{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:44:10Z","timestamp":1768902250765,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Auburn University Animal Health and Disease Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoX"],"abstract":"<jats:p>Leydig cells (LCs) in the testes produce the male sex hormone testosterone (T). Several xenobiotics, including clinical drugs, supplements, and environmental chemicals, are known to disrupt T homeostasis. Notably, some of these xenobiotics are known to activate the pregnane X receptor (PXR), a ligand-dependent nuclear receptor. However, it is currently unknown whether PXR is expressed in LCs and whether PXR activation alters T synthesis in rodent LCs. Therefore, in this study, we sought to determine whether PXR is expressed in rodent LCs and whether pregnenolone 16-alpha carbonitrile (PCN), the prototype agonist of rodent PXR, regulates T biosynthesis in rodent LCs. Hormonal as well as protein and gene expression analyses were conducted in rat primary LCs and MA-10 mouse Leydig cells. Results showed that PXR was expressed at the mRNA and protein level in both rat primary LCs and MA-10 cells. Incubation of rat primary LCs with PCN resulted in a significant decrease in T secretion. This PCN-induced decrease in T secretion was associated with decreased protein expression of key steroidogenic enzymes such as 3\u03b2-HSD and CYP17A1. RNA-seq results from MA-10 cells showed that PCN down-regulated the transcripts of steroidogenic enzymes and proteins involved in the T synthesis pathway. Together, these results suggest that PCN, an agonist of rodent PXR, can regulate T biosynthesis in rodent LCs by down-regulating the expression of the steroidogenic enzymes involved in T biosynthesis. Our results are significant as they provide a potential novel mechanism for disruption of testosterone homeostasis by a variety of xenobiotics.<\/jats:p>","DOI":"10.3390\/jox14030071","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T01:52:31Z","timestamp":1726624351000},"page":"1256-1267","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pregnenolone 16-Alpha Carbonitrile, an Agonist of Rodent Pregnane X Receptor, Regulates Testosterone Biosynthesis in Rodent Leydig Cells"],"prefix":"10.3390","volume":"14","author":[{"given":"Julia M.","family":"Salamat","sequence":"first","affiliation":[{"name":"109 Greene Hall, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth M.","family":"Ayala","sequence":"additional","affiliation":[{"name":"109 Greene Hall, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0376-4682","authenticated-orcid":false,"given":"Chen-Che J.","family":"Huang","sequence":"additional","affiliation":[{"name":"109 Greene Hall, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank S.","family":"Wilbanks","sequence":"additional","affiliation":[{"name":"109 Greene Hall, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0185-2208","authenticated-orcid":false,"given":"Rachel C.","family":"Knight","sequence":"additional","affiliation":[{"name":"109 Greene Hall, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benson T.","family":"Akingbemi","sequence":"additional","affiliation":[{"name":"109 Greene Hall, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5806-0183","authenticated-orcid":false,"given":"Satyanarayana R.","family":"Pondugula","sequence":"additional","affiliation":[{"name":"109 Greene Hall, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"key":"ref_1","first-page":"16","article-title":"Revisiting the role of testosterone: Are we missing something?","volume":"19","author":"Tyagi","year":"2017","journal-title":"Rev. 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