{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:06:40Z","timestamp":1790701600726,"version":"4.1.0"},"reference-count":157,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T00:00:00Z","timestamp":1679270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CNRS and University of Montpellier","award":["2020\/01\/025"],"award-info":[{"award-number":["2020\/01\/025"]}]},{"name":"French National Research Program for Environmental","award":["2020\/01\/025"],"award-info":[{"award-number":["2020\/01\/025"]}]},{"name":"Occupational Health of ANSES","award":["2020\/01\/025"],"award-info":[{"award-number":["2020\/01\/025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-steroidal anti-inflammatory drugs (NSAIDs) and 17\u03b1-ethinyl-estradiol (EE2) are among the most relevant endocrine-disrupting pharmaceuticals found in the environment, particularly in surface and drinking water due to their incomplete removal via wastewater treatment plants. Exposure of pregnant mice to NSAID therapeutic doses during the sex determination period has a negative impact on gonadal development and fertility in adults; however, the effects of their chronic exposure at lower doses are unknown. In this study, we investigated the impact of chronic exposure to a mixture containing ibuprofen, 2hydroxy-ibuprofen, diclofenac, and EE2 at two environmentally relevant doses (added to the drinking water from fetal life until puberty) on the reproductive tract in F1 exposed mice and their F2 offspring. In F1 animals, exposure delayed male puberty and accelerated female puberty. In post-pubertal F1 testes and ovaries, differentiation\/maturation of the different gonad cell types was altered, and some of these modifications were observed also in the non-exposed F2 generation. Transcriptomic analysis of post-pubertal testes and ovaries of F1 (exposed) and F2 animals revealed significant changes in gene expression profiles and enriched pathways, particularly the inflammasome, metabolism and extracellular matrix pathways, compared with controls (non-exposed). This suggested that exposure to these drug cocktails has an intergenerational impact. The identified Adverse Outcome Pathway (AOP) networks for NSAIDs and EE2, at doses that are relevant to everyday human exposure, will improve the AOP network of the human reproductive system development concerning endocrine disruptor chemicals. It may serve to identify other putative endocrine disruptors for mammalian species based on the expression of biomarkers.<\/jats:p>","DOI":"10.3390\/ijms24065890","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T03:15:03Z","timestamp":1679368503000},"page":"5890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cocktails of NSAIDs and 17\u03b1 Ethinylestradiol at Environmentally Relevant Doses in Drinking Water Alter Puberty Onset in Mice Intergenerationally"],"prefix":"10.3390","volume":"24","author":[{"given":"Pascal","family":"Philibert","sequence":"first","affiliation":[{"name":"D\u00e9veloppement et Pathologie de la Gonade, Institut de G\u00e9n\u00e9tique Humaine, Centre National de la Recherche Scientifique (CNRS), Universit\u00e9 de Montpellier, 34090 Montpellier, France"},{"name":"Laboratoire de Biochimie et Biologie Mol\u00e9culaire, H\u00f4pital Car\u00e8meau, CHU de N\u00eemes, 30900 N\u00eemes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"D\u00e9jardin","sequence":"additional","affiliation":[{"name":"D\u00e9veloppement et Pathologie de la Gonade, Institut de G\u00e9n\u00e9tique Humaine, Centre National de la Recherche Scientifique (CNRS), Universit\u00e9 de Montpellier, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lissa","family":"Girard","sequence":"additional","affiliation":[{"name":"D\u00e9veloppement et Pathologie de la Gonade, Institut de G\u00e9n\u00e9tique Humaine, Centre National de la Recherche Scientifique (CNRS), Universit\u00e9 de Montpellier, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Durix","sequence":"additional","affiliation":[{"name":"IExplore-RAM, Institut de G\u00e9nomique Fonctionnelle, Centre National de la Recherche Scientifique, Universit\u00e9 de Montpellier and Institut National de la Sant\u00e9 Et de la Recherche M\u00e9dicale (INSERM), 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Alicia","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"MGX-Montpellier GenomiX, UMS Biocampus, Universit\u00e9 de Montpellier, CNRS, INSERM, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Mialhe","sequence":"additional","affiliation":[{"name":"MGX-Montpellier GenomiX, UMS Biocampus, Universit\u00e9 de Montpellier, CNRS, INSERM, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6689-7373","authenticated-orcid":false,"given":"Mathieu","family":"Tardat","sequence":"additional","affiliation":[{"name":"Biologie des S\u00e9quences R\u00e9p\u00e9t\u00e9es, Institut de G\u00e9n\u00e9tique Humaine, Centre National de la Recherche Scientifique, Universit\u00e9 de Montpellier, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Poulat","sequence":"additional","affiliation":[{"name":"D\u00e9veloppement et Pathologie de la Gonade, Institut de G\u00e9n\u00e9tique Humaine, Centre National de la Recherche Scientifique (CNRS), Universit\u00e9 de Montpellier, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2333-1745","authenticated-orcid":false,"given":"Brigitte","family":"Boizet-Bonhoure","sequence":"additional","affiliation":[{"name":"D\u00e9veloppement et Pathologie de la Gonade, Institut de G\u00e9n\u00e9tique Humaine, Centre National de la Recherche Scientifique (CNRS), Universit\u00e9 de Montpellier, 34090 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1289\/ehp.1104477","article-title":"Pharmaceuticals and personal care products in the environment: What are the big questions?","volume":"120","author":"Boxall","year":"2012","journal-title":"Environ. 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