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Its mammary toxicity and molecular mechanisms remain poorly defined. Here, we integrated network toxicology, transcriptomics, and in vivo\/in vitro validation to investigate 6PPDQ triggered mammary toxicity during adolescent exposure in mice. Network toxicology screened core targets and identified the MAPK signaling pathway as a key regulatory axis. Adolescent 6PPDQ exposure decreased mammary gland weight and length, induced pathological lesions, inhibited epithelial proliferation, and disrupted apoptotic homeostasis. Further assays confirmed that 6PPDQ caused mitochondrial dysfunction, oxidative stress, and inflammation. Mechanistically, 6PPDQ mediated mammary injury through p38 MAPK cascade activation, and p38 inhibition alleviated such adverse effects. This study elucidates a distinct p38 MAPK-dependent mechanism driving 6PPDQ-related developmental mammary toxicity, advancing the mechanistic understanding of health risks posed by rubber-derived quinone contaminants.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c06357","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:02:02Z","timestamp":1785859322000},"page":"25102-25118","source":"Crossref","is-referenced-by-count":1,"title":["6PPDQ Exposure\nInduces Mammary Developmental Damage\nthrough Mitochondrial Dysfunction Mediated by the p38 MAPK Signaling\nPathway"],"prefix":"10.1021","volume":"74","author":[{"given":"Caihong","family":"Wang","sequence":"first","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunmeng","family":"Song","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingqiang","family":"Ma","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Fu","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4135-553X","authenticated-orcid":true,"given":"Yuanxiang","family":"Jin","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2026081910185240800_cit1","doi-asserted-by":"publisher","first-page":"178848","DOI":"10.1016\/j.scitotenv.2025.178848","article-title":"Projecting airborne\ntire wear particle emissions in the United States in the era of electric\nvehicles","volume":"967","author":"Foroutan","year":"2025","journal-title":"Sci. Total Environ."},{"key":"2026081910185240800_cit2","doi-asserted-by":"publisher","first-page":"108677","DOI":"10.1016\/j.envint.2024.108677","article-title":"Environmental\nprofiles, hazard identification, and toxicological hallmarks of emerging\ntire rubber-related contaminants 6PPD and 6PPD-quinone","volume":"187","author":"Jiang","year":"2024","journal-title":"Environ. Int."},{"key":"2026081910185240800_cit3","doi-asserted-by":"publisher","first-page":"121527","DOI":"10.1016\/j.atmosenv.2025.121527","article-title":"6PPD quinone formation\nfrom 6PPD via a radical process\nand its competing reactions","volume":"361","author":"Chae","year":"2025","journal-title":"Atmos. Environ."},{"key":"2026081910185240800_cit4","doi-asserted-by":"publisher","first-page":"118201","DOI":"10.1016\/j.envres.2024.118201","article-title":"Association between 6PPD-quinone\nexposure and BMI, influenza, and diarrhea in children","volume":"247","author":"Zhang","year":"2024","journal-title":"Environ. Res."},{"key":"2026081910185240800_cit5","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.jes.2024.07.011","article-title":"Child exposure to N-(1,3-dimethylbutyl)-N\u2019-phenyl-p-phenylenediamine\n(6PPD) and its derived quinone (6PPDQ) in e-waste areas: Urinary concentrations,\nsources, and health effect assessment","volume":"153","author":"Dai","year":"2025","journal-title":"J. Environ.\nSci. (Beijing, China)"},{"key":"2026081910185240800_cit6","doi-asserted-by":"publisher","first-page":"136176","DOI":"10.1016\/j.jhazmat.2024.136176","article-title":"p-phenylenediamines\n(PPDs) and PPD-quinones (PPD-Qs) in human urine and breast milk samples:\nUrgent need for focus on PPD-Qs and the establishment of health threshold\ncriteria","volume":"480","author":"Wu","year":"2024","journal-title":"J. Hazard. Mater."},{"key":"2026081910185240800_cit7","doi-asserted-by":"publisher","first-page":"164842","DOI":"10.1016\/j.scitotenv.2023.164842","article-title":"Four-week repeated exposure to tire-derived 6-PPD quinone\ncauses multiple organ injury in male BALB\/c mice","volume":"894","author":"He","year":"2023","journal-title":"Sci. Total Environ."},{"key":"2026081910185240800_cit8","doi-asserted-by":"publisher","first-page":"170679","DOI":"10.1016\/j.scitotenv.2024.170679","article-title":"Environmentally realistic\ndose of tire-derived metabolite 6PPD-Q exposure causes intestinal\njejunum and ileum damage in mice via cannabinoid receptor-activated\ninflammation","volume":"918","author":"Yang","year":"2024","journal-title":"Sci. Total Environ."},{"issue":"3","key":"2026081910185240800_cit9","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1021\/acs.est.4c09276","article-title":"Long-Term\nExposure to Tire-Derived 6-PPD Quinone Causes Neurotoxicity and Neuroinflammation\nvia Inhibition of HTR2A in C57BL\/6 Mice","volume":"59","author":"Ma","year":"2025","journal-title":"Environ.\nSci. Technol."},{"key":"2026081910185240800_cit10","doi-asserted-by":"publisher","first-page":"131495","DOI":"10.1016\/j.jhazmat.2023.131495","article-title":"Long-term\nexposure to 6-PPD quinone reduces reproductive capacity by enhancing\ngermline apoptosis associated with activation of both DNA damage and\ncell corpse engulfment in Caenorhabditis elegans","volume":"454","author":"Hua","year":"2023","journal-title":"J. Hazard. Mater."},{"key":"2026081910185240800_cit11","doi-asserted-by":"publisher","first-page":"161836","DOI":"10.1016\/j.scitotenv.2023.161836","article-title":"Oral exposure to tire\nrubber-derived\ncontaminant 6PPD and 6PPD-quinone induce hepatotoxicity in mice","volume":"869","author":"Fang","year":"2023","journal-title":"Sci. Total Environ."},{"key":"2026081910185240800_cit12","doi-asserted-by":"publisher","first-page":"154285","DOI":"10.1016\/j.tox.2025.154285","article-title":"Oral exposure to tire rubber-derived\ncontaminant 6PPD and 6PPD-quinone induces intestinal toxicity in mice","volume":"518","author":"Fang","year":"2025","journal-title":"Toxicology"},{"key":"2026081910185240800_cit13","doi-asserted-by":"publisher","first-page":"118494","DOI":"10.1016\/j.ecoenv.2025.118494","article-title":"Respiratory toxicity\nmechanism of 6PPD and 6PPD-quinone: An integrated\nstudy based on network toxicology and molecular docking","volume":"301","author":"Li","year":"2025","journal-title":"Ecotoxicol. Environ. 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Lett."},{"key":"2026081910185240800_cit16","doi-asserted-by":"publisher","first-page":"171220","DOI":"10.1016\/j.scitotenv.2024.171220","article-title":"Evaluation of 6-PPD\nquinone toxicity on lung of male BALB\/c mice by quantitative proteomics","volume":"922","author":"He","year":"2024","journal-title":"Sci. Total Environ."},{"issue":"48","key":"2026081910185240800_cit17","doi-asserted-by":"publisher","first-page":"19295","DOI":"10.1021\/acs.est.3c05325","article-title":"Exposure to 6-PPD Quinone\nat Environmentally Relevant Concentrations\nInhibits Both Lifespan and Healthspan in C. elegans","volume":"57","author":"Hua","year":"2023","journal-title":"Environ. Sci. 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Cell.\nEndocrinol."},{"issue":"4","key":"2026081910185240800_cit26","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.devcel.2017.10.007","article-title":"WNT-Mediated Regulation\nof FOXO1 Constitutes\na Critical Axis Maintaining Pubertal Mammary Stem Cell Homeostasis","volume":"43","author":"Sreekumar","year":"2017","journal-title":"Dev. Cell"},{"issue":"23","key":"2026081910185240800_cit27","doi-asserted-by":"publisher","first-page":"15235","DOI":"10.1021\/acs.est.0c03998","article-title":"Probing the Mechanism of Hepatotoxicity of Hexabromocyclododecanes\nthrough Toxicological Network Analysis","volume":"54","author":"Dai","year":"2020","journal-title":"Environ.\nSci. Technol."},{"key":"2026081910185240800_cit28","first-page":"31","article-title":"Network toxicology:\nA new science","volume":"2016","author":"Zhang","year":"2016","journal-title":"Comput. ecol. softw."},{"issue":"21","key":"2026081910185240800_cit29","doi-asserted-by":"publisher","first-page":"10204","DOI":"10.1021\/acs.est.5c03906","article-title":"Combined Analysis\nof Network Toxicology and Multiomics Revealed the Potential Mechanism\nof 6PPDQ-Induced Hepatotoxicity in Mice","volume":"59","author":"Li","year":"2025","journal-title":"Environ.\nSci. Technol."},{"issue":"3","key":"2026081910185240800_cit30","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1177\/030098589002700304","article-title":"Diphenylamine-induced renal papillary necrosis and\nnecrosis of the pars recta in laboratory rodents","volume":"27","author":"Lenz","year":"1990","journal-title":"Vet. Pathol."},{"issue":"2","key":"2026081910185240800_cit31","doi-asserted-by":"publisher","first-page":"140","DOI":"10.3390\/antiox13020140","article-title":"Sodium Butyrate Alleviates Free Fatty Acid-Induced\nSteatosis in Primary Chicken Hepatocytes via Regulating the ROS\/GPX4\/Ferroptosis\nPathway","volume":"13","author":"Cheng","year":"2024","journal-title":"Antioxidants"},{"issue":"6525","key":"2026081910185240800_cit32","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1126\/science.abd6951","article-title":"A ubiquitous tire rubber-derived chemical induces acute mortality\nin coho salmon","volume":"371","author":"Tian","year":"2021","journal-title":"Science"},{"issue":"12","key":"2026081910185240800_cit33","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1017\/S1751731109990589","article-title":"Mammary gland secretion: hormonal\ncoordination of endocytosis\nand exocytosis","volume":"3","author":"Truchet","year":"2009","journal-title":"Animal"},{"issue":"9","key":"2026081910185240800_cit34","doi-asserted-by":"publisher","first-page":"803","DOI":"10.3390\/metabo12090803","article-title":"Non-Esterified\nFatty Acid Induces ER Stress-Mediated Apoptosis via ROS\/MAPK Signaling\nPathway in Bovine Mammary Epithelial Cells","volume":"12","author":"Yan","year":"2022","journal-title":"Metabolites"},{"key":"2026081910185240800_cit35","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.semcancer.2021.05.010","article-title":"RAF-MEK-ERK pathway in cancer evolution\nand treatment","volume":"85","author":"Ullah","year":"2022","journal-title":"Semin. 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