{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T21:06:45Z","timestamp":1780520805926,"version":"3.54.1"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jing-Jin-Ji Regional Integrated Environmental Improvement-National Science and Technology Major Project","award":["2025ZD1205901"],"award-info":[{"award-number":["2025ZD1205901"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Michler\u2019s Ketone (MK) is widely utilized as an additive in pigments, dyes, and other colorants, and has become a non-negligible environmental presence. Currently, environmental monitoring data and toxicity data for MK are extremely limited, and its specific mechanisms of neurotoxicity remain poorly characterized. A zebrafish model was employed to systematically delineate the neurotoxic mechanisms of MK through the integration of network toxicology predictions, transcriptomic profiling, and RT-qPCR validation. The results demonstrated that MK exposure was found to induce oxidative stress in zebrafish larvae, which subsequently disrupted the calcium signaling pathway and triggered apoptosis, ultimately leading to neurodevelopmental and locomotor behavioral impairments. This study provides a fundamental basis for elucidating MK\u2019s developmental neurotoxicity mechanisms, while also holding significant value for its ecological risk assessment.<\/jats:p>","DOI":"10.3390\/biology15010003","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:03:46Z","timestamp":1766142226000},"page":"3","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of the Neurotoxic Effects and Mechanisms of Michler\u2019s Ketone as Investigated by Network Toxicology and Transcriptomics"],"prefix":"10.3390","volume":"15","author":[{"given":"Jun","family":"Hu","sequence":"first","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianke","family":"Zha","sequence":"additional","affiliation":[{"name":"Nursing Program, Kangda College of Nanjing Medical University, Lianyungang 222000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilin","family":"Jin","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Fan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Toxicology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Department of Toxicology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hu","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Nanjing Institute of Environmental Sciences, Ministry of Ecology and Environment, Nanjing 210042, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1111\/php.13619","article-title":"Michler\u2019s Ketone: Beta-Cyclodextrin Host-Guest Inclusion Complex for Enhancing the Ultraviolet Protection Factor of Poplin Cotton Fabric","volume":"98","author":"Krishnamoorthy","year":"2022","journal-title":"Photochem. Photobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.3358\/shokueishi.47.99","article-title":"Migration of bisphenol A and benzophenones from paper and paperboard products used in contact with food","volume":"47","author":"Ozaki","year":"2006","journal-title":"Shokuhin Eiseigaku Zasshi"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.fct.2004.03.010","article-title":"Chemical analysis and genotoxicological safety assessment of paper and paperboard used for food packaging","volume":"42","author":"Ozaki","year":"2004","journal-title":"Food Chem. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1080\/15287398209530216","article-title":"DNA damage induced by auramine O in liver, kidney, and bone marrow of rats and mice, and in a human cell line (alkaline elution assay and SCE induction)","volume":"9","author":"Parodi","year":"1982","journal-title":"J. Toxicol. Environ. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/0165-1161(82)90003-6","article-title":"Reliability of the hepatocyte primary culture\/DNA repair test in testing of coded carcinogens and noncarcinogens","volume":"97","author":"Williams","year":"1982","journal-title":"Mutat. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1093\/mutage\/1.1.17","article-title":"The effect of Michler\u2019s ketone on cell division, chromosome number and structure in cultured Chinese hamster cells","volume":"1","author":"Lafi","year":"1986","journal-title":"Mutagenesis"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1021\/es0626279","article-title":"Determination of xenobiotic intrinsic clearance in freshly isolated hepatocytes from rainbow trout (Oncorhynchus mykiss) and rat and its application in bioaccumulation assessment","volume":"41","author":"Han","year":"2007","journal-title":"Environ. Sci. Technol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.2174\/0929867311320190005","article-title":"Zebrafish as a genetic model in pre-clinical drug testing and screening","volume":"20","author":"Gibert","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_9","first-page":"435","article-title":"Advancing toxicology research using in vivo high throughput toxicology with small fish models","volume":"33","author":"Planchart","year":"2016","journal-title":"ALTEX"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1080\/10408444.2024.2342448","article-title":"Zebrafish and nematodes as whole organism models to measure developmental neurotoxicity","volume":"54","author":"Hughes","year":"2024","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1136\/jmedgenet-2011-100211","article-title":"Fetal akinesia: Review of the genetics of the neuromuscular causes","volume":"48","author":"Ravenscroft","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10072","DOI":"10.1007\/s12035-024-04245-x","article-title":"Isavuconazole Induces Neurodevelopment Defects and Motor Behaviour Impairment in Zebrafish Larvae","volume":"61","author":"Zhang","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107745","DOI":"10.1016\/j.envint.2023.107745","article-title":"Neurodevelopmental toxicity of organophosphate flame retardant triphenyl phosphate (TPhP) on zebrafish (Danio rerio) at different life stages","volume":"172","author":"Zhang","year":"2023","journal-title":"Environ. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"150210","DOI":"10.1016\/j.scitotenv.2021.150210","article-title":"A systematic comparison of neurotoxicity of bisphenol A and its derivatives in zebrafish","volume":"805","author":"Gu","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115892","DOI":"10.1016\/j.ecoenv.2023.115892","article-title":"Effects of exposure to 3,6-DBCZ on neurotoxicity and AhR pathway during early life stages of zebrafish (Danio rerio)","volume":"270","author":"Wang","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1529-8027.2000.00026.x","article-title":"Influence of aging on peripheral nerve function and regeneration","volume":"5","author":"Verdu","year":"2000","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0361-9230(01)00694-3","article-title":"Expression domains of neuroD (nrd) in the early postembryonic zebrafish brain","volume":"57","author":"Mueller","year":"2002","journal-title":"Brain Res. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.bbrc.2007.08.163","article-title":"Co-localization and interaction of DPYSL3 and GAP43 in primary cortical neurons","volume":"363","author":"Kowara","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1083\/jcb.149.7.1443","article-title":"Shared and unique roles of CAP23 and GAP43 in actin regulation, neurite outgrowth, and anatomical plasticity","volume":"149","author":"Frey","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"24799","DOI":"10.1007\/s11356-020-09045-z","article-title":"Oxidative stress and mitochondrial dysfunction in organophosphate pesticide-induced neurotoxicity and its amelioration: A review","volume":"27","author":"Farkhondeh","year":"2020","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6685204","DOI":"10.1155\/2021\/6685204","article-title":"Oxidative Stress as a Common Key Event in Developmental Neurotoxicity","volume":"2021","author":"Nishimura","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s12035-023-03559-6","article-title":"Nrf2 Signaling Pathway: A Potential Therapeutic Target in Combating Oxidative Stress and Neurotoxicity in Chemotherapy-Induced Cognitive Impairment","volume":"61","author":"Lal","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"ref_23","first-page":"19","article-title":"Impacts of oxidative stress on acetylcholinesterase transcription, and activity in embryos of zebrafish (Danio rerio) following Chlorpyrifos exposure","volume":"172\u2013173","author":"Schlenk","year":"2015","journal-title":"Comp. Biochem. Physiol. C Toxicol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"22777","DOI":"10.1039\/C8RA04250K","article-title":"The assessment of the eco-toxicological effect of gabapentin on early development of zebrafish and its antioxidant system","volume":"8","author":"Li","year":"2018","journal-title":"RSC Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"C817","DOI":"10.1152\/ajpcell.00139.2004","article-title":"Calcium, ATP, and ROS: A mitochondrial love-hate triangle","volume":"287","author":"Brookes","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/j.1749-6632.2010.05634.x","article-title":"Oxidative stress caused by mitochondrial calcium overload","volume":"1201","author":"Peng","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","first-page":"136","article-title":"p53, apoptosis and radiosensitivity\u2013experimental and clinical data","volume":"25","author":"Weber","year":"2002","journal-title":"Onkologie"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"mjac074","DOI":"10.1093\/jmcb\/mjac074","article-title":"The ARTS of p53-dependent mitochondrial apoptosis","volume":"14","author":"Hao","year":"2023","journal-title":"J. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1023\/B:APPT.0000031457.90890.13","article-title":"Caspase-9 regulation: An update","volume":"9","author":"Johnson","year":"2004","journal-title":"Apoptosis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41420-020-00349-0","article-title":"The caspase-3\/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer","volume":"6","author":"Jiang","year":"2020","journal-title":"Cell Death Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1080\/15376516.2025.2548842","article-title":"Neurotoxicity mechanisms of pyrethroids studied by network toxicology and molecular docking","volume":"35","author":"Lin","year":"2025","journal-title":"Toxicol. Mech. Methods"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/1\/3\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T11:27:39Z","timestamp":1766143659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/1\/3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,19]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["biology15010003"],"URL":"https:\/\/doi.org\/10.3390\/biology15010003","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,19]]}}}