiates physiological and behavioral responses that are transduced through neural pathways.
In addition to the olfactory/chemosensory system, animals have evolved inducible enzymes and transporters to facilitate the biotransformation and elimination of toxic compounds encountered in the environment [2], [3], [4]. The enzymatic components of this inducible biotransformation system are well-known and include monooxygenases in the cytochrome P450 superfamily as well as conjugating enzymes such as the glutathione transferases and glucuronosyl transferases. The transporter components of this system include the ATP binding cassette (ABC) proteins, which act as efflux pumps to remove metabolites of endogenous and xenobiotic chemicals from cells [5]. The sensory component of this system consists of soluble receptors that regulate the expression of the biotransformation and transporter genes in response to environmental chemicals. These receptors include several members of the steroid/nuclear receptor superfamily [6], [7], [8], [9], [10] as well as the aryl hydrocarbon receptor (AHR), a member of the basic-helix-loop-helix (bHLH)–Per-ARNT-Sim (PAS) gene superfamily and the subject of this review.
This adaptive function of the AHR is well-known and has been studied for more than 30 years. Initially, scientists were intrigued by the extreme toxic potency of chlorinated dibenzo-p-dioxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in animals [11], [12]. Later, they became fascinated by the potency of TCDD for eliciting biochemical effects [13], [14] such as induction of aryl hydrocarbon hydroxylase (AHH) activity (now known to be catalyzed primarily by cytochrome P4501A1 (CYP1A1)), as well as by the strict structure–activity relationships for this effect [15], [16], [17] and the dramatic mouse strain differences in sensitivity [18], [19]. These observations led to the prediction [20] and then discovery [21] of the AHR as an ‘induction receptor’ that controls the expression of AHH activity. Since that time, the mechanism by which the AHR regulates the induction of adaptive enzymes, especially CYP1A1, has been studied extensively [22]. Although originally thought to have a relatively narrow structural specificity [23], the AHR is now known to recognize an impressive range of chemical structures, including non-aromatic and non-halogenated compounds [24]. Such promiscuity is understandable in the context of this adaptive function.
Although it is clear that, in regulating biotransformation enzymes, the AHR serves an important adaptive function, other data suggest that the function of this protein is much more complex. For example, the toxicities associated with exposure to TCDD and related compounds [23], [25] lead one to conclude that these chemicals are interfering with important physiological functions in addition to inducing biotransformation enzymes. Cloning of the AHR cDNA [26], [27] and gene [28] in rodents has resulted in fundamental advances in our understanding of the AHR and its possible functions. AHR-null mice [29], [30] were used to demonstrate that the AHR is necessary for most, if not all, of the effects of TCDD and (presumably) other PHAHs [31], [32], [33], [34], [35], [36], [37]. More importantly, examination of AHR-null mice that had not been treated with exogenous chemicals revealed alterations in the liver, immune system, ovary, heart, and other organs [29], [30], [36], [38], [39], [40], [41], [42], [43]. Although some of these effects could be secondary to loss of regulation of biotransformation enzymes, it seems likely that at least some of these changes are due to a loss of other AHR functions. What are these functions?
One approach to understanding AHR function has been to study it in a broader biological context, by characterizing the AHR in diverse species. Such studies are valuable for several reasons. First, by using a variety of animal models, it is possible to take advantage of the unique features of each model. The fly Drosophila melanogaster[44], [45], the nematode Caenorhabditis elegans[46], [47], the zebrafish Danio rerio[48], [49], the pufferfish Takifugurubripes[50], [51] and other model species each offer advantages that can be exploited to better understand AHR function. Second, comparative studies can lead to the identification of novel features of the AHR that can provide new information about its functions and mechanisms. Finally, studies carried out in diverse species provide phylogenetic information that allows inferences to be made about the evolution of the AHR signaling pathway. This review summarizes recent findings that relate to AHR diversity among animal species and the evolutionary history of the AHR gene and its functions, as inferred from molecular studies in vertebrate and invertebrate animals.
Section snippets
AHR diversity
The AHR is a member of the bHLH-PAS superfamily of transcription factors [52], [53], [54]. Proteins with PAS-related domains occur in organisms as diverse as animals, plants, fungi, bacteria, and archea [53], [55], [56], [57], [58], [59]. In contrast, AHR homologs are known only from metazoans, but they are present in several phyla and in model species for which powerful genetic and developmental approaches have been established. The presence of AHRs in a variety of animal species provides an
AHR repressor: a third member of the AHR family
Fujii-Kuriyama and coworkers recently identified a mouse protein closely related to the AHR, designated AHR repressor (AHRR) [162]. Although in some features it closely resembles the AHRs, it differs in several interesting ways. AHR and AHRR share a high degree of sequence identity in the bHLH and PAS-A domains, but the AHRR PAS-B domain, which in AHRs constitutes the ligand-binding domain [26], [163], [164], [165], is highly divergent in AHRR [162]. Consistent with this, the AHRR does not bind
Diversity and diversification of the bHLH–PAS gene superfamily in metazoans
The availability of completed genome sequences for C. elegans[139], D. melanogaster[167], and Homo sapiens[168], [169] has provided an opportunity to compare the diversity of bHLH–PAS genes in two invertebrates and a vertebrate chordate (Table 3). The C. elegans genome contains at least five bHLH–PAS genes, while at least 12 have been identified in D. melanogaster and 23 are known from humans. For at least three genes (AHR, ARNT, and HIF, and possibly Met, Sim, or Trh), there are confirmed
Concluding remarks
What have comparative studies taught us about the AHR signaling pathway? Certainly, it is clear now that the AHR is an ancient protein that was present in early bilateral metazoans and exists today in at least three extant invertebrate phyla. In the vertebrate lineage, however, the AHR gene has undergone duplication and diversification resulting in a family of AHR-related genes (AHR1, AHR2, AHRR), all apparently involved in dioxin signaling.
Even within the vertebrates, the diversity of AHR and
Acknowledgements
This work was supported by NIH grant ES06272. I thank Jo Anne Powell-Coffman for generously communicating results and sequences prior to publication and Sibel Karchner, Rebeka Merson, and Robert Tanguay for helpful comments on the manuscript. I also thank many colleagues who contributed to the findings reviewed here. This is contribution number 10588 from the Woods Hole Oceanographic Institution.
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