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Although this decline remains unexplained, lifestyle factors may affect male fertility. Recently, several studies highlighted a potential link between non-steroidal anti-inflammatory drug (NSAID) usage, such as naproxen and ibuprofen, and declining male fertility. However, the mechanisms by which these common analgesics affect male fertility, including their effects on the blood\u2013testis barrier (BTB), remain poorly characterized. Utilizing an in vitro rhesus macaque non-human primate (NHP) BTB model, we demonstrate that serum levels of naproxen and ibuprofen alter the function of BTB. Following short-term naproxen and ibuprofen treatment of NHP primary Sertoli cells, we show that these NSAIDs increase the transepithelial electrical resistance, indicating an overall strengthening of the Sertoli cell junctions. Furthermore, naproxen and ibuprofen treatment alter the expression of genes involved in maintaining the BTB. Specifically, the genes that were significantly expressed in response to ibuprofen exposure were enriched for human phenotypic abnormalities linked to male factor infertility. Together, these results suggest that short-term naproxen and ibuprofen treatment disrupt the function of the BTB by altering the integrity of the Sertoli cell junctions, proposing a potential role of NSAIDs in male factor infertility.<\/jats:p>","DOI":"10.3390\/ijms27073033","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:32:47Z","timestamp":1774611167000},"page":"3033","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Naproxen and Ibuprofen Exposure Alter the Blood\u2013Testis Barrier in a Novel In Vitro Model"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5452-3243","authenticated-orcid":false,"given":"Krista M. 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University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"name":"Pittsburgh Development Center, Division of Developmental & Regenerative Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6106-0360","authenticated-orcid":false,"given":"Elizabeth","family":"Waters","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA 30602, USA"},{"name":"Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"McClellan","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA 30602, USA"},{"name":"Regenerative Bioscience Center, 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