Aryl hydrocarbon receptors: diversity and evolution

Animals have evolved inducible enzymatic defenses to facilitate the biotransformation and elimination of toxic compounds encountered in the environment. The sensory component of this system consists of soluble receptors that regulate the expression of certain isoforms of cytochrome P450, other enzymes, and transporters in response to environmental chemicals. These receptors include several members of the steroid/nuclear receptor superfamily as well as the aryl hydrocarbon receptor (AHR), a member of the bHLH-PAS gene superfamily. In addition to its adaptive functions, the AHR serves poorly understood physiological roles; interference with those roles by dioxins and related chemicals causes toxicity. One approach to understanding the physiological significance of the AHR is to characterize its structure, function, and regulation in diverse species, including mammals, birds, fish, and invertebrates. These animal groups include model species with unique features that can be exploited to broaden our understanding of AHR function. Studies carried out in diverse species also provide phylogenetic information that allows inferences about the evolutionary history of the AHR. This review summarizes the current understanding of AHR diversity among animal species and the evolution of the AHR signaling pathway, as inferred from molecular studies in vertebrate and invertebrate animals. The AHR gene has undergone duplication and diversification in vertebrate animals, resulting in at least three members of an AHR gene family: AHR1, AHR2, and AHR repressor. The inability of invertebrate AHR homologs to bind dioxins and related chemicals, along with other evidence, suggests that the adaptive role of the AHR as a regulator of xenobiotic metabolizing enzymes may have been a vertebrate innovation. The physiological functions of the AHR during development appear to be ancestral to the adaptive functions. Sensitivity to the developmental toxicity of dioxins and related chemicals may have had its origin in the evolution of dioxin-binding capacity of the AHR in the vertebrate lineage.     

Estrous cycle-dependent changes in the expression of aromatic hydrocarbon receptor (AHR) and AHR-nuclear translocator (ARNT) mRNAs in the rat ovary and liver

The aromatic hydrocarbon receptor (AHR) and AHR nuclear translocator protein (ARNT) mediate the toxic effects of a wide variety of halogenated and polycyclic aromatic hydrocarbons. While it can be assumed that AHR has an endogenous function, its role in reproduction is currently undefined. The present study seeks to examine the regulation of AHR and ARNT mRNAs in liver and ovarian tissues across the rat estrous cycle. Message for hepatic AHR was increased significantly on the morning of proestrus, and decreased dramatically by the evening of proestrus; while hepatic ARNT mRNA was significantly decreased between diestrus and the morning of proestrus, and between the evening of proestrus and the morning of estrus. Ovarian AHR mRNA was unchanged from diestrus to proestrus, and was decreased on the evening of proestrus. Changes in the expression of ARNT mRNA mirrored changes in the liver. To assess interaction between the AHR- and estrogen-receptor (ER)-signaling pathways and to test the hypothesis that estrogen regulates AHR mRNA, 25-day-old female rats were injected with either 17beta-estradiol, the ER antagonist ICI 182 780, or with vehicle, and hepatic AHR mRNA was measured. Treatment with estrogen or the estrogen antagonist did not alter the abundance of AHR mRNA in the liver. These data suggest that while estrogen may not be the key regulator of AHR mRNA expression, a factor associated with the rat reproductive cycle may be important in regulating the expression of both the AHR and ARNT genes in the ovary and liver.     

The AH receptor of the most dioxin-sensitive species, guinea pig, is highly homologous to the human AH receptor

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) brings about a wide spectrum of toxic and biochemical changes, most of which are mediated by the AH receptor (AHR). Recent cloning of the AHR from the two most TCDD-resistant laboratory animals, Han/Wistar (Kuopio) rats and hamsters, suggested a critical role for the C-terminal transactivation domain structure in TCDD sensitivity. Here we cloned the AHR from the most TCDD-susceptible species, guinea pig. The N-terminus of its AHR was highly similar to that in the resistant animals. However, the C-terminal Q-rich subdomain was only about half the size of this subunit in the hamster AHR. There was a distinct correlation across published mammalian species between the number of glutamine residues in the Q-rich subdomain and sensitivity to the acute lethality of TCDD. The closest homolog of the Guinea pig receptor turned out to be the human AHR, which may be relevant for dioxin risk assessment.