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Using integrated multi-omics, enzymology, and histopathology, we investigated the organ-specific toxicity of chronic LYN exposure (0.01, 1\u202f\u03bcg\/L for 60 days) in female mandarin fish (Siniperca chuatsi). LYN induced severe, dose-dependent hepatic necrosis, driven by concurrent blockade of the 2-oxocarboxylic acid metabolism pathway (via idh1 suppression) and ammonia detoxification failure. Additionally, LYN triggered a multi-node blockade of the ubiquinoid antioxidant system through coordinated downregulation of hpda, nqo1, and ggcx, resulting in oxidative collapse (increased ROS, MDA, ALT; decreased T-AOC, NQO1, IDH1). In contrast, ovaries remained histologically intact with no masculinization. Ovarian resilience involved dual adaptation: recalibration of steroidogenesis (downregulation of cyp19a, hsd11b2, and cpeb2 coupled with esr1 upregulation) and, for the first time in teleost gonads under progestin exposure, upregulation of ABCC efflux transporters (abcc2\/3), via l-arginine\/Nrf2 signaling. These findings reveal that LYN causes catastrophic hepatic metabolic collapse while ovarian tissue maintains homeostasis through active detoxification and steroidogenic reprogramming, providing a mechanistic basis for multi-organ risk assessment of progestins.<\/jats:p>","DOI":"10.1021\/acs.est.6c07917","type":"journal-article","created":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T14:01:22Z","timestamp":1788703282000},"page":"26229-26245","source":"Crossref","is-referenced-by-count":0,"title":["Organ-Specific\nToxicity\nof Lynestrenol in Mandarin\nFish: Hepatic Metabolic Collapse versus Ovarian Resilience through\nEfflux Transporter Activation"],"prefix":"10.1021","volume":"60","author":[{"given":"Weibin","family":"Li","sequence":"first","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijian","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyue","family":"Lin","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Cai","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Deng","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1978-5557","authenticated-orcid":true,"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Han","sequence":"additional","affiliation":[{"name":"Guangzhou University , , ,","place":["Guangzhou, P. R. China, 510006"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"issue":"9","key":"2026092210113811100_cit1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.23807","article-title":"Metabolomics\nand cellular altered\npathways in cancer biology: A review","volume":"38","author":"Bhardwaj","year":"2024","journal-title":"J. Biochem.\nMol. Toxicol."},{"key":"2026092210113811100_cit2","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.chemosphere.2018.10.130","article-title":"Rapid masculinization and effects on the liver of female western\nmosquitofish (Gambusia affinis) by norethindrone","volume":"216","author":"Hou","year":"2019","journal-title":"Chemosphere"},{"issue":"56","key":"2026092210113811100_cit3","doi-asserted-by":"publisher","first-page":"85211","DOI":"10.1007\/s11356-022-21786-7","article-title":"Does thermal stress modulate the biochemical and physiological\nresponses of Ruditapes decussatus exposed to the progestin levonorgestrel?","volume":"29","author":"Mannai","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"2026092210113811100_cit4","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2023.162740","article-title":"Levonorgestrel\ncauses feminization\nand dose-dependent masculinization in medaka fish (Oryzias latipes): Endocrine-disruption activity and\nits correlation with sex reversal","volume":"876","author":"Watanabe","year":"2023","journal-title":"Sci. Total\nEnviron."},{"key":"2026092210113811100_cit5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2020.110496","article-title":"Norethindrone\nalters mating behaviors, ovary histology, hormone production and transcriptional\nexpression of steroidogenic genes in zebrafish (Danio rerio)","volume":"195","author":"Hou","year":"2020","journal-title":"Ecotoxicol. Environ.\nSaf."},{"key":"2026092210113811100_cit6","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2023.168693","article-title":"Gestodene\ncauses masculinization of the western mosquitofish (Gambusia affinis): Insights from ovary metabolomics","volume":"912","author":"Li","year":"2024","journal-title":"Sci. Total Environ."},{"issue":"2","key":"2026092210113811100_cit7","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1677\/joe.0.0470251","article-title":"Metabolism\nof lynestrenol to norethisterone\nby liver homogenate","volume":"47","author":"Mazaheri","year":"1970","journal-title":"J. Endocrinol."},{"issue":"3","key":"2026092210113811100_cit8","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/0010-7824(82)90078-6","article-title":"Serum levels\nand pharmacokinetics\nof norethisterone after ingestion of lynestrenol: its relation to\ndose and stage of the menstrual cycle","volume":"26","author":"Kuhl","year":"1982","journal-title":"Contraception"},{"issue":"1-2","key":"2026092210113811100_cit9","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jsbmb.2007.09.025","article-title":"Identification\nof the human cytochrome P450 enzymes involved in the in vitro biotransformation\nof lynestrenol and norethindrone","volume":"110","author":"Korhonen","year":"2008","journal-title":"J. Steroid\nBiochem. Mol. 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Rep."},{"key":"2026092210113811100_cit26","doi-asserted-by":"publisher","DOI":"10.1016\/j.aquaculture.2025.743548","article-title":"Highly effective masculinization\nof mandarin fish (Siniperca chuatsi) using Etonogestrel: A practical\nmethod for aquaculture and transcriptomic mechanism elucidation","volume":"614","author":"Zhou","year":"2026","journal-title":"Aquaculture"},{"key":"2026092210113811100_cit27","doi-asserted-by":"publisher","DOI":"10.1016\/j.aqrep.2021.100802","article-title":"Characterization of\ndmrts and their potential role in gonadal development\nof mandarin fish (Siniperca chuatsi)","volume":"21","author":"Han","year":"2021","journal-title":"Aquacult. Rep."},{"key":"2026092210113811100_cit28","doi-asserted-by":"publisher","DOI":"10.1016\/j.anireprosci.2025.108030","article-title":"Levonorgestrel-induced\nsex reversal in mandarin fish (Siniperca chuatsi): An effective protocol for all-female production and its aquaculture\napplications","volume":"283","author":"Liu","year":"2025","journal-title":"Anim. Reprod. Sci."},{"issue":"3","key":"2026092210113811100_cit29","doi-asserted-by":"publisher","DOI":"10.3390\/toxins16030149","article-title":"Integration of Multi-Omics, Histological,\nand Biochemical Analysis\nReveals the Toxic Responses of Nile Tilapia Liver to Chronic Microcystin-LR\nExposure","volume":"16","author":"Li","year":"2024","journal-title":"Toxins"},{"key":"2026092210113811100_cit30","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2021.149554","article-title":"Prediction of adverse effects of\neffluents containing phenolic compounds in the Ba River on the ovary\nof fish (Hemiculter leucisculus) using\ntranscriptomic and metabolomic analyses","volume":"801","author":"Guo","year":"2021","journal-title":"Sci.\nTotal Environ."},{"key":"2026092210113811100_cit31","doi-asserted-by":"publisher","DOI":"10.3389\/fmars.2023.1243767","article-title":"Integrated\ntranscriptomic\nand metabolomic analyses identify key factors in the vitellogenesis\nof juvenile Sichuan bream (Sinibrama taeniatus)","volume":"10","author":"Zhao","year":"2023","journal-title":"Front. 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Res. Toxicol."},{"issue":"1","key":"2026092210113811100_cit38","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1093\/ajcp\/28.1.56","article-title":"A colorimetric method\nfor the determination of serum\nglutamic oxalacetic and glutamic pyruvic transaminases","volume":"28","author":"Reitman","year":"1957","journal-title":"Am. J. Clin. Pathol."},{"issue":"1","key":"2026092210113811100_cit39","first-page":"158","article-title":"Studies\non the quantitative and qualitative characterization\nof erythrocyte glutathione peroxidase","volume":"70","author":"Paglia","year":"1967","journal-title":"J. Lab\nClin. Med."},{"issue":"1","key":"2026092210113811100_cit40","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","article-title":"Measurement of protein using bicinchoninic acid","volume":"150","author":"Smith","year":"1985","journal-title":"Anal. Biochem."},{"issue":"6","key":"2026092210113811100_cit41","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/BF00202202","article-title":"The nature and significance\nof liver\ncell vacuolation following hepatocellular injury--an analysis based\non observations on rats rendered tolerant to hepatotoxic damage","volume":"428","author":"Nayak","year":"1996","journal-title":"Virchows Arch."},{"key":"2026092210113811100_cit42","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemosphere.2021.130049","article-title":"Norethindrone\ncauses cellular and hepatic injury in\nzebrafish by compromising the metabolic processes associated with\nantioxidant defence: Insights from metabolomics","volume":"275","author":"Wang","year":"2021","journal-title":"Chemosphere"},{"issue":"39","key":"2026092210113811100_cit43","doi-asserted-by":"publisher","first-page":"4865","DOI":"10.3748\/wjg.15.4865","article-title":"Biochemical mechanisms in drug-induced liver injury:\ncertainties and doubts","volume":"15","author":"Grattagliano","year":"2009","journal-title":"World J. 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Fish Biol."},{"issue":"3","key":"2026092210113811100_cit47","doi-asserted-by":"publisher","DOI":"10.3390\/toxins16030149","article-title":"Integration of Multi-Omics, Histological,\nand Biochemical analysis\nReveals the Toxic Responses of Nile Tilapia Liver to Chronic Microcystin-LR\nExposure","volume":"16","author":"Li","year":"2024","journal-title":"Toxins"},{"issue":"7","key":"2026092210113811100_cit48","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076441","article-title":"Effects of\nCurcumin on Oxidative Stress and Ferroptosis in Acute\nAmmonia Stress-Induced Liver Injury in Gibel Carp (Carassius gibelio)","volume":"24","author":"Wu","year":"2023","journal-title":"Int. J.\nMol. Sci."},{"issue":"11","key":"2026092210113811100_cit49","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13111316","article-title":"Protective Effects\nof 17-\u03b2E(2) on the Primary Hepatocytes of Rainbow Trout (Oncorhynchus mykiss) Under Acute Heat Stress","volume":"13","author":"Zhao","year":"2024","journal-title":"Antioxidants"},{"issue":"3","key":"2026092210113811100_cit50","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.cca.2004.01.006","article-title":"Effects of 17-beta estradiol and 4-nonylphenol on phase\nII electrophilic detoxification pathways in largemouth bass (Micropterus salmoides) liver","volume":"137","author":"Hughes","year":"2004","journal-title":"Comp. Biochem. Physiol., Part C: Toxicol. 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