Este artículo es de Acceso Abierto y puede ser descargado en su versión final desde nuestro repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most of the toxic and endocrine-disruptive actions of aromatic compounds in the ovary. Paradoxically, this receptor has been shown to play important roles in normal female reproductive function as well. Although knowledge of AHR expression regulation in the ovary is of crucial significance to understand the receptor biology and its function in reproductive physiology, there are only limited data in this area. The purpose of the present study was to establish the possible regulation that AHR might undergo in ovarian cells. Here we show that the hormones FSH and estradiol are able to reduce AHR protein and transcript levels in granulosa cells in a way that parallels the changes observed in ovarian tissue across the rat estrous cycle. These findings suggest that estradiol and FSH would be cycle-associated endogenous modulators of AHR expression. In addition, we show that in granulosa cells the receptor is rapidly downregulated via proteasomal degradation following treatment with AHR ligands. However, prolonged treatment with an agonist caused an increase in Ahr mRNA levels. These actions would constitute a regulatory mechanism that both attenuates AHR signal rapidly and replenishes the cellular receptor pool in the long term. In conclusion, our results indicate that AHR expression is regulated by classical hormones and by its own ligands in granulosa cells. © 2006 by the Society for the Study of Reproduction, Inc.


Documento: Artículo
Título:Regulation of aryl hydrocarbon receptor expression in rat granulosa cells
Autor:Bussmann, U.A.; Barañao, J.L.
Filiación:Instituto de Biología y Medicina Experimental-CONICET, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina
Palabras clave:Estradiol; Follicle-stimulating hormone; Granulosa cells; Ovary; Toxicology; aromatic compound; aromatic hydrocarbon receptor; cell receptor; endocrine disruptor; estradiol; follitropin; hormone; ligand; messenger RNA; transcription factor; animal cell; article; controlled study; down regulation; estrus cycle; female; female genital system; granulosa cell; hormonal regulation; nonhuman; ovary; ovary cell culture; physiology; priority journal; protein expression; protein function; rat; receptor upregulation; reproduction; signal transduction; Animals; beta-Naphthoflavone; Blotting, Western; Cell Line; Cytochrome P-450 CYP1A1; Down-Regulation; Enzyme Inhibitors; Estradiol; Female; Follicle Stimulating Hormone; Gene Expression Regulation; Granulosa Cells; Ovary; Proteasome Endopeptidase Complex; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon; Reproduction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger
Página de inicio:360
Página de fin:369
Título revista:Biology of Reproduction
Título revista abreviado:Biol. Reprod.
CAS:estradiol, 50-28-2; follitropin, 9002-68-0; beta-Naphthoflavone, 6051-87-2; Cytochrome P-450 CYP1A1, EC; Enzyme Inhibitors; Estradiol, 50-28-2; Follicle Stimulating Hormone, 9002-68-0; Proteasome Endopeptidase Complex, EC; Receptors, Aryl Hydrocarbon; RNA, Messenger


  • Hahn, M.E., The aryl hydrocarbon receptor: A comparative perspective (1998) Comp Biochem Physiol C Pharmacol Toxicol Endocrinol, 121, pp. 23-53
  • Safe, S.H., Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds (1995) Pharmac Ther, 67, pp. 247-281
  • Mandal, P.K., Dioxin: A review of its environmental effects and its aryl hydrocarbon receptor biology (2005) J Comp Physiol [B], 175, pp. 221-230
  • Gonzales, F.K., Fernandez-Salguero, P., The aryl hydrocarbon receptor: Studies using the AHR-null mice (1998) Drug Metab Dispos, 26, pp. 1194-1198
  • Safe, S., Wang, F., Porter, W., Duan, R., McDougal, A., Ah receptor agonists as endocrine disruptors: Antiestrogenic activity and mechanisms (1998) Toxicol Lett, 102-103, pp. 343-347
  • Safe, S., Molecular biology of the Ah receptor and its role in carcinogenesis (2001) Toxicol Lett, 120, pp. 1-7
  • Schwarz, M., Appel, K.E., Carcinogenic risks of dioxin: Mechanistic considerations (2005) Regul Toxicol Pharmacol, 43, pp. 19-34
  • Davis, B.J., Mccurdy, E.A., Miller, B.D., Lucier, G.W., Tritscher, A.M., Ovarian tumors in rats induced by chronic 2,3,7,8-tetrachlorodibenzo-p- dioxin treatment (2000) Cancer Res, 60, pp. 5414-5419
  • Pocar, P., Fischer, B., Klonisch, T., Hombach-Klonisch, S., Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction (2005) Reproduction, 129, pp. 379-389
  • Baba, T., Mimura, J., Nakamura, N., Harada, N., Yamamoto, M., Morohashi, K., Fujii-Kuriyama, Y., Intrinsic function of the aryl hydrocarbon (dioxin) receptor as a key factor in female reproduction (2005) Mol Cell Biol, 25, pp. 10040-10051
  • Franczak, A., Nynca, A., Valdez, K.E., Mizinga, K.M., Petroff, B.K., Effects of acute and chronic exposure to the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin on the transition to reproductive senescence in female Sprague-Dawley rats (2006) Biol Reprod, 74, pp. 125-130
  • Bussmann, U.A., Bussmann, L.E., Baranao, J.L., An aryl hydrocarbon receptor agonist amplifies the mitogenic actions of estradiol in granulosa cells: Evidence of involvement of the cognate receptors (2006) Biol Reprod, 74, pp. 417-426
  • Ohtake, F., Takeyama, K., Matsumoto, T., Kitagawa, H., Yamamoto, Y., Nohara, K., Tohyama, C., Fujii-Kuriyama, Y., Modulation of estrogen receptor signalling by association with the activated dioxin receptor (2003) Nature, 423, pp. 545-550
  • Puga, A., Tomlinson, C.R., Xia, Y., Ah receptor signals cross-talk with multiple developmental pathways (2005) Biochem Pharmacol, 69, pp. 199-207
  • Crawford, R.B., Holsapple, M.P., Kaminski, N., Leukocyte activation induces aryl hydrocarbon receptor up-regulation, DNA binding, and increased Cyp1a1 expression in the absence of exogenous ligand (1997) Mol Pharmacol, 52, pp. 921-927
  • Chang, C., Puga, A., Constitutive activation of the aromatic hydrocarbon receptor (1998) Mol Cell Biol, 18, pp. 525-535
  • Komura, K., Hayashi, S., Makino, I., Poellinger, L., Tanaka, H., Aryl hydrocarbon receptor/dioxin receptor in human monocytes and macrophages (2001) Mol Cell Biochem, 226, pp. 107-118
  • Sadek, C.M., Allen-Hoffmann, B.L., Cytochrome P4501A1 is rapidly induced in normal human keratinocytes in the absence of xenobiotics (1994) J Biol Chem, 269, pp. 16067-16074
  • Mufti, N.A., Bleckwenn, N.A., Babish, J.G., Shuler, M.L., Possible involvement of the Ah receptor in the induction of cytochrome P-4501A1 under conditions of hydrodynamic shear in microcarrier-attached hepatoma cell lines (1995) Biochem Biophys Res Commun, 208, pp. 144-152
  • Zaher, H., Fernandez-Salguero, P.M., Letterio, J., Sheikh, M.S., Fomace, A.J., Roberts, A.B., Gonzalez, F.J., The involvement of aryl hydrocarbon receptor in the activation of transforming growth factor-beta and apoptosis (1998) Mol Pharmacol, 54, pp. 312-321
  • Elizondo, G., Fernandez-Salguero, P., Sheikh, M.S., Kim, G.Y., Fomace, A.J., Lee, K.S., Gonzalez, F.J., Altered cell cycle control at the G(2)/M phases in aryl hydrocarbon receptor-null embryo fibroblast (2000) Mol Pharmacol, 57, pp. 1056-1063
  • Monk, S.A., Denison, M.S., Rice, R.H., Transient expression of CYP1A1 in rat epithelial cells cultured in suspension (2001) Arch Biochem Biophys, 393, pp. 154-162
  • Leighton, J.K., Canning, S., Guthrie, H.D., Hammond, J.M., Expression of cytochrome P450 1A1, an estrogen hydroxylase, in ovarian granulosa cells is developmentally regulated (1995) J Steroid Biochem Mol Biol, 52, pp. 351-356
  • Dey, A., Nebert, D.W., Markedly increased constitutive CYP1A1 mRNA levels in the fertilized ovum of the mouse (1998) Biochem Biophys Res Commun, 251, pp. 657-1461
  • Hankinson, O., The aryl hydrocarbon receptor complex (1995) Annu Rev Pharmacol Toxicol, 35, pp. 307-340
  • Schmidt, J.V., Bradfield, C.A., Ah receptor signaling pathways (1996) Annu Rev Cell Dev Biol, 12, pp. 55-89
  • Rushmore, T.H., Kong, A.N., Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes (2002) Curr Drug Metab, 5, pp. 481-490
  • Ma, Q., Induction of CYP1A1. The AhR/DRE paradigm: Transcription, receptor regulation, and expanding biological roles (2001) Curr Drug Metab, 2, pp. 149-164
  • Fujii-Kuriyama, Y., Mimura, J., Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes (2005) Biochem Biophys Res Commun, 338, pp. 311-317
  • Davarinos, N.A., Pollenz, R.S., Aryl hydrocarbon receptor imported into the nucleus following ligand binding is rapidly degraded via the cytosplasmic proteasome following nuclear export (1999) J Biol Chem, 274, pp. 28708-28715
  • Ma, Q., Baldwin, K.T., 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced degradation of aryl hydrocarbon receptor (AhR) by the ubiquitin-proteasome pathway. Role of the transcription activation and DNA binding of AhR (2000) J Biol Chem, 275, pp. 8432-8438
  • Song, Z., Pollenz, R.S., Ligand-dependent and independent modulation of aryl hydrocarbon receptor localization, degradation, and gene regulation (2002) Mol Pharmacol, 62, pp. 806-816
  • Pollenz, R.S., The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation (2002) Chem Biol Interact, 141, pp. 41-61
  • Franc, M.A., Pohjanvirta, R., Tuomisto, J., Okey, A.B., Persistent, low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: Effect on aryl hydrocarbon receptor expression in a dioxin-resistance model (2001) Toxicol Appl Pharmacol, 175, pp. 43-53
  • Kitajima, M., Khan, K.N., Fujishita, A., Masuzaki, H., Ishimaru, T., Histomorphometric alteration and cell-type specific modulation of arylhydrocarbon receptor and estrogen receptor expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin and l7beta-estradiol in mouse experimental model of endometriosis (2004) Reprod Toxicol, 18, pp. 793-801
  • Wakai, S., Yokoo, K., Takahashi, H., Muto, T., Suzuki, Y., Kanai, Y., Hano, H., Endou, H., CYP1 and AhR expression in 7,12-dimethylbenz-[a]anthracene-induced mammary carcinoma of rats prenatally exposed to 3,3′,4,4′,5- pentachlorobiphenyl (2005) Toxicology, 211, pp. 231-241
  • Nishizawa, H., Imanishi, S., Manabe, N., Effects of exposure in utero to bisphenol a on the expression of aryl hydrocarbon receptor, related factors, and xenobiotic metabolizing enzymes in murine embryos (2005) J Reprod Dev, 51, pp. 593-605
  • Aluru, N., Vuori, K., Vijayan, M.M., Modulation of Ah receptor and CYP1A1 expression by alpha-naphthoflavone in rainbow trout hepatocytes (2005) Comp Biochem Physiol C Toxicol Pharmacol, 141, pp. 40-49
  • Vaziri, C., Schneider, A., Sherr, D.H., Faller, D.V., Expression of the aryl hydrocarbon receptor is regulated by serum and mitogenic growth factors in murine 3T3 fibroblasts (1996) J Biol Cnem, 271, pp. 25921-25927
  • Dohr, O., Abel, J., Transforming growth factor-beta1 coregulates mRNA expression of aryl hydrocarbon receptor and cell-cycle-regulating genes in human cancer cell lines (1997) Biochem Biophys Res Commun, 241, pp. 86-91
  • Wolff, S., Harper, P.A., Wong, J.M., Mostert, V., Wang, Y., Abel, J., Cell-specific regulation of human aryl hydrocarbon receptor expression by transforming growth factor-beta(1) (2001) Mol Pharmacol, 59, pp. 716-724
  • Hayashi, S., Okabe-Kado, J., Honma, Y., Kawajiri, K., Expression of Ah receptor (TCDD receptor) during human monocytic differentiation (1995) Carcinogenesis, 16, pp. 1403-1409
  • Wanner, R., Brommer, S., Czanietzki, B.M., Rosenbach, T., The differentiation-related upregulation of aryl hydrocarbon receptor transcript levels is suppressed by retinoic acid (1995) Biochem Biophys Res Commun, 209, pp. 706-711
  • Shimba, S., Hayashi, M., Ohno, T., Tezuka, M., Transcriptional regulation of the AhR gene during adipose differentiation (2003) Biol Pharm Bull, 26, pp. 1266-1271
  • Chaffin, C.L., Stouffer, R.L., Duffy, D.M., Gonadotropin and steroid regulation of steroid receptor and aryl hydrocarbon receptor messenger ribonucleic acid in macaque granulosa cells during the periovulatory interval (1999) Endocrinology, 140, pp. 4753-4760
  • Chaffin, C.L., Trewin, A.L., Hutz, K.J., Estrous cycle-dependent changes in the expression of aromatic hydrocarbon receptor (AHR) and AHR-nuclear translocator (ARNT) mRNAs in the rat ovary and liver (2000) Chem Biol Interact, 124, pp. 205-216
  • Bley, M.A., Saragüeta, P.E., Barañao, J.L., Concerted stimulation of rat granulosa cell deoxyribonucleic acid synthesis by sex steroids and follicle-stimulating hormone (1997) J Steroid Biochem Mol Biol, 62, pp. 11-19
  • Bley, M.A., Simón, J.C., Saragüeta, P.E., Barañao, J.L., Hormonal regulation of rat granulosa cell deoxyribonucleic acid synthesis: Effects of estrogens (1991) Biol Reprod, 44, pp. 880-888
  • Bley, M.A., Simón, J.C., Estévez, A.G., Jiménez De Asúa, L., Barañao, J.L., Effect of follicle-stimulating hormone on insulin-like growth factor-I-stimulated rat granulosa cell deoxyribonucleic acid synthesis (1992) Endocrinology, 131, pp. 1223-1229
  • Dasmahapatra, A.K., Wimpee, B.A., Trewin, A.L., Hutz, R.J., 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases steady-state estrogen receptor-beta mRNA levels after CYP1A1 and CYP1B1 induction in rat granulosa cells in vitro (2001) Mol Cell Endocrinol, 182, pp. 39-48
  • Timsit, Y.E., Chia, F.S., Bhathena, A., Riddick, D.S., Aromatic hydrocarbon receptor expression and function in liver of hypophysectomized male rats (2002) Toxicol Appl Pharmacol, 185, pp. 136-145
  • Sokal, R.R., Rohlf, F.J., (1995) Biometry, , New York: WH Freeman and Co
  • Whitlock Jr., J.P., Induction of cytochrome P4501A1 (1999) Annu Rev Pharmacol Toxicol, 39, pp. 103-125
  • Gu, Y.Z., Hogenesch, J.B., Bradfield, C.A., The PAS superfamily: Sensors of environmental and developmental signals (2000) Annu Rev Pharmacol Toxicol, 40, pp. 519-561
  • Butler, R.A., Kelley, M.L., Powell, W.H., Hahn, M.E., Van Beneden, R.J., An aryl hydrocarbon receptor (AHR) homologue from the soft-shell clam. Mya arenaria: Evidence that invertebrate AHR homologues lack 2,3,7,8-tetrachlorodibenzo-p-dioxin and beta-naphthoflavone binding (2001) Gene, 278, pp. 223-234
  • Mimura, J., Fujii-Kuriyama, Y., Functional role of AhR in the expression of toxic effects by TCDD (2003) Biochim Biophys Acta, 1619, pp. 263-268
  • Wonnke, M., Stoner, M., Saville, B., Safe, S., Crosstalk between estrogen receptor alpha and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes (2000) FEBS Lett, 478, pp. 109-112
  • Schultz, R., Suominen, J., Varre, T., Hakovirta, H., Parvinen, M., Toppari, J., Pelto-Huikko, M., Expression of aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator messenger ribonucleic acids and proteins in rat and human testis (2003) Endocrinology, 144, pp. 767-776
  • Benedict, J.C., Miller, K.P., Lin, T.M., Greenfeld, C., Babus, J.K., Peterson, R.E., Flaws, J.A., Aryl hydrocarbon receptor regulates growth, but not atresia, of mouse preantral and antral follicles (2003) Biology of Reproduction, 68, pp. 1511-1517
  • Wentworth, J.N., Buzzeo, R., Pollenz, R.S., Functional characterization of aryl hydrocarbon receptor (zfAHR2) localization and degradation in zebrafish (Danio rerio) (2004) Biochem Pharmacol, 67, pp. 1363-1372
  • Song, Z., Pollenz, R.S., Functional analysis of murine aryl hydrocarbon (AH) receptors defective in nuclear import: Impact on AH receptor degradation and gene regulation (2003) Mol Pharmacol, 63, pp. 597-606
  • Pahl, H.L., Baeuerle, P.A., Control of gene expression by proteolysis (1996) Curr Opin Cell Biol, 8, pp. 340-347


---------- APA ----------
Bussmann, U.A. & Barañao, J.L. (2006) . Regulation of aryl hydrocarbon receptor expression in rat granulosa cells. Biology of Reproduction, 75(3), 360-369.
---------- CHICAGO ----------
Bussmann, U.A., Barañao, J.L. "Regulation of aryl hydrocarbon receptor expression in rat granulosa cells" . Biology of Reproduction 75, no. 3 (2006) : 360-369.
---------- MLA ----------
Bussmann, U.A., Barañao, J.L. "Regulation of aryl hydrocarbon receptor expression in rat granulosa cells" . Biology of Reproduction, vol. 75, no. 3, 2006, pp. 360-369.
---------- VANCOUVER ----------
Bussmann, U.A., Barañao, J.L. Regulation of aryl hydrocarbon receptor expression in rat granulosa cells. Biol. Reprod. 2006;75(3):360-369.