{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:47:49Z","timestamp":1791838069710,"version":"4.3.4"},"reference-count":83,"publisher":"American Chemical Society (ACS)","issue":"6","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013088","name":"Qinglan Project of Jiangsu Province of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013088","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012246","name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Natural Science Foundation of China (NSFC)","award":["81872650"],"award-info":[{"award-number":["81872650"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China (NSFC)","award":["82273668"],"award-info":[{"award-number":["82273668"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China (NSFC)","award":["82574133"],"award-info":[{"award-number":["82574133"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Growing evidence suggests that exposure to metals, such as molybdenum, contributes to significant health risks. However, very little is known about its potential male reproductive toxicity due to paternal exposure across generations. The aim of the present study was to investigate the male reproductive toxicity of paternal exposure to sodium molybdate (Na2MoO4) across generations and reveal the underlying mechanism. Adult F0 male C57 mice were administered sodium molybdate at doses of 0.01 and 0.1 mg\/kg\/day. The assessment included testicular toxicity evaluation and metabolomic profiling, followed by mechanistic studies in vivo and in vitro from F0 to F2. A large sample of case-control study including 958 subjects verified the findings. Reduced sperm counts and damages to seminiferous tubules across generations were observed in Mo-treated groups. Metabolomics analysis revealed a transgenerational elevation of 17\u03b1-hydroxyprogesterone (17\u03b1-OHP) in the testes of Mo-treated groups. Apoptosis and ferroptosis were enhanced in GC-2 cells in vitro after 17\u03b1-OHP treatment and were validated in vivo. Molecular competition experiments revealed that 17\u03b1-OHP competes for the NADPH binding site in FSP1, hindering FSP1\u2019s catalytic function, as supported by metabolomics analysis. Enzyme activity analysis found a reduction in FSP1 activity after 17\u03b1-OHP treatment, promoting ferroptosis and apoptosis in GC-2 cells in vitro. AHCY was identified as a potential target and was reduced after Mo exposure both in vivo and in vitro, accompanied by testicular DNA hypomethylation and elevated expression of key enzymes for 17\u03b1-OHP synthesis across generations, including Hsd3b and Cyp17a1. Human studies revealed that Mo exposure was associated with an increased risk of male infertility via 17\u03b1-OHP. This study innovatively elucidated the mechanisms by which paternal Mo exposure induced transgenerational male reproductive toxicity through metabolic and epigenetic alterations using human, mouse, and in vitro models.<\/jats:p>","DOI":"10.1021\/ehp.6c00223","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T16:41:43Z","timestamp":1784220103000},"page":"726-746","source":"Crossref","is-referenced-by-count":0,"title":["17\u03b1-Hydroxyprogesterone\nMediates Mo-Induced\nSperm-Mediated Transgenerational Inheritance of Impaired Spermatogenesis"],"prefix":"10.1021","volume":"134","author":[{"given":"Kun","family":"Zhou","sequence":"first","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Song","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingtong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Tang","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusheng","family":"Guan","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhui","family":"Hu","sequence":"additional","affiliation":[{"name":"Sir Run Run Hospital of Nanjing Medical University , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5742-5080","authenticated-orcid":true,"given":"Minjian","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]},{"name":"Nanjing Medical University , , , ,","place":["Nanjing, China, 211166"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"issue":"4","key":"2026101215563482000_cit1","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3390\/toxics6040065","article-title":"Heavy Metal Mixture\nExposure and Effects in Developing Nations: An Update","volume":"6","author":"Anyanwu","year":"2018","journal-title":"Toxics"},{"key":"2026101215563482000_cit2","doi-asserted-by":"publisher","first-page":"110173","DOI":"10.1016\/j.cbi.2022.110173","article-title":"Essential metals in\nhealth and disease","volume":"367","author":"Jomova","year":"2022","journal-title":"Chem. 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Nutr\nBiochem"},{"issue":"9","key":"2026101215563482000_cit23","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1177\/0748233718779478","article-title":"Chronic co-exposure\nto low levels of brominated flame retardants\nand heavy metals induces reproductive toxicity in zebrafish","volume":"34","author":"Chen","year":"2018","journal-title":"Toxicol Ind. 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Sci."},{"key":"2026101215563482000_cit26","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1016\/j.chemosphere.2019.04.092","article-title":"Paternal benzo[a]pyrene\nexposure alters the sperm DNA methylation levels of imprinting genes\nin F0 generation mice and their unexposed F1\u20132 male offspring","volume":"228","author":"Zhang","year":"2019","journal-title":"Chemosphere"},{"key":"2026101215563482000_cit27","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/B978-0-12-822946-0.00021-0","article-title":"Molybdenum","volume-title":"Handbook on the Toxicology of Metals","author":"Albin","year":"2022"},{"issue":"3","key":"2026101215563482000_cit28","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1177\/0960327111405862","article-title":"Impairment\nof mice spermatogenesis by sodium arsenite","volume":"31","author":"Ferreira","year":"2012","journal-title":"Hum. Exp. Toxicol."},{"key":"2026101215563482000_cit29","unstructured":"Opinion of the Scientific Committee on Food on the\nTolerable Upper\nIntake Level of Molybdenum. Tolerable Upper Intake Levels for Vitamins\nand Minerals. 2000. https:\/\/www.efsa.europa.eu\/sites\/default\/files\/efsa_rep\/blobserver_assets\/ndatolerableuil.pdf."},{"issue":"2","key":"2026101215563482000_cit30","doi-asserted-by":"publisher","DOI":"10.23749\/mdl.v113i2.12877","article-title":"Accidental\ningestion of sodium molybdate at the workplace followed by short-term\nbiomonitoring","volume":"113","author":"Bernasconi","year":"2022","journal-title":"Med. 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Atomic Spectrom."},{"issue":"13\u201314","key":"2026101215563482000_cit38","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.clinbiochem.2016.05.012","article-title":"Simultaneous\nquantification of 17-hydroxyprogesterone, androstenedione, testosterone\nand cortisol in human serum by LC-MS\/MS using TurboFlow online sample\nextraction","volume":"49","author":"Gervasoni","year":"2016","journal-title":"Clin Biochem."},{"key":"2026101215563482000_cit39","doi-asserted-by":"publisher","first-page":"1226829","DOI":"10.3389\/fmolb.2023.1226829","article-title":"Transcriptomic\nsignatures for human\nmale infertility","volume":"10","author":"Hodz\u030cic\u0301","year":"2023","journal-title":"Front Mol. 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Hazard Mater."},{"issue":"5","key":"2026101215563482000_cit42","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1111\/cts.12324","article-title":"An Untargeted\nMetabolomics Analysis of Antipsychotic Use in Bipolar Disorder","volume":"8","author":"Burghardt","year":"2015","journal-title":"Clin Transl Sci."},{"issue":"4","key":"2026101215563482000_cit43","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1080\/13506129.2021.1958775","article-title":"Metabolomics analysis\nfor diagnosis and biomarker discovery of transthyretin amyloidosis","volume":"28","author":"Olsson","year":"2021","journal-title":"Amyloid"},{"issue":"1","key":"2026101215563482000_cit44","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1097\/01.ASN.0000103872.60993.06","article-title":"Absence of\nassociation between organic solvent exposure and risk of chronic renal\nfailure: a nationwide population-based case-control study","volume":"15","author":"Fored","year":"2004","journal-title":"J. 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