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Aromatic Hydrocarbon Receptor
The Experts below are selected from a list of 714 Experts worldwide ranked by ideXlab platform
Reinhold J Hutz – 1st expert on this subject based on the ideXlab platform
Familiar and novel reproductive endocrine disruptors: xenoestrogens, dioxins and nanoparticles.Current trends in endocrinology, 2020Co-Authors: Reinhold J Hutz, Monika G Baldridge, Carvan Mj, Jeremy K. Larson, Liu Q, Stelzer Rv, King-heiden Tc, Shahnoor N, Julien KAbstract:
Environmental contaminants are known to exert endocrine-disrupting effects on the reproductive axis of animals. Many of these molecules can affect steroid biosynthesis or estrogen-Receptor signaling by behaving as estrogen-like molecules (“xenoestrogens”), or by exerting estrogenmodulatory effects. Exposure to some compounds has been correlated with the skewing of sex ratios in aquatic species, feminization and demasculinization of male animals, declines in human sperm counts, and overall diminution in fertility of birds, fish, and mammals. We herein devote space to several classes of endocrine-disrupting compounds (EDCs), including estrogenic substances such as bisphenol A (BPA), molecules that can behave at times anti-estrogenically while activating the Aromatic Hydrocarbon Receptor (AHR), such as dioxins (a known human carcinogen), and novel, ubiquitous molecules such as nanoparticles, particularly gold nanoparticles (GNPs), that appear to alter the sexsteroid biosynthetic pathway.
autoradiographic localization of Aromatic Hydrocarbon Receptor ahr in rhesus monkey ovaryAmerican Journal of Primatology, 2007Co-Authors: Monika G Baldridge, Reinhold J HutzAbstract:
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic congener of a large class of manmade pollutants that persist in the environment. TCDD exerts its toxic effects, in part, by binding to its Receptor known as the Aromatic Hydrocarbon Receptor (AHR). TCDD is estrogen modulatory and in some systems its Receptor associates directly with estrogen Receptors via co-activator molecules. TCDD inhibits steroid synthesis in human ovarian granulosa cells and AHR is found in these cells. We have previously shown that AHR is found in whole rhesus monkey ovary, but have yet to establish its location. In the present study, we set out to show that radiolabeled TCDD binds to monkey ovarian follicles and that this binding is Receptor mediated. Ovaries from Macaca mulatta were sectioned on a cryostat at 10 µ m; and sections were incubated with either control vehicle, 3H-TCDD, or 3H-TCDD plus alpha-naphthoflavone (ANF), a known Receptor-blocking agent. Here, we show for the first time specific binding of TCDD to the granulosa cells of antral follicles and other regions of the rhesus monkey ovary. Our data indicate a 60-fold increase in binding with 3H-TCDD over that of control, and that this binding is reduced to the levels seen in controls with the addition of the competitive antagonist ANF. These findings support the hypothesis that TCDD directly affects primate ovarian function via the AHR. Am. J. Primatol. 69:681–691, 2007. © 2006 Wiley-Liss, Inc.
Estrous cycle-regulated expression of CYP1B1 mRNA in the rat ovary.Comparative Biochemistry and Physiology B, 2002Co-Authors: A K Dasmahapatra, Amanda L Trewin, Reinhold J HutzAbstract:
CYP1B1, a member of the cytochrome P450 superfamily, is expressed constitutively in the steroidogenic tissues of mammals and is inducible by peptide hormones, cAMP and Aromatic Hydrocarbon Receptor (AHR) ligands. The mechanism of induction of this cytochrome P450 is similar to that for CYP1A1, i.e. through the Aromatic Hydrocarbon Receptor (AHR) signaling pathway. We have recently reported that CYP1B1, but not CYP1A1, is expressed in rat granulosa cells (GC) in the absence of any external stimulus. The induction of CYP1B1 mRNA in rat GC by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vitro was followed by an increase in AHR and estrogen Receptor (ER-β) RNA levels. Estrous cycle-dependent expression of AHR, AHR-nuclear translocator (ARNT) and ER-mRNAs in the rat ovary was reported. We suggest that CYP1B1 may play a major role in the regulation of rat ovarian function/cycle but until now this has been unexplored experimentally. The present study was therefore aimed at examining the expression of CYP1A1, CYP1B1 and ER-mRNA in rat ovarian tissues throughout the estrous cycle to establish any correlation in the expressions of these mRNAs in rat ovary. Total RNA was extracted from the ovary and liver of cycling adult rats and the mRNAs were analyzed using relative RT-PCR with gene-specific primers for the target mRNA and for RPL 19 or S16 primers as an internal control. The results indicated that in the ovary, CYP1B1 mRNA increased significantly on the evening of proestrus and dramatically decreased on the morning of estrus, while ER-mRNA remained unaltered throughout the estrous cycle. CYP1A1 mRNA in the ovary and both CYP1A1 and CYP1B1 mRNAs in the liver were undetectable. That the sudden decrease of ovarian CYP1B1 mRNA on the morning of estrus was not an effect of the LH surge was verified in vitro using our short-term GC culture model. GC prepared from rats super-stimulated with equine chorionic gonadotropin (eCG) were cultured for 6 h with or without LH and TCDD. It was observed that both CYP1A1 and CYP1B1 mRNAs were induced by TCDD with no apparent effect of LH. It is suggested that the high level of CYP1B1 mRNA expression on the evening of proestrus in rat ovary might be involved in metabolism of estrogens to catecholestrogen (a known effect of CYP1B1), and that expression is unaffected in GC by LH.
James P Whitlock – 2nd expert on this subject based on the ideXlab platform
Myb-binding Protein 1a Augments AhR-dependent Gene ExpressionJournal of Biological Chemistry, 2002Co-Authors: Letetia C. Jones, Steven T Okino, Thomas J. Gonda, James P WhitlockAbstract:
We have studied the mechanism by which an acidic domain (amino acids 515-583) of the Aromatic Hydrocarbon Receptor (AhR) transactivates a target gene. Studies with glutathione S-transferase fusion proteins demonstrate that the wild-type acidic domain associates in vitro with Myb-binding protein la, whereas a mutant domain (F542A, 1569A) does not. AhR-defective cells reconstituted with an AhR containing the wild-type acidic domain exhibit normal AhR function; however, cells reconstituted with an AhR containing the mutant acidic domain do not function normally. Transient transfection of Myb-binding protein la into mouse hepatoma cells is associated with augmentation of AhR-dependent gene expression. Such augmentation does not occur when Myb-binding protein la is transfected into AhR-defective cells that have been reconstituted with an AhR that lacks the acidic domain. We infer that 1) Myb-binding protein la associates with AhR, thereby enhancing transactivation, and 2) the presence of AhR’s acidic domain is both necessary and sufficient for Myb-binding protein la to increase AhR-dependent gene expression.
Accessibility and Activity of the Promoter for a Dioxin-Inducible Ecto-ATPase GeneArchives of Biochemistry and Biophysics, 2001Co-Authors: James P WhitlockAbstract:
We have analyzed the core promoter for a dioxin-inducible ecto-ATPase gene in mouse hepatoma cells. The transcriptional initiation site maps to a region that contains neither a TATA sequence nor a consensus initiator sequence nor a downstream promoter element. The core promoter has constitutive activity that does not require either the Aromatic Hydrocarbon Receptor or its heterodimerization partner Arnt. Two GC-rich regions contribute approximately equally to the constitutive activity. Proteins constitutively occupy the GC-rich regions in chromatin. The promoter assumes a non-nucleosomal configuration in its native chromosomal setting in both uninduced and dioxin-induced cells. Our findings imply that the GC-rich regions together with their cognate binding proteins carry out core promoter functions for the ecto-ATPase gene. The promoter is constitutively accessible in situ, and chromatin structure is not a limiting factor for dioxin-inducible ecto-ATPase transcription in intact cells.
the Aromatic Hydrocarbon Receptor transcription and endocrine aspects of dioxin actionVitamins and Hormones Series, 2000Co-Authors: Steven T Okino, James P WhitlockAbstract:
Abstract The widespread and persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo- p -dioxin elicits adaptive and adverse biological responses by inducing changes in gene transcription. Some of dioxin’s effect reflect disruption of endocrine homeostatis. The Aromatic Hydrocarbon Receptor protein, together with its heterodimerization partner, the Aromatic Hydrocarbon Receptor nuclear translocator protein, mediates dioxin action. There are notable similarities between the mechanism of dioxin action and the mechanisms of steroid/retinoid/thyroid hormone action. Studies of dioxin action may provide insights into the regulation of hormone-responsive genes and endocrine physiology.
David H Sherr – 3rd expert on this subject based on the ideXlab platform
Aryl Hydrocarbon Receptor (AhR) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology studyEnvironmental Health, 2003Co-Authors: Brenda A Jensen, Jennifer J Schlezinger, Rebecca J Leeman, David H SherrAbstract:
Bone marrow stromal cells produce cytokines required for the normal growth and development of all eight hematopoietic cell lineages. Aberrant cytokine production by stromal cells contributes to blood cell dyscrasias. Consequently, factors that alter stromal cell cytokine production may significantly compromise the development of normal blood cells. We have shown that environmental chemicals, such as Aromatic Hydrocarbon Receptor (AhR) agonists, suppress B lymphopoiesis by modulating bone marrow stromal cell function. Here, we extend these studies to evaluate the potential for two prototypic AhR agonists, 7,12-dimethylbenz [a]anthracene (DMBA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), to alter stromal cell cytokine responses.
bax caspase 2 and caspase 3 are required for ovarian follicle loss caused by 4 vinylcyclohexene diepoxide exposure of female mice in vivoEndocrinology, 2003Co-Authors: Yasushi Takai, David H Sherr, Gloria I Perez, Jennifer J Schlezinger, Stanley J Korsmeyer, Jacqueline Canning, Richard Kolesnick, Junying Yuan, Richard A Flavell, Jonathan L TillyAbstract:
The industrial chemical, 4-vinylcyclohexene diepoxide (VCD), kills oocytes within immature follicles in the ovaries of mice and rats and is considered a potential occupational health hazard. It has been reported that VCD-induced follicle loss occurs via a cell death process involving elevated expression of Bax, a proapoptotic Bcl-2 family member, and increased caspase-3-like activity. We have previously shown that oocytes lacking acid sphingomyelinase (ASMase; an enzyme that generates the proapoptotic stress sensor ceramide), the Aromatic Hydrocarbon Receptor (Ahr), Bax, or caspase-2 are resistant to apoptosis induced by other chemical toxicants. Therefore, this study was designed to investigate the functional importance of ASMase, Ahr, Bax, and caspase-2 as well as the related executioner enzyme caspase-3 to VCD-induced ovotoxicity in mice using gene knockout technology. For each gene mutant mouse line, wild-type and homozygous-null female siblings derived from heterozygous matings were given once-daily …
ligand activation of the Aromatic Hydrocarbon Receptor transcription factor drives bax dependent apoptosis in developing fetal ovarian germ cellsEndocrinology, 2002Co-Authors: Tiina Matikainen, David H Sherr, Gloria I Perez, Stanley J Korsmeyer, Toshitake Moriyama, Yutaka Morita, Jonathan L TillyAbstract:
We recently reported that a targeted disruption of the gene encoding the Aromatic Hydrocarbon Receptor (AHR) in mice reduces fetal oocyte apoptosis, leading to a 2-fold increase in the number of primordial follicles endowed at birth. Although the identity of the natural ligand(s) for the AHR remains to be unequivocally established, these findings indicate that the level of AHR function is an important physiological determinant of how many oocytes will succumb to apoptosis during development of the fetal ovaries. Furthermore, the AHR is a well established Receptor for polycyclic Aromatic Hydrocarbons (PAHs), a class of ubiquitous environmental chemicals known to cause the death of female germ cells in fetal life. Given the possibility that the AHR serves as a key mediator of fetal oocyte death under both physiological and pathological situations, this study was conducted to more fully examine the impact of PAH-AHR interaction on fetal ovarian germ cells. In addition, experiments were designed to begin identification of the mechanism(s) by which ligand activation of the AHR induces prenatal oocyte depletion after transplacental exposure of fetuses to PAHs in vivo. Embryonic d 13.5 murine fetal ovaries cultured in the presence of PAHs exhibited a high level of germ cell loss via apoptosis that was prevented by the selective AHR antagonist, -napthoflavone (ANF). Immunohistochemical analysis revealed an accumulation of Bax protein in germ cells of fetal ovaries exposed to PAHs before the onset of apoptosis, whereas cotreatment with ANF inhibited the induction of Bax expression. The functional importance of increased Bax expression to the cytotoxic response was confirmed by findings that fetal ovarian germ cell loss caused by in utero exposure of wild-type female fetuses to PAHs was not observed in Bax-deficient female fetuses exposed in parallel. We conclude that a central role exists for the AHR in transducing the actions of PAHs in fetal ovarian germ cells, and that the proapoptotic Bcl-2 family member, Bax, is a required mediator of PAH-induced oocyte loss in female fetuses exposed to PAHs in utero. (Endocrinology 143: 615– 620, 2002)