{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:42:21Z","timestamp":1785404541357,"version":"3.56.0"},"reference-count":46,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-23523731"],"award-info":[{"award-number":["RS-2025-23523731"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2026-25479500"],"award-info":[{"award-number":["RS-2026-25479500"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2025-23523731"],"award-info":[{"award-number":["RS-2025-23523731"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2026-25479500"],"award-info":[{"award-number":["RS-2026-25479500"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Triazole fungicides are ubiquitous environmental contaminants. However, their specific effects on the male reproductive system remain unclear. We investigated the toxicological effects of hexaconazole (HEX) on testicular function and elucidated its underlying molecular mechanisms. Although 8 weeks of HEX administration in mice did not affect body weight or gross testicular morphology, it significantly reduced sperm motility and circulating testosterone levels. Correspondingly, HEX exposure markedly downregulated germ cell (DDX4) and meiotic markers (SYCP3) as well as key steroidogenic related gene, including 3\u03b2-HSD, Cyp11a1, and Star. HEX induced the excessive production of reactive oxygen species (ROS) and elicited molecular and biochemical features consistent with ferroptosis, an iron-dependent form of regulated cell death, predominantly in interstitial Leydig cells. This process is characterized by increased intracellular labile iron accumulation, enhanced lipid peroxidation (BODIPY fluorescence), and pronounced dysregulation of ferroptosis-associated regulators, including the upregulation of Tfrc, Slc11a2, and Acsl4, concomitant with substantial depletion of Gpx4, an antioxidant related gene. Consistent with in vivo findings, in vitro experiments using primary Leydig cells demonstrated that HEX-induced oxidative stress directly compromised cell viability and steroidogenic function. Thus, Leydig cell ferroptosis is associated with underlying HEX-induced reproductive toxicity, linking endocrine disruption to impaired spermatogenesis. Furthermore, we identified the ferroptosis-mediated antioxidant defense system as a potential molecular target for mitigating reproductive risks associated with triazole fungicide exposure.<\/jats:p>","DOI":"10.3390\/ijms27146428","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6428","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hexaconazole-Induced Male Reproductive Toxicity Through ROS-Mediated Ferroptosis and Impaired Leydig Cell Steroidogenesis"],"prefix":"10.3390","volume":"27","author":[{"given":"Ran","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Livestock, Korea National University of Agriculture and Fisheries, Jeonju-si 54874, Jeonbuk, Republic of Korea"},{"name":"Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju 27475, Chungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon Woo","family":"Sim","sequence":"additional","affiliation":[{"name":"Department of Animal Biotechnology, College of Life Science, Sangji University, Wonju-si 26339, Gangwon-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won-Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Livestock, Korea National University of Agriculture and Fisheries, Jeonju-si 54874, Jeonbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-2052","authenticated-orcid":false,"given":"Hyun-Jung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju 27475, Chungbuk, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1007\/s10661-011-2061-3","article-title":"The decline and residues of hexaconazole in tomato and soil","volume":"184","author":"Liang","year":"2012","journal-title":"Environ. 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