{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T13:37:02Z","timestamp":1767706622322,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:00:00Z","timestamp":1621382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["32-55738.98 and 31003A-138067"],"award-info":[{"award-number":["32-55738.98 and 31003A-138067"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Autocrine\/paracrine factors generated in response to 17\u03b2-estradiol (E2) within the fallopian tube (FT) facilitate fertilization and early embryo development for implantation. Since cyclic AMP (cAMP) plays a key role in reproduction, regulation of its synthesis by E2 may be of biological\/pathophysiological relevance. Herein, we investigated whether cAMP production in FT cells (FTCs) is regulated by E2 and environmental estrogens (EE\u2019s; xenoestrogens and phytoestrogens). Under basal conditions, low levels of extracellular cAMP were detectable in bovine FTCs (epithelial cells and fibroblasts; 1:1 ratio). Treatment of FTCs with forskolin (AC; adenylyl cyclase activator), isoproterenol (\u03b2-adrenoceptor agonist) and IBMX (phosphodiesterase (PDE) inhibitor) dramatically (&gt;10 fold) increased cAMP; whereas LRE1 (sAC; soluble AC inhibitor) and 2\u2019,5\u2019-dideoxyadenosine (DDA; transmembrane AC (tmAC)) inhibitor decreased cAMP. Comparable changes in basal and stimulated intracellular cAMP were also observed. Ro-20-1724 (PDE-IV inhibitor), but not milrinone (PDE-III inhibitor) nor mmIBMX (PDE-I inhibitor), augmented forskolin-stimulated cAMP levels, suggesting that PDE-IV dominates in FTCs. E2 increased cAMP levels and CREB phosphorylation in FTCs, and these effects were mimicked by EE\u2019s (genistein, 4-hydroxy-2\u2019,4\u2019,6\u2019-trichlorobiphenyl, 4-hydroxy-2\u2019,4\u2019,6\u2019-dichlorobiphenyl). Moreover, the effects of E2 and EE were blocked by the tmAC inhibitor DDA, but not by the ER\u03b1\/\u03b2 antagonist ICI182780. Moreover, BAPTA-AM (intracellular-Ca2+ chelator) abrogated the effects of E2, but not genistein, on cAMP suggesting differential involvement of Ca2+. Treatment with non-permeable E2-BSA induced cAMP levels and CREB-phosphorylation; moreover, the stimulatory effects of E2 and EEs on cAMP were blocked by G15, a G protein-coupled estrogen receptor (GPER) antagonist. E2 and IBMX induced cAMP formation was inhibited by LRE1 and DDA suggesting involvement of both tmAC and sAC. Our results provide the first evidence that in FTCs, E2 and EE\u2019s stimulate cAMP synthesis via GPER. Exposure of the FT to EE\u2019s and PDE inhibitors may result in abnormal non-cyclic induction of cAMP levels which may induce deleterious effects on reproduction.<\/jats:p>","DOI":"10.3390\/cells10051250","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T12:58:07Z","timestamp":1621429087000},"page":"1250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Modulation of Cyclic AMP Levels in Fallopian Tube Cells by Natural and Environmental Estrogens"],"prefix":"10.3390","volume":"10","author":[{"given":"Marinella","family":"Rosselli","sequence":"first","affiliation":[{"name":"Department of Reproductive Endocrinology, University Hospital Zurich, Areal Wagi Schlieren, Wagistrasse 14, CH 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara P. S.","family":"Cometti","sequence":"additional","affiliation":[{"name":"Department of Reproductive Endocrinology, University Hospital Zurich, Areal Wagi Schlieren, Wagistrasse 14, CH 8952 Schlieren, Switzerland"},{"name":"R&amp;D Scientific Affairs, IBSA Institut Biochimique SA, Via del Piano 29, P.O. Box 266, CH 6915 Pambio-Noranco, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte","family":"Leeners","sequence":"additional","affiliation":[{"name":"Department of Reproductive Endocrinology, University Hospital Zurich, Areal Wagi Schlieren, Wagistrasse 14, CH 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta Ewa","family":"Szutkowska","sequence":"additional","affiliation":[{"name":"Department of Reproductive Endocrinology, University Hospital Zurich, Areal Wagi Schlieren, Wagistrasse 14, CH 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8101-6009","authenticated-orcid":false,"given":"Edwin K.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology &amp; Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghvendra K.","family":"Dubey","sequence":"additional","affiliation":[{"name":"Department of Reproductive Endocrinology, University Hospital Zurich, Areal Wagi Schlieren, Wagistrasse 14, CH 8952 Schlieren, Switzerland"},{"name":"Department of Pharmacology &amp; Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JOE-16-0302","article-title":"Oviduct: Roles in fertilization and early embryo development","volume":"232","author":"Li","year":"2017","journal-title":"J. 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