Abstract
Studies of TCDD toxicity stimulated identification of the responsible aryl hydrocarbon receptor (AHR), a multifunctional, ligand-activated transcription factor of the basic helix–loop–helix/Per-Arnt-Sim family. Accumulating evidence suggests a role of this receptor in homeostasis of stem/progenitor cells, in addition to its known role in xenobiotic metabolism. (1) Regulation of myelopoiesis is complex. As one example, AHR-mediated downregulation of human CD34+ progenitor differentiation to monocytes/macrophages is discussed. (2) Accumulation of TCDD in sebum leads to deregulation of sebocyte differentiation via Blimp1-mediated inhibition of c-Myc signaling and stimulation of Wnt-mediated proliferation of interfollicular epidermis. The resulting sebaceous gland atrophy and formation of dermal cysts may explain the pathogenesis of chloracne, the hallmark of TCDD toxicity. (3) TCDD treatment of confluent liver stem cell-like rat WB-F344 cells leads to release from cell–cell contact inhibition via AHR-mediated crosstalk with multiple signaling pathways. Further work is needed to delineate AHR function in crosstalk with other signaling pathways.
Similar content being viewed by others
References
Bock KW (2016) Toward elucidation of dioxin-mediated chloracne and Ah receptor functions. Biochem Pharmacol 112:1–5
Bock KW (2017) Human and rodent aryl hydrocarbon receptor (AHR): From mediator of dioxin toxicity to physiologic functions and therapeutic options. Biol Chem. doi:10.1515/hsz-2016-0303
Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR, Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP (2010) Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329:1345–1348
Braeuning A, Sanna R, Huelsken J, Schwarz M (2009) Inducibility of drug-metabolizing enzymes by xenobiotics in mice with liver-specific knockout of Ctnnb1. Drug Metab Disp 37:1138–1145
Braeuning A, Köhle C, Buchmann A, Schwarz M (2011) Coordinate regulation of cytochrome P450 1A1 expression in mouse liver by the aryl hydrocarbon receptor and the beta-catenin pathway. Toxicol Sci 122:16–25
Bunaciu RP, Yen A (2011) Activation of the aryl hydrocarbon receptor AhR promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4. Cancer Res 71:2371–2380
Bunaciu RP; Jensen HA; MacDonald RJ; LaTocha DH; Varner JD; Yen A (2015) 6-Formylindolo[3,2-b]carbazole (FICZ) modulates the signalsome responsible for RA-induced differentiation of HL-60 myeloblastic leukemia cells. Plos One. doi:10.1371/journal.prone.0135668
Chesire DR, Dunn TA, Ewing CM, Luo J, Isaacs WB (2004) Identification of aryl hydrocarbon receptor as a putative Wnt/β-catenin pathway target gene in prostate cancer cells. Cancer Res 64:2523–2533
Consonni D, Pesatori AC, Zocchetti C, Sindaco R, D’Oro LC, Rubagotti M, Bertazzi PA (2008) Mortality in a population exposed to dioxin after the Seveso, Italy, accident in 1976: 25 years of follow up. Am J Epidemiol 167:847–858
Denison MS, Soshilov AA, He G; Degroot DE, Zhao B (2011) Exactly the same but different: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (Dioxin) receptor. Toxicol Sci 124, 1–22
Dietrich C, Kaina B (2010) The aryl hydrocarbon receptor (AhR) in the regulation of cell-cell contact and tumor growth. Cacinogemnesis 31:1319–1328
Dietrich C, Faust D, Budt S, Moskwa M, Kunz A, Bock KW, Oesch F (2002) 2,3,7,8-Tetrachlorodibenzo-p-dioxin-dependent release from contact inhibition in WB-F344 cells: involvement of cyclin A. Toxicol Appl Pharmacol 183:117–126
Esser C, Rannug A, Stockinger B (2009) The aryl hydrocarbon receptor in immunity. Cell 30:447–453
Faust D, Vondracek J, Krcmar P, Smerdova L, Prochazkova J, Hruba E, Hulinkova P, Kaina B, Dietrich C, Machala M (2013) AHR-mediated changes in global gene expression in rat liver progenitor cells. Arch Toxicol 87:681–698
Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SST, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ (1995) Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268:722–726
Friedman AD (2007) Transcriptional control of granulocyte and monocyte development. Oncogene 26:6816–6828
Frye M, Gardner C, Li ER, Arnold I, Watt FM (2003) Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment. Development 130:2793–2808
Fujii-Kuriyama Y, Kawajiri K (2010) Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli. Proc Jpn Acad Ser B86(86):40–52
Gasiewicz TA, Singh KP, Bennett JA (2014) The Ah receptor in stem cell cycling, regulation, and quiescence. Ann NY Acad Sci USA 1310:1–7
Gerbal-Chaloin S, Dume AS, Briolotti P, Klieber S, Raulet E, Duret C, Fabre JM, Ramos J, Maurel P, Daujat-Chavanieu M (2014) The WNT/β-catenin pathway is a transcriptional regulator of CYP2E1, CYP1A2, and aryl hydrocarbon receptor gene expression in primary human hepatocytes. Mol Pharmacol 86:624–634
Gu YZ, Hogenesch JB, Bradfield CA (2000) The PAS superfamily: sensors of environmental and developmental signals. Ann Rev Pharmacol Toxicol 40:519–561
Haarmann-Stemmann T, Esser C, Krutmann J (2015) The Janus-faced role of aryl hydrocarbon receptor signaling in the skin: consequences for prevention and treatment of skin disorders. J Invest Dermatol 135:2572–2576
Hayashi SI, Okabe-Kado J, Honma Y, Kawajiri K (1995) Expression of Ah receptor (TCDD receptor) during human monocytic differentiation. Carcinogenesis 16:1403–1409
Horsley V, O’Carroll D, Tooze R, Ohinata Y, Saito M, Obukhanych T, Nussenzweig M, Tarakhovsky A, Fuchs E (2006) Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell 126:597–609
Hubbard TD, Murray IA, Perdew GH (2015) Indole and tryptophan metabolism: endogenous and dietary routes to ah receptor activation. Drug Metab Disp 43:1522–1535
Ibabao CN, Bunaciu RP, Schaefer DMW, Yen A (2015) The AhR agonist VAF347 augments retinoic acid-induced differentiation in leukemia cells. FEBS Open Bio 5:308–318
Ikuta T, Ohba M, Zouboulis CC, Fujii-Kuriyama Y, Kawajiri K (2010) B lymphocyte-induced maturation protein 1 is a novel target of aryl hydrocarbon receptor. J Dermatol Sci 58:211–216
Itoh T (2016) Stem/progenitor cells in liver regeneration. Hepatology 64:663–668
Ju Q, Fimmel S, Hinz N, Stahlmann R, Xia L, Zouboulis CC (2011) 2,3,7,8-tetrachlorodibenzo-p-dioxin alters sebaceous gland differentiation in vitro. Exp Dermatol 20:320–325
Kim JB, Greber B, Arauzo-Bravo MJ, Meyer J, Park KI, Zaehres H, Schöler HR (2009) Direct reprogramming of human neural stem cells by Oct4. Nature 461:649–653
Kimmig J, Schulz KH (1957) Berufliche Akne (sog. Chlorakne) durch chlorierte aromatische zyklische Äther. Dermatologica 115:540–546
Ko CI, Fan Y, de Gannes M, Wang Q, Xia Y, Puga A (2016) Repression of the aryl hydrocarbon receptor is required to maintain mitotic progression and prevent loss of pluripotency of embryonic stem cells. Stem Cells 34:2825–2839
Kretzschmar K, Cottle DL, Donati G, Chiang MF, Quist SR, Gollnick HP, Natsuga K, Lin KI, Watt FM (2014) Blimp1 is required for postnatal epidermal homeostasis but does not define a sebaceous gland progenitor under steady-state conditions. Stem Cell Rep 3:620–633
Lo Celso C, Berta MA, Braun KM, Frye M, Lyle S, Zouboulis CC, Watt FM (2008) Characterization of bipotential epidermal progenitors derived from human sebaceous gland: Contrasting roles of c-Myc and β-Catenin. Stem Cells 26:1241–1252
Ma Q, Whitlock JP (1996) The aromatic hydrocarbon receptor modulates the Hepa1c1c7 cell cycle and differentiated state independently of dioxin. Mol Cell Biol 16:2144–2150
Marlowe JL, Puga A (2005) Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J Cell Biochem 96:1174–1184
Mitchell KA, Elferink CJ (2009) Timing is everything: consequences of transient and sustained AhR activity. Biochem Pharmacol 77:947–956
Mulero-Navarro S, Fernandez-Salguero P (2016) New Trends in aryl hydrocarbon receptor biology. Front Cell Dev Biol 4:1–14
Münzel P, Bock-Hennig B, Schieback S, Gschaidmeier H, Beck-Gschaidmeier S, Bock KW (1996) Growth modulation of hepatocytes and rat liver epithelial cells (WB-F344) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Carcinogenesis 17:197–202
Nguyen LP, Bradfield CA (2008) The search for endogenous activators of the aryl hydrocarbon receptor. Chem Res Toxicol 21:102–116
Orkin SH, Zon LI (2006) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132:631–644
Page ME, Lombard P, Ng F, Göttgens B, Jensen KB (2013) The epidermis comproses autonomous compartments maintained by distinct stem cell populations. Cell Stem Cell 13:471–482
Pantelejev AA, Bickers DR (2006) Dioxin-induced chloracne - reconstructing the cellular and molecular mechanisms of a classic environmental disease. Exp Dermatol 15:705–730
Parent R, Marion MJ, Furio L, Trepo C, Petit MA (2004) Origin and characterization of a human bipotent liver progenitor cell line. Gastroenterology 126:1147–1156
Platzer B, Richter S, Kneidinger D, Waltenberger D, Woisetschläger M, Strobl H (2009) Aryl hydrocarbon receptor activation inhibits in vitro differentiation of human monocytes and Langerhans dendritic cells. J Immunol 183:66–74
Prochazkova J, Kabatkova M, Bryja V, Umannova L, Bernatik O, Kozubik A, Machala M, Vondracek J (2011) The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors. Toxicol Sci 122, 349–360
Quintana FJ, Sherr DH (2013) Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev 65:1148–1161
Sakai S, Kajiume T, Inoue H, Kanno R, Miyazaki M, Ninomiya Y, Kanno M (2003) TCDD treatment eliminates the long-term reconstitution activity of hematopoetic stem cells. Toxicol Sci 72:84–91
Saurat JH, Kaya G, Saxer-Sekulic N, Pardo B, Becker M, Fontao L, Mottu F, Caraux P, Pham XC, Barde C, Fontao F, Zennegg M, Schmid P, Schaad O, Descombes P, Sorg O (2012) The cutaneous lesions of dioxin exposure: lessons from the poisoning of Viktor Yushchenko. Toxicol Sci 125:310–317
Schmidt JV, Su GHT, Reddy JK, Simon MC, Bradfield CA (1996) Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci USA 93:6731–6736
Singh KP, Wyman A, Casado FL, Garrett RW, Gasiewicz TA (2009) Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells. Carcinogenesis 30:11–19
Singh KP, Bennett JA, Casado FL, Walrath JL, Welle SL, Gasiewicz TA (2014) Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoetic stem cell exhaustion and development of a myeloproliferative disorder in aging mice. Stem Cells Dev 23:95–106
Smirnova A, Wincent E, Vikström Bergander L, Alsberg T, Bergman J, Rannug A, Rannug U (2016) Evidence for new light-independent pathways for generation of the endogenous aryl hydrocarbon receptor agonist FICZ. Chem Res Toxicol 29:75–86
Strassel C, Brouard N, Mallo L, Receveur N, Mangin P, Eckly A, Bieche I, Tarte K, Gachet C, Lanza F (2016) Aryl hydrocarbon receptor-dependent enrichment of a megakaryocytic precursor with high potential to produce proplatelets. Blood 127:2231–2240
Suskind RR (1985) Chloracne, ‘the hallmark of dioxin intoxication’. Scand J Work Environ Health 11:165–171
Svobodova J, Kabatkova M, Smerdova l, Brenerova P, Dvorak Z, Machala M, Vondracek J (2015) The aryl hydrocarbon receptor-dependent disruption of contact inhibition in rat liver WB-F344 epithelial cells is linked with induction of survivin, but not with inhibition of apoptosis. Toxicol 333:37–44
Thomas M, Bayha C, Vetter S, Hofmann U, Schwarz M, Zanger UM, Braeuning A (2015) Activating and inhibitory functions of WNT/β-catenin in the induction of cytochromes P450 by nuclear receptors in HepaRG cells. Mol Pharmacol 87:1013–1020
Thomsen JS, Kietz S, Ström A, Gustavsson JA (2004) Hes-1, a novel target gene for aryl hydrocarbon receptor. Mol Pharmacol 65:165–171
Tian J, Feng Y, Fu H, Xie HQ, Jiang JX, Zhao B (2015) The aryl hydrocarbon receptor: a key bridging molecule of external and internal chemical signals. Environ Sci Technol 49:9518–9531
Unnisa Z, Singh KP, Henry EC, Donegan CL, Bennett JA, Gasiewicz TA (2016) Aryl hydrocarbon receptor deficiency in an exon 3 deletion mouse model promotes hematopoietic stem cell proliferation and impacts endosteal niche cells. Stem Cells Int. doi:10.1155/2016/4536187
Vondracek J, Machala M (2016) Environmental ligands of the aryl hydrocarbon receptor and their effects in models of adult liver progenitor cells. Stem Cell Int. doi:10.1155/2016/4326194
Wagner JE, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D, Blazar BR, Tolar J, Le C, Jones J, Cooke MP, Bleul CC (2016) Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 18:144–155
Wang Q, Kurita H, Carreira V, Ko CL, Fan Y, Zhang X, Biesiada J, Medvedovic MM, Puga A (2016) Ah receptor activation by dioxin disrupts activin, BMP, and Wnt signals during early differentiation of mouse embryonic stem cells and inhibits cardiomyocyte functions. Toxicol Sci 149:346–357
Watt FM, Hogan BLM (2000) Out of Eden: stem cells and their niches. Science 287:211–216
Wincent E, Amini N, Luecke S, Glatt H, Bergman J, Crescenzi C, Rannug A, Rannug U (2009) The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J Biol Chem 284:2690–2696
Zouboulis CC, Seltmann H, Neitzel H, Orfanos CE (1999) Establishment and characterization of an immortilized human sebaceous gland cell line (SZ95). J Invest Dermatol 113:1011–1020
Acknowledgements
Valuable help of Dr. Christoph Köhle in preparing the figures is greatly appreciated.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bock, K.W. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated deregulation of myeloid and sebaceous gland stem/progenitor cell homeostasis. Arch Toxicol 91, 2295–2301 (2017). https://doi.org/10.1007/s00204-017-1965-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-017-1965-2