Halogenated aromatic hydrocarbons, represented by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are environmental pollutants that are produced by minor side-reactions in chemical manufacturing processes and by combustion of waste materials. These chemicals cause potent and pleiotropic toxicity, including teratogenesis, immune suppression, epithelial disorders, and tumor production in experimental animals. At the molecular level, aldehyde dehydrogenase, quinone reductase, and various drug-metabolizing enzymes are induced by the chemicals in some cultured cells and some tissues of experimental animals. All these biologic effects are thought to be mediated by an intracellular arylhydrocarbon receptor (AHR). Ema et al. (1994) isolated human cDNA for the AHR gene. This gene encodes a basic/helix-loop-helix protein that mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin.
NCBI Summary:
The aryl hydrocarbon (Ah) receptor is involved in the induction of several enzymes that participate in xenobiotic metabolism. The ligand-free, cytosolic form of the Ah receptor is complexed to heat shock protein 90. Binding of ligand, which includes dioxin and polycyclic aromatic hydrocarbons, results in translocation of the ligand-binding subunit only to the nucleus. Induction of enzymes involved in xenobiotic metabolism occurs through binding of the ligand-bound Ah receptor to xenobiotic responsive elements in the promoters of genes for these enzymes. This gene encodes a protein that forms a complex with the ligand-bound Ah receptor, and is required for receptor function. The encoded protein has also been identified as the beta subunit of a heterodimeric transcription factor, hypoxia-inducible factor 1 (HIF1). A t(1;12)(q21;p13) translocation, which results in a TEL-ARNT fusion protein, is associated with acute myeloblastic leukemia. Three alternatively spliced variants encoding different isoforms have been described for this gene. [provided by RefSeq]
General function
Receptor, Nucleic acid binding, DNA binding, Transcription factor
Comment
AhR is a transcription factor for which the endogenous ligand is not known. AhR can bind and be activated by a wide variety of xenobiotic compounds, resulting in changes to several endocrine systems. Cytosolic dioxin receptor, also referred to as Ah receptor, translocates to the nucleus upon binding of ligand. Ligands include dioxin and polycyclic aromatic hydrocarbons (PAH). The complex then initiates transcription of a battery of cytochrome P450 genes involved in xenobiotic metabolism. These P450 cytochromes are important in the activation of polycyclic aromatic hydrocarbons (found in cigarette smoke and smog) and certain heterocyclic amines (found in cooked meat) to carcinogenic intermediates.
Cellular localization
Cytoplasmic, Nuclear
Comment
The ligand-free, cytosolic form of the Ah receptor is a multimeric complex consisting of a ligand-binding subunit and a 90-kD heat-shock protein (HSP90). Binding of ligand leads to the nuclear translocation of only the ligand-binding subunit, where it activates CYP1A1 gene transcription through interaction with specific DNA sequences termed xenobiotic responsive elements
(XREs).
Results of Heimler et al. (1998) suggest that TCDD perturbed E2 secretion by depletion of A4 precursor and increased apoptotic cell death of human luteal granulosa cells (LGC) in a dose- and time-dependent fashion. Studies of Enan et al. (1996)a and (1996)b showed that treatment of human LGCs with TCDD produced a time- and dose-dependent decrease in the cellular uptake of glucose. Cytochalasin B, a specific inhibitor of facilitative glucose transporter proteins, totally abolished the portion of glucose transport activity that is sensitive to TCDD. Pretreatment of the cells with the Ah receptor blockers 4,7-phenanthroline and alpha-naphthoflavone antagonised the effect of TCDD on 3H-Me-glucose uptake. Structure-activity relationship studies with TCDD and three dioxin congeners revealed a rank order for their potency in the inhibition of glucose transport consistent with the previously determined biological activity of TCDD and the other dioxin congeners. Treatment of cells for 48 h with 10 nM TCDD substantially reduced PKA and progesterone production. Also, administration of AhR agonists to human luteinized granulosa cells in culture decreases cAMP, estradiol, and progesterone production.
Expression regulated by
LH, Steroids, Eicosanoids
Comment
Using macaque granulosa cells during controlled ovarian stimulation cycles before and after administration of the ovulatory hCG bolus, Chaffin et al. (1999) reported that AhR mRNA was not detectable in granulosa cells aspirated before hCG in any animal but by 12 h after hCG, AhR mRNA was abundant. It further increased at 24 h post-hCG and remained at this level 36 h after hCG. They indicated that the gonadotropin-regulated pattern of AhR expression in macaque granulosa cells suggests that this receptor has a potentially important role in ovulation and luteinization.
Ovarian localization
Oocyte, Granulosa, Luteal cells
Comment
Robles et al explored AhR expression patterns in the murine ovary. Immunohistochemical analysis of ovaries indicated that AhR protein was abundantly and exclusively expressed in oocytes and granulosa cells of follicles at all stages of development.
Signaling by Hypoxia-Inducible Factors is Critical for Ovulation In Mice. Kim J et al. The steroid hormone progesterone, acting via its nuclear receptor, is a major regulator of the process of ovulation. Female mice lacking progesterone receptor (PGR) exhibit an anovulatory phenotype due to failure in follicular rupture. To identify the PGR-regulated pathways that control ovulation, we analyzed global changes in gene expression in the ovaries of wild type (WT) and Pgr-null mice subjected to gonadotropin-induced superovulation. Our analysis uncovered several genes whose expression was reduced in the Pgr-null ovaries compared with the WT ovaries immediately preceding ovulation. Interestingly, these genes included three hypoxia-inducible factors (HIFs): HIF-1alpha, HIF-2alpha, and HIF-1beta. These transcription factors form alphabeta heterodimers, which regulate the transcription of specific cellular genes, thereby mediating adaptive response of the tissue to low oxygen levels. We observed that the expression of mRNAs and proteins corresponding to HIF-1alpha, HIF-2alpha, and HIF-1beta was induced in a PGR-dependent manner, specifically in the granulosa cells of the preovulatory follicles. Inhibition of the HIF transcriptional activity by echinomycin, a small-molecule inhibitor that suppresses the binding of HIF alphabeta heterodimers to target genes, blocked ovulation by preventing the rupture of the preovulatory follicles. Echinomycin specifically inhibited the expression of genes that are known regulators of ovulation, such as a disintegrin and metalloproteinase with thrombospondin-like motifs-1 (ADAMTS-1) and endothelin-2. Furthermore, echinomycin reduced the expression of vascular endothelial growth factor A, a key factor controlling vascularization/angiogenesis during ovulation. Collectively, these findings unveiled a novel ovarian role for the HIF transcription factors during the ovulatory period in mice.
Follicle stages
Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Histomorphometric analysis of serial ovarian sections revealed a two-fold higher number of primordial follicles in Ahr-null versus wild-type females at day 4 postpartum Robles et al . This phenotype likely results from a cell-intrinsic death defect in the developing germ line since AhR-deficiency attenuated the magnitude of oocyte apoptosis in fetal ovaries cultured without hormonal support for 72 h. It was proposed that the AhR, activated by an as yet unknown endogenous ligand(s), serves to regulate the size of the oocyte reserve endowed at birth by affecting germ cell death during female gametogenesis.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Le Provost F et al 2002 reported that the aryl hydrocarbon receptor (AhR) and its nuclear translocator (Arnt) are dispensable for normal mammary gland development but are required for fertility.
The aryl hydrocarbon receptor (AhR) and its nuclear translocator (Arnt) are transcription factors that play a role in the detection of and adaptation to environmental signals. AhR-null mice are viable but show impaired lactation. Deletion of the Arnt gene from the mouse genome results in embryonic lethality. To determine the role of Arnt in mammary development and function, the authors inactivated the Arnt gene in mammary epithelium using Cre-loxP recombination. Inactivation of the Arnt gene during pregnancy did not disrupt alveolar development or the ability of dams to nurse their litters. In contrast, dams in which the Arnt gene had been inactivated during puberty and in ovaries were subfertile, exhibited retarded mammary development, and impaired mammary function.