Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response

Polycyclic aromatic hydrocarbons (PAHs), dioxin-like compounds (DLCs) and structurally-related environmental pollutants may contribute to the pathogenesis of various diseases and disorders, primarily by activating the aryl hydrocarbon receptor (AHR) and modulating downstream cellular responses. Acco...

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Autores principales:	Christian Vogeley, Natalie C. Sondermann, Selina Woeste, Afaque A. Momin, Viola Gilardino, Frederick Hartung, Markus Heinen, Sophia K. Maaß, Melina Mescher, Marius Pollet, Katharina M. Rolfes, Christoph F.A. Vogel, Andrea Rossi, Dieter Lang, Stefan T. Arold, Motoki Nakamura, Thomas Haarmann-Stemmann
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Aldo-keto reductase 1C3 Aryl hydrocarbon receptor Environmental pollutants Epidermal growth factor receptor Dioxin-like compounds Polycyclic aromatic hydrocarbons Environmental sciences GE1-350
Acceso en línea:	https://doaj.org/article/0dcb6567f7fe460b927f10a91863a021
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spelling	oai:doaj.org-article:0dcb6567f7fe460b927f10a91863a0212021-11-22T04:16:58ZUnraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response0160-412010.1016/j.envint.2021.106989https://doaj.org/article/0dcb6567f7fe460b927f10a91863a0212022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0160412021006140https://doaj.org/toc/0160-4120Polycyclic aromatic hydrocarbons (PAHs), dioxin-like compounds (DLCs) and structurally-related environmental pollutants may contribute to the pathogenesis of various diseases and disorders, primarily by activating the aryl hydrocarbon receptor (AHR) and modulating downstream cellular responses. Accordingly, AHR is considered an attractive molecular target for preventive and therapeutic measures. However, toxicological risk assessment of AHR-modulating compounds as well as drug development is complicated by the fact that different ligands elicit remarkably different AHR responses. By elucidating the differential effects of PAHs and DLCs on aldo–keto reductase 1C3 expression and associated prostaglandin D2 metabolism, we here provide evidence that the epidermal growth factor receptor (EGFR) substantially shapes AHR ligand-induced responses in human epithelial cells, i.e. primary and immortalized keratinocytes and breast cancer cells. Exposure to benzo[a]pyrene (B[a]P) and dioxin-like polychlorinated biphenyl (PCB) 126 resulted in a rapid c-Src-mediated phosphorylation of EGFR. Moreover, both AHR agonists stimulated protein kinase C activity and enhanced the ectodomain shedding of cell surface-bound EGFR ligands. However, only upon B[a]P treatment, this process resulted in an auto-/paracrine activation of EGFR and a subsequent induction of aldo–keto reductase 1C3 and 11-ketoreduction of prostaglandin D2. Receptor binding and internalization assays, docking analyses and mutational amino acid exchange confirmed that DLCs, but not B[a]P, bind to the EGFR extracellular domain, thereby blocking EGFR activation by growth factors. Finally, nanopore long-read RNA-seq revealed hundreds of genes, whose expression is regulated by B[a]P, but not by PCB126, and sensitive towards pharmacological EGFR inhibition. Our data provide novel mechanistic insights into the ligand response of AHR signaling and identify EGFR as an effector of environmental chemicals.Christian VogeleyNatalie C. SondermannSelina WoesteAfaque A. MominViola GilardinoFrederick HartungMarkus HeinenSophia K. MaaßMelina MescherMarius PolletKatharina M. RolfesChristoph F.A. VogelAndrea RossiDieter LangStefan T. AroldMotoki NakamuraThomas Haarmann-StemmannElsevierarticleAldo-keto reductase 1C3Aryl hydrocarbon receptorEnvironmental pollutantsEpidermal growth factor receptorDioxin-like compoundsPolycyclic aromatic hydrocarbonsEnvironmental sciencesGE1-350ENEnvironment International, Vol 158, Iss , Pp 106989- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aldo-keto reductase 1C3 Aryl hydrocarbon receptor Environmental pollutants Epidermal growth factor receptor Dioxin-like compounds Polycyclic aromatic hydrocarbons Environmental sciences GE1-350
spellingShingle	Aldo-keto reductase 1C3 Aryl hydrocarbon receptor Environmental pollutants Epidermal growth factor receptor Dioxin-like compounds Polycyclic aromatic hydrocarbons Environmental sciences GE1-350 Christian Vogeley Natalie C. Sondermann Selina Woeste Afaque A. Momin Viola Gilardino Frederick Hartung Markus Heinen Sophia K. Maaß Melina Mescher Marius Pollet Katharina M. Rolfes Christoph F.A. Vogel Andrea Rossi Dieter Lang Stefan T. Arold Motoki Nakamura Thomas Haarmann-Stemmann Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response
description	Polycyclic aromatic hydrocarbons (PAHs), dioxin-like compounds (DLCs) and structurally-related environmental pollutants may contribute to the pathogenesis of various diseases and disorders, primarily by activating the aryl hydrocarbon receptor (AHR) and modulating downstream cellular responses. Accordingly, AHR is considered an attractive molecular target for preventive and therapeutic measures. However, toxicological risk assessment of AHR-modulating compounds as well as drug development is complicated by the fact that different ligands elicit remarkably different AHR responses. By elucidating the differential effects of PAHs and DLCs on aldo–keto reductase 1C3 expression and associated prostaglandin D2 metabolism, we here provide evidence that the epidermal growth factor receptor (EGFR) substantially shapes AHR ligand-induced responses in human epithelial cells, i.e. primary and immortalized keratinocytes and breast cancer cells. Exposure to benzo[a]pyrene (B[a]P) and dioxin-like polychlorinated biphenyl (PCB) 126 resulted in a rapid c-Src-mediated phosphorylation of EGFR. Moreover, both AHR agonists stimulated protein kinase C activity and enhanced the ectodomain shedding of cell surface-bound EGFR ligands. However, only upon B[a]P treatment, this process resulted in an auto-/paracrine activation of EGFR and a subsequent induction of aldo–keto reductase 1C3 and 11-ketoreduction of prostaglandin D2. Receptor binding and internalization assays, docking analyses and mutational amino acid exchange confirmed that DLCs, but not B[a]P, bind to the EGFR extracellular domain, thereby blocking EGFR activation by growth factors. Finally, nanopore long-read RNA-seq revealed hundreds of genes, whose expression is regulated by B[a]P, but not by PCB126, and sensitive towards pharmacological EGFR inhibition. Our data provide novel mechanistic insights into the ligand response of AHR signaling and identify EGFR as an effector of environmental chemicals.
format	article
author	Christian Vogeley Natalie C. Sondermann Selina Woeste Afaque A. Momin Viola Gilardino Frederick Hartung Markus Heinen Sophia K. Maaß Melina Mescher Marius Pollet Katharina M. Rolfes Christoph F.A. Vogel Andrea Rossi Dieter Lang Stefan T. Arold Motoki Nakamura Thomas Haarmann-Stemmann
author_facet	Christian Vogeley Natalie C. Sondermann Selina Woeste Afaque A. Momin Viola Gilardino Frederick Hartung Markus Heinen Sophia K. Maaß Melina Mescher Marius Pollet Katharina M. Rolfes Christoph F.A. Vogel Andrea Rossi Dieter Lang Stefan T. Arold Motoki Nakamura Thomas Haarmann-Stemmann
author_sort	Christian Vogeley
title	Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response
title_short	Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response
title_full	Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response
title_fullStr	Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response
title_full_unstemmed	Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response
title_sort	unraveling the differential impact of pahs and dioxin-like compounds on akr1c3 reveals the egfr extracellular domain as a critical determinant of the ahr response
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/0dcb6567f7fe460b927f10a91863a021
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Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response

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