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      Ibuprofen results in alterations of human fetal testis development

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          Abstract

          Among pregnant women ibuprofen is one of the most frequently used pharmaceutical compounds with up to 28% reporting use. Regardless of this, it remains unknown whether ibuprofen could act as an endocrine disruptor as reported for fellow analgesics paracetamol and aspirin. To investigate this, we exposed human fetal testes (7–17 gestational weeks (GW)) to ibuprofen using ex vivo culture and xenograft systems. Ibuprofen suppressed testosterone and Leydig cell hormone INSL3 during culture of 8–9 GW fetal testes with concomitant reduction in expression of the steroidogenic enzymes CYP11A1, CYP17A1 and HSD17B3, and of INSL3. Testosterone was not suppressed in testes from fetuses younger than 8 GW, older than 10–12 GW, or in second trimester xenografted testes (14–17 GW). Ex vivo, ibuprofen also affected Sertoli cell by suppressing AMH production and mRNA expression of AMH, SOX9, DHH, and COL2A1. While PGE2 production was suppressed by ibuprofen, PGD2 production was not. Germ cell transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen. We conclude that, at concentrations relevant to human exposure and within a particular narrow ‘early window’ of sensitivity within first trimester, ibuprofen causes direct endocrine disturbances in the human fetal testis and alteration of the germ cell biology.

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          Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition.

          Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.
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            Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.

            Constitutive cyclooxygenase (COX-1; prostaglandin-endoperoxide synthase, EC 1.14.99.1) is present in cells under physiological conditions, whereas COX-2 is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions, such as inflammation. Therefore, we have assessed the relative inhibitory effects of some nonsteroidal antiinflammatory drugs on the activities of COX-1 (in bovine aortic endothelial cells) and COX-2 (in endotoxin-activated J774.2 macrophages) in intact cells, broken cells, and purified enzyme preparations (COX-1 in sheep seminal vesicles; COX-2 in sheep placenta). Similar potencies of aspirin, indomethacin, and ibuprofen against the broken cell and purified enzyme preparations indicated no influence of species. Aspirin, indomethacin, and ibuprofen were more potent inhibitors of COX-1 than COX-2 in all models used. The relative potencies of aspirin and indomethacin varied only slightly between models, although the IC50 values were different. Ibuprofen was more potent as an inhibitor of COX-2 in intact cells than in either broken cells or purified enzymes. Sodium salicylate was a weak inhibitor of both COX isoforms in intact cells and was inactive against COX in either broken cells or purified enzyme preparations. Diclofenac, BW 755C, acetaminophen, and naproxen were approximately equipotent inhibitors of COX-1 and COX-2 in intact cells. BF 389, an experimental drug currently being tested in humans, was the most potent and most selective inhibitor of COX-2 in intact cells. Thus, there are clear pharmacological differences between the two enzymes. The use of such models of COX-1 and COX-2 activity will lead to the identification of selective inhibitors of COX-2 with presumably less side effects than present therapies. Some inhibitors had higher activity in intact cells than against purified enzymes, suggesting that pure enzyme preparations may not be predictive of therapeutic action.
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              Use of over-the-counter medications during pregnancy.

              The most common medications used in pregnancy are nonprescription or over-the-counter medications, although there has been little research on their risks or safety. We describe the patterns of over-the-counter medication use among pregnant women. Data were collected in 2 case-control studies of birth defects: the Slone Epidemiology Center Birth Defects Study (BDS) and the National Birth Defects Prevention Study (NBDPS). Among 7563 mothers of malformed and nonmalformed offspring in the Slone Epidemiology Center Birth Defects Study and 2970 mothers of nonmalformed offspring in the National Birth Defects Prevention Study, acetaminophen, ibuprofen, and pseudoephedrine were used by at least 65%, 18%, and 15%, respectively. Among women in the Slone Epidemiology Center Birth Defects Study, the use in pregnancy of aspirin and chlorpheniramine decreased from 1976 to 2004 and of ibuprofen, pseudoephedrine, diphenhydramine, dextromethorphan, and guaifenesin increased. Among women in the National Birth Defects Prevention Study, the use of acetaminophen, pseudoephedrine, diphenhydramine, and guaifenesin was higher during pregnancy than before pregnancy. Findings show that over-the-counter medications are used by most pregnant women. Studies that examine specific over-the-counter medications in relation to specific birth defects are necessary to better inform pregnant women about risks and safety.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                10 March 2017
                2017
                : 7
                : 44184
                Affiliations
                [1 ]Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset – Inserm UMR 1085) , Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France
                [2 ]LUNAM Université, Oniris, USC INRA 1329, Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA) , Nantes, F-44307, France
                [3 ]MRC Centre for Reproductive Health, University of Edinburgh, Queens Medical Research Institute, 47 Little France Crescent , Edinburgh, EH16 4TJ, UK
                [4 ]Laboratorium of Genomic and Molecular Biomedicine, Department of Biology, University of Copenhagen , Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark
                [5 ]CHU de Rennes, Service de Gynécologie , Hôpital Sud, 16, boulevard de Bulgarie, F-35700 Rennes, France
                [6 ]Ecole des hautes études en santé publique (EHESP), Avenue Léon Bernard , F-35043 RENNES, France
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep44184
                10.1038/srep44184
                5345102
                28281692
                19a5a33b-bf79-49c7-a00e-3187cb5a9f5a
                Copyright © 2017, The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 21 October 2016
                : 03 February 2017
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