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This study systematically characterized the neurodevelopmental toxicity of these compounds and evaluated their associated environmental risks within the adverse outcome pathway framework. Molecular docking and radioligand binding assays identified integrin \u03b1v\u03b23 as a primary molecular target for all tested OPAs and NOPEs, with tris(2,4-di-tert-butylphenyl)phosphate (AO168\u2550O) exhibiting high binding affinity. Exposure to AO168\u2550O at environmentally relevant concentrations (\u226550 \u03bcg\/L) triggered significant behavioral deficits in zebrafish larvae, including reduced locomotion, altered exploratory preference, and irregular locomotor patterning. In vivo imaging and molecular analyses revealed that AO168\u2550O induced motor neuron abnormalities and suppressed neurogenesis markers. Transcriptomic profiling elucidated that AO168\u2550O disrupted MAPK and calcium signaling pathways via integrin \u03b1v\u03b23 targeting, driving the observed neurotoxicity. Crucially, the derived integrin \u03b1v\u03b23 binding threshold (0.7 \u03bcg\/L) is comparable to reported environmental concentrations, providing a critical early warning for aquatic ecosystems. Furthermore, \u201cGenes-to-Pathways\u201d analysis demonstrated high conservation of this toxicological pathway between zebrafish and humans, highlighting a potential human health risk. These findings deliver strong evidence for the hazard assessment of AO168\u2550O and offer valuable insights for managing other emerging NOPEs.<\/jats:p>","DOI":"10.1021\/acs.est.6c07562","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:01:12Z","timestamp":1789700472000},"page":"27023-27034","source":"Crossref","is-referenced-by-count":0,"title":["Neurodevelopmental\nToxicity of Tris(2,4-di-\n                    <i>tert<\/i>\n                    -Butylphenyl)phosphate:\nMechanistic Insights from Laboratory\nModels and Implications for Human Health"],"prefix":"10.1021","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0107-2869","authenticated-orcid":true,"given":"Jian","family":"Li","sequence":"first","affiliation":[{"name":"Beijing Normal University , , ,","place":["Beijing, China, 100875"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Ji","sequence":"additional","affiliation":[{"name":"Beijing Normal University , , ,","place":["Beijing, China, 100875"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1319-2307","authenticated-orcid":true,"given":"Yun","family":"Liu","sequence":"additional","affiliation":[{"name":"Ministry of Ecology and Environment , , ,","place":["Guangzhou, China, 510655"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyue","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Normal University , , ,","place":["Beijing, China, 100875"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fang","sequence":"additional","affiliation":[{"name":"Beijing Normal University , , ,","place":["Beijing, China, 100875"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5021-7062","authenticated-orcid":true,"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaifeng","family":"Rao","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Normal University , , ,","place":["Beijing, China, 100875"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunjiang","family":"Yu","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"issue":"10","key":"2026092909071261900_cit1","doi-asserted-by":"publisher","first-page":"4187","DOI":"10.1021\/acs.est.2c08239","article-title":"Organophosphite antioxidants\nand novel organophosphate esters in dust from China: Large-scale distribution\nand heterogeneous phototransformation","volume":"57","author":"Zhang","year":"2023","journal-title":"Environ.\nSci. 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Lett."},{"key":"2026092909071261900_cit4","doi-asserted-by":"publisher","first-page":"109205","DOI":"10.1016\/j.envint.2024.109205","article-title":"Novel organophosphate esters and\ntheir transformation products in\noffshore sediment from Eastern China: Occurrence, temporal trend,\nand risk assessment","volume":"195","author":"Gao","year":"2025","journal-title":"Environ. Int."},{"issue":"24","key":"2026092909071261900_cit5","doi-asserted-by":"publisher","first-page":"10740","DOI":"10.1021\/acs.est.3c10611","article-title":"Contamination\nstatus of novel organophosphate\nesters derived from organophosphite antioxidants in soil and the effects\non soil bacterial communities","volume":"58","author":"Gao","year":"2024","journal-title":"Environ. 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Toxicol."},{"issue":"18","key":"2026092909071261900_cit47","doi-asserted-by":"publisher","first-page":"7254","DOI":"10.1021\/acs.est.2c09416","article-title":"Discovery of three organothiophosphate\nesters in river water using\nhigh-resolution mass spectrometry","volume":"57","author":"Li","year":"2023","journal-title":"Environ.\nSci. Technol."},{"issue":"32","key":"2026092909071261900_cit48","doi-asserted-by":"publisher","first-page":"14506","DOI":"10.1021\/acs.est.4c04891","article-title":"Integration of nontarget\nscreening and QSPR models to identify novel organophosphate esters\nof high priority in aquatic environment","volume":"58","author":"Zhang","year":"2024","journal-title":"Environ.\nSci. 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