{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T10:44:37Z","timestamp":1785926677585,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong Provincial Basic and Applied Basic Research Foundation, China","award":["2023A1515010970"],"award-info":[{"award-number":["2023A1515010970"]}]},{"name":"Talents\u2019 Plan Foundation of Guangdong Second Provincial General Hospital","award":["2024F003"],"award-info":[{"award-number":["2024F003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>As a commonly present organophosphorus flame retardant and persistent organic pollutant, 2-ethylhexyl diphenyl phosphate (EHDPP) has been observed to be genotoxic in cultured human hepatoma (HepG2) cells which depends on CYP activities. Yet, its impacts on hepatic Cyp expression, hepatotoxicity and genotoxicity in intact mammalians remain unidentified. In this study, adult male C57BL\/6J mice received EHDPP by gastric gavage at doses of 50, 100, and 150 mg\/kg (b.w.)\/d for 7 d, then the hepatic expression of several Cyp proteins, aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) was analyzed by Western blotting; hepatoxicity was determined by serum ALT\/AST activities and hepatic histological examination, while genotoxicity by comet assay, phosphorylated histone (\u03b3-H2AX) protein, micronucleus test, and Pig-a assay. A micronucleus test in mouse hepatoma (Hepa1-6) cells in vitro was employed to observe the modulating effect of PCB 126 (100 nM)\/BAY-218 (700 nM) (Ahr-Cyp1a1 activator\/inhibitor). The results indicated that EHDPP induced hepatic Cyp1a1, 2e1, AhR, Cyp1a2, Cyp3a4 and PXR proteins and histologic liver damage at 50 mg\/kg\/d and\/or higher doses, while at the highest dose (150 mg\/kg\/d) with hepatic DNA damage and micronucleus formation in bone marrow polychromatic erythrocytes. The result of Pig-a assay (at 14 and 28 d) was negative. In Hepa1-6 cells EHDPP induced micronucleus marginally; however, this effect was enhanced by PCB 126, while abolished by BAY-218. This study suggests that EHDPP may enhance protein expression of hepatic Cyp1a1, Cyp2e1, AhR and PXR and induce liver damage and DNA\/chromosome damage in mice; Cyp1a1 might be a major activating enzyme.<\/jats:p>","DOI":"10.3390\/toxics14080691","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:16:22Z","timestamp":1785921382000},"page":"691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["2-Ethylhexyl Diphenyl Phosphate (EHDPP) Induces Hepatic Expression of Cytochrome P450s, Liver Damage, and Genotoxicity in Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Zhao","family":"Zhou","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbin","family":"Gao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Biotechnology Research Institute, 11 Fengxin Road, Science City, Guangzhou 510663, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunda","family":"Zhu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lvlue","family":"Cai","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Biotechnology Research Institute, 11 Fengxin Road, Science City, Guangzhou 510663, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijing","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqi","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Science and Education, Guangdong Second Provincial General Hospital, 466 Xingang Middle Road, Guangzhou 510317, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2636-6479","authenticated-orcid":false,"given":"Yungang","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119810","DOI":"10.1016\/j.ecoenv.2026.119810","article-title":"Environmental occurrence, human exposure and multidimensional toxicity effects of 2-ethylhexyl diphenyl phosphate (EHDPP): Toxicological mechanism analysis and future research prospects","volume":"310","author":"Wu","year":"2026","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"161648","DOI":"10.1016\/j.scitotenv.2023.161648","article-title":"A new look at rubber recycling and recreational surfaces: The inorganic and OPE chemistry of vulcanised elastomers used in playgrounds and sports facilities","volume":"868","author":"Moreno","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"106833","DOI":"10.1016\/j.aquatox.2024.106833","article-title":"Bringing the emerging organophosphate flame retardants (eOPFRs) into view: A hidden ecological and human health threat","volume":"267","author":"Shi","year":"2024","journal-title":"Aquat. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"165198","DOI":"10.1016\/j.scitotenv.2023.165198","article-title":"Organohalogenated flame retardants and organophosphate esters from home and preschool dust in Sweden: Pollution characteristics, indoor sources and intake assessment","volume":"896","author":"Tao","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"144752","DOI":"10.1016\/j.scitotenv.2020.144752","article-title":"A critical review of human exposure to organophosphate esters with a focus on dietary intake","volume":"771","author":"Gbadamosi","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"138702","DOI":"10.1016\/j.chemosphere.2023.138702","article-title":"Organophosphate esters (OPEs) in the marine environment: Spatial distribution and profiles in French coastal bivalves","volume":"330","author":"Aminot","year":"2023","journal-title":"Chemosphere"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"151348","DOI":"10.1016\/j.scitotenv.2021.151348","article-title":"Occurrence, potential sources and risks of organophosphate esters in the high-elevation region, Tibet, China","volume":"806","author":"You","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"167169","DOI":"10.1016\/j.scitotenv.2023.167169","article-title":"High-resolution mass spectrometry-based screening and dietary intake assessment of organophosphate esters in foodstuffs from South China","volume":"905","author":"Chen","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105698","DOI":"10.1016\/j.envint.2020.105698","article-title":"Organophosphate esters and their metabolites in paired human whole blood, serum, and urine as biomarkers of exposure","volume":"139","author":"Hou","year":"2020","journal-title":"Environ. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10122","DOI":"10.1021\/acs.est.5c01992","article-title":"Adverse effects of aryl organophosphate esters on reproduction","volume":"59","author":"Li","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5056","DOI":"10.1021\/acs.est.0c06809","article-title":"Maternal transfer of 2-ethylhexyl diphenyl phosphate leads to developmental toxicity possibly by blocking the retinoic acid receptor and retinoic X receptor in Japanese medaka (Oryzias latipes)","volume":"55","author":"Li","year":"2021","journal-title":"Environ. Sci. Technol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"125281","DOI":"10.1016\/j.jhazmat.2021.125281","article-title":"Evaluation of hepatotoxicity induced by 2-ethylhexyldiphenyl phosphate based on transcriptomics and its potential metabolism pathway in human hepatocytes","volume":"413","author":"Zhu","year":"2021","journal-title":"J. Hazard. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119854","DOI":"10.1016\/j.ecoenv.2026.119854","article-title":"Environmental flame retardant EHDPP stabilizes EGFR to accelerate lung cancer progression: Integrated network toxicology, bioinformatics, and in vitro evidence","volume":"311","author":"Ding","year":"2026","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"124020","DOI":"10.1016\/j.jhazmat.2020.124020","article-title":"The risk and impact of organophosphate esters on the development of female-specific cancers: Comparative analysis of patients with benign and malignant tumors","volume":"404","author":"Liu","year":"2021","journal-title":"J. Hazard. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/BF02917283","article-title":"DNA strand breaks in mammalian tissues induced by methylarsenics","volume":"21","author":"Yamanaka","year":"1989","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1093\/mutage\/gez044","article-title":"Effect of 2-acetylaminofluorene and its genotoxic metabolites on DNA adduct formation and DNA damage in 3D reconstructed human skin tissue models","volume":"36","author":"Downs","year":"2021","journal-title":"Mutagenesis"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0009-2797(97)00023-9","article-title":"Induction of glutathione depletion, p53 protein accumulation and cellular transformation by tetrachlorohydroquinone, a toxic metabolite of pentachlorophenol","volume":"105","author":"Wang","year":"1997","journal-title":"Chem. Biol. Interact."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/BF00364847","article-title":"Isolation and identification of metabolites of 2-ethylhexyl diphenyl phosphate in rats","volume":"61","author":"Minegishi","year":"1988","journal-title":"Arch. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105056","DOI":"10.1016\/j.envint.2019.105056","article-title":"Biomonitoring of organophosphate triesters and diesters in human blood in Jiangsu Province, eastern China: Occurrences, associations, and suspect screening of novel metabolites","volume":"131","author":"Ya","year":"2019","journal-title":"Environ. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"117527","DOI":"10.1016\/j.envpol.2021.117527","article-title":"Human CYP enzyme-activated clastogenicity of 2-ethylhexyl diphenyl phosphate (a flame retardant) in mammalian cells","volume":"285","author":"Chen","year":"2021","journal-title":"Environ. Pollut."},{"key":"ref_21","unstructured":"OECD (2025). Test Guideline No. 470: Mammalian Erythrocyte Pig-A Gene Mutation Assay, Organization for Economic Co-Operation and Development."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112017","DOI":"10.1016\/j.cbi.2026.112017","article-title":"Potent genotoxicity of phenytoin in adult male C57BL\/6J mice, an effect requiring metabolic activation (possibly by Cyp2c enzymes)","volume":"431","author":"Chen","year":"2026","journal-title":"Chem. Biol. Interact."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153281","DOI":"10.1016\/j.scitotenv.2022.153281","article-title":"Gestational exposure to GenX induces hepatic alterations by the gut-liver axis in maternal mice: A similar mechanism as PFOA","volume":"820","author":"Xu","year":"2022","journal-title":"Sci. Total. Environ."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/em.21758","article-title":"Flow cytometric analysis of Pig-a gene mutation and chromosomal damage induced by procarbazine hydrochloride in CD-1 mice","volume":"54","author":"Phonethepswath","year":"2013","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.mrgentox.2007.04.010","article-title":"The genotoxic and cytotoxic effects of nicotine in the mouse bone marrow","volume":"632","author":"Attia","year":"2007","journal-title":"Mutat. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1002\/em.21912","article-title":"Genotoxicity of 1-methylpyrene and 1-hydroxymethylpyrene in Chinese hamster V79-derived cells expressing both human CYP2E1 and SULT1A1","volume":"56","author":"Jiang","year":"2015","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1007\/s00204-023-03489-1","article-title":"Induction of clastogenesis and gene mutations by carbamazepine (at its therapeutically effective serum levels) in mammalian cells and the dependence on human CYP2B6 enzyme activity","volume":"97","author":"Wang","year":"2023","journal-title":"Arch. Toxicol."},{"key":"ref_28","unstructured":"Brooke, D.N., Crookes, M.J., Quarterman, P., and Burns, J. (2009). Environmental Risk Evaluation Report: 2-Ethylhexyl Diphenyl Phosphate (CAS No. 1241-94-7)."},{"key":"ref_29","unstructured":"Mitsubishi Chemical Safety Institute Ltd (2000). 2-Ethylhexyl Diphenyl Phosphate, Existing Chemical Toxicity Test Report, National Institute of Health Sciences."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0006-2952(97)00476-0","article-title":"Effect of phenobarbital on hepatic CYP1A1 and CYP1A2 in the Ahr-null mouse","volume":"55","author":"Zaher","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0009-2797(97)00035-5","article-title":"Regulation of hepatic CYP1A isozymes by piperonyl butoxide and acenaphthylene in the mouse","volume":"105","author":"Ryu","year":"1997","journal-title":"Chem. Biol. Interact."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.taap.2011.01.008","article-title":"Induction of cytochromes P450 1A1 and 1A2 by tanshinones in human HepG2 hepatoma cell line","volume":"252","author":"Zhang","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104957","DOI":"10.1016\/j.tiv.2020.104957","article-title":"Indirect co-cultivation of HepG2 with differentiated THP-1 cells induces AHR signalling and release of pro-inflammatory cytokines","volume":"68","author":"Padberg","year":"2020","journal-title":"Toxicol. Vitr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.abb.2006.09.017","article-title":"Regulation and induction of CYP3A11, CYP3A13 and CYP3A25 in C57BL\/6J mouse liver","volume":"457","author":"Down","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"898","DOI":"10.3945\/jn.108.103572","article-title":"Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner","volume":"139","author":"Li","year":"2009","journal-title":"J. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.toxlet.2017.03.028","article-title":"Pregnane X receptor regulates the AhR\/Cyp1A1 pathway and protects liver cells from benzo-[\u03b1]-pyrene-induced DNA damage","volume":"275","author":"Cui","year":"2017","journal-title":"Toxicol. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/sj.onc.1209788","article-title":"Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole","volume":"26","author":"Huang","year":"2007","journal-title":"Oncogene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/FPC.0b013e32831665ea","article-title":"Inhibition of CYP3A4 expression by ketoconazole is mediated by the disruption of pregnane X receptor, steroid receptor coactivator-1, and hepatocyte nuclear factor 4alpha interaction","volume":"19","author":"Lim","year":"2009","journal-title":"Pharmacogenet. Genom."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"10001","DOI":"10.1021\/acs.est.1c02189","article-title":"Influence of bisphenol compounds at nanomolar concentrations on chromosome damage induced by metabolically activated carcinogens in HepG2 cells","volume":"55","author":"Yu","year":"2021","journal-title":"Environ. Sci. Technol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.toxlet.2014.11.007","article-title":"In vitro metabolism of 2-ethylhexyldiphenyl phosphate (EHDPHP) by human liver microsomes","volume":"232","author":"Erratico","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"116559","DOI":"10.1016\/j.ecoenv.2024.116559","article-title":"Melatonin improves mouse oocyte quality from 2-ethylhexyl diphenyl phosphate-induced toxicity by enhancing mitochondrial function","volume":"280","author":"Zhang","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"116878","DOI":"10.1016\/j.ecoenv.2024.116878","article-title":"EHDPP induces proliferation inhibition and apoptosis to spermatocyte: Insights from transcriptomic and metabolomic profiles","volume":"284","author":"Wang","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"153160","DOI":"10.1016\/j.scitotenv.2022.153160","article-title":"Organophosphate flame retardantsinduce oxidative stress and Chop\/Caspase 3-related apoptosis via Sod1\/p53\/Map3k6\/Fkbp5 in NCI-1975 cells","volume":"819","author":"Meng","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"104918","DOI":"10.1016\/j.psj.2025.104918","article-title":"New findings on the antagonism of the environmental chemical toxicity 2-ethylhexyl diphenyl phosphate: Glycyrrhizic acid as an Nrf2 activator targets Nrf2\/ROS\/STAT3 signalling crosstalk to alleviate thymic injury in chicks","volume":"104","author":"Luo","year":"2025","journal-title":"Poult. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"106890","DOI":"10.1016\/j.psj.2026.106890","article-title":"Integrated network toxicology and molecular docking revealed that 2-eth-ylhexyldiphenylphosphoric acid induces nephrotoxicity in chickens by activating the ROS\/JNK pathway","volume":"105","author":"Tang","year":"2026","journal-title":"Poult. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110216","DOI":"10.1016\/j.cbi.2022.110216","article-title":"Oxidative stress and ferroptosis involved in 2-ethylhexyl diphenyl phosphate -induced hepatotoxicity in chicken","volume":"368","author":"Yang","year":"2022","journal-title":"Chem. Biol. Interact."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.envint.2019.04.055","article-title":"Organophosphate esters (OPEs) in Chinese foodstuffs: Dietary intake estimation via a market basket method, and suspect screening using high-resolution mass spectrometry","volume":"128","author":"Zhao","year":"2019","journal-title":"Environ. Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.scitotenv.2016.06.137","article-title":"Brominated, chlorinated and phosphate organic contaminants in house dust from Portugal","volume":"569\u2013570","author":"Coelho","year":"2016","journal-title":"Sci. Total Environ."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"140136","DOI":"10.1016\/j.scitotenv.2020.140136","article-title":"Catching flame retardants and pesticides in silicone wristbands: Evidence of exposure to current and legacy pollutants in Uruguayan children","volume":"740","author":"Travis","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"119980","DOI":"10.1016\/j.envpol.2022.119980","article-title":"Accumulative levels, temporal and spatial distribution of common chemical pollutants in the blood of Chinese adults","volume":"311","author":"Kou","year":"2022","journal-title":"Environ. Pollut."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/14\/8\/691\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:57:51Z","timestamp":1785923871000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/14\/8\/691"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["toxics14080691"],"URL":"https:\/\/doi.org\/10.3390\/toxics14080691","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]}}}