{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T10:27:38Z","timestamp":1786616858881,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81873204"],"award-info":[{"award-number":["81873204"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["81873204"],"award-info":[{"award-number":["81873204"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004829","name":"Sichuan Provincial Science and Technology Plan","doi-asserted-by":"publisher","award":["2024YFFK0036"],"award-info":[{"award-number":["2024YFFK0036"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010822","name":"Chengdu Science and Technology Bureau","doi-asserted-by":"publisher","award":["2024-YF05-01959-SN"],"award-info":[{"award-number":["2024-YF05-01959-SN"]}],"id":[{"id":"10.13039\/501100010822","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024-YF05-01959-SN"],"award-info":[{"award-number":["2024-YF05-01959-SN"]}],"id":[{"id":"https:\/\/ror.org\/00xfea068","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Bisphenols (BPs) are widespread environmental endocrine disruptors, but their potential depression-related neurotoxicity has not been systematically assessed. Here, we combined machine learning (ML), network toxicology, molecular docking, and in vivo experiments to screen 26 bisphenols for depression-related neurotoxic risk. We first integrated bisphenol A (BPA)-related targets with depression-related genes to build a chemical-gene-phenotype-disease network and an adverse outcome pathway (AOP) framework. We then used nine ML algorithms to rank the predicted risk of the 26 bisphenols. Molecular docking showed that the predicted high-risk compounds had strong binding affinity for estrogen receptor 1 (ESR1). The AOP analysis further suggested the involvement of the ESR1\u2013cAMP response element-binding protein 1 (CREB1)\u2013glutamate ionotropic receptor N-methyl-D-aspartate type subunit 2B (GRIN2B) pathway. In vivo experiments showed that BPA exposure caused neuronal damage in the cornu ammonis 3 (CA3) region of the rat hippocampus and significantly reduced the messenger RNA (mRNA) expression of the corresponding genes Esr1, Creb1, and Grin2b in hippocampal tissue. Overall, this study screened and prioritized the model-predicted depression-related neurotoxic risk of 26 bisphenols, supports a role for the ESR1\u2013CREB1\u2013GRIN2B pathway in BPA-induced neurotoxicity, and provides mechanistic evidence for bisphenol risk assessment.<\/jats:p>","DOI":"10.3390\/ijms27167218","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:31:09Z","timestamp":1786613469000},"page":"7218","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systematic Screening of Depression-Related Neurotoxicity Across 26 Bisphenols Reveals an ESR1\u2013CREB1\u2013GRIN2B-Associated Mechanism"],"prefix":"10.3390","volume":"27","author":[{"given":"Li","family":"Xie","sequence":"first","affiliation":[{"name":"Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanliang","family":"Yuan","sequence":"additional","affiliation":[{"name":"College of Information and Communication Engineering, Harbin Engineering University, Harbin 150001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Gan","sequence":"additional","affiliation":[{"name":"Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongheng","family":"Ma","sequence":"additional","affiliation":[{"name":"Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Mountain Surface Processes and Ecological Regulation, Institute of Mountain Hazards and Environment, University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Xu","sequence":"additional","affiliation":[{"name":"Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihong","family":"Li","sequence":"additional","affiliation":[{"name":"Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137763","DOI":"10.1016\/j.chemosphere.2023.137763","article-title":"Bisphenol A and its substitutes in the aquatic environment: Occurrence and toxicity assessment","volume":"315","author":"Krawczyk","year":"2023","journal-title":"Chemosphere"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1080\/10408444.2024.2388712","article-title":"A critical review to identify data gaps and improve risk assessment of bisphenol A alternatives for human health","volume":"54","author":"Zalko","year":"2024","journal-title":"Crit. 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