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Previous studies have suggested a role of these compounds in the shedding of signaling molecules, such as tumor necrosis factor \u03b1 (TNF\u2010\u03b1). The aim of this work was to evaluate the effect of BPA and NP on the sheddase ADAM17 and its newly discovered regulators iRhom1 and iRhom2 in the release of EGFR\u2010ligands. We report that BPA and NP can stimulate the release of the ADAM17\u2010substrates HB\u2010EGF and TGF\u2010\u03b1. In cells lacking ADAM17 (<jats:italic>Adam17<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mEFs) BPA\u2010stimulated release of HB\u2010EGF, but not TGF\u2010\u03b1, was strongly reduced, whereas NP\u2010stimulated shedding of HB\u2010EGF and TGF\u2010\u03b1 was completely abolished. Inactivation of both ADAM17 and the related ADAM10 (<jats:italic>Adam10\/17<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mEFs) completely prevented the release of these substrates. In the absence of iRhom1, BPA\u2010 or NP\u2010stimulated release of HB\u2010EGF or TGF\u2010\u03b1 was comparable to wild\u2010type control mEFs, conversely the BPA\u2010induced release of HB\u2010EGF was abolished in <jats:italic>iRhom2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mEFs. The defect in shedding of HB\u2010EGF in <jats:italic>iRhom2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mEF cells could be rescued by overexpressing iRhom2. Interestingly, the NP\u2010stimulated release of HB\u2010EGF was not affected by the absence of iRhom2, suggesting that NP could potentially activate both ADAM10 and ADAM17. We tested this hypothesis using betacellulin (BTC), an EGFR\u2010ligand that is a substrate for ADAM10. We found that NP, but not BPA stimulated the release of BTC in <jats:italic>Adam17<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>, <jats:italic>iRhom2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>, or <jats:italic>iRhom1\/2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>, but not in <jats:italic>Adam10\/17<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> cells. Taken together, our results suggest that BPA and NP stimulate the release of EGFR\u2010ligands by differentially activating ADAM17 or ADAM10. The identification of specific effects of these endocrine disruptors on ADAM10 and ADAM17 will help to provide a better understanding of their roles in cell signaling and proinflammatory processes, and provide new potential targets for treatment of reproductive or inflammatory diseases such as asthma or breast cancer that are promoted by xenoestrogens.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.26097","type":"journal-article","created":{"date-parts":[[2017,7,13]],"date-time":"2017-07-13T13:28:14Z","timestamp":1499952494000},"page":"2247-2256","source":"Crossref","is-referenced-by-count":24,"title":["The xenoestrogens biphenol\u2010A and nonylphenol differentially regulate metalloprotease\u2010mediated shedding of EGFR ligands"],"prefix":"10.1002","volume":"233","author":[{"given":"Paulina","family":"Urriola\u2010Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Facultad de Ciencias Biol\u00f3gicas, Departamento de Fisiolog\u00eda Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"},{"name":"Instituto de Qu\u00edmica Pontificia Universidad Cat\u00f3lica de Valpara\u00edso Valpara\u00edso Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[{"name":"Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York New York"},{"name":"Department of Biochemistry, Cellular and Molecular Biology Weill Cornell Graduate School of Medical Sciences New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Maretzky","sequence":"additional","affiliation":[{"name":"Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"McIlwain","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Baxter Laboratory in Stem Cell Biology Stanford University Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tak W.","family":"Mak","sequence":"additional","affiliation":[{"name":"Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Center University Health Network Toronto, Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan G.","family":"Reyes","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica Pontificia Universidad Cat\u00f3lica de Valpara\u00edso Valpara\u00edso Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl P.","family":"Blobel","sequence":"additional","affiliation":[{"name":"Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York New York"},{"name":"Institute for Advanced Study Technische Universit\u00e4t M\u00fcnchen Garching Germany"},{"name":"Department of Physiology, Biophysics and Systems Biology Weill Cornell University New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7499-5501","authenticated-orcid":false,"given":"Ricardo D.","family":"Moreno","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Biol\u00f3gicas, Departamento de Fisiolog\u00eda Pontificia Universidad Cat\u00f3lica de Chile Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,8,25]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214400"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2009.02.022"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2009.09.005"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/385729a0"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1548"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu120"},{"key":"e_1_2_5_8_1","unstructured":"E.P.A. 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