{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T05:12:19Z","timestamp":1778649139966,"version":"3.51.4"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to identify novel risk factors for diabetic retinopathy (DR) and to explore whether phthalate exposure contribute to DR pathogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed data from the 2017\u20132018 National Health and Nutrition Examination Survey (NHANES) and an independent clinical cohort using multiple feature-selection methods. To investigate the potential mechanisms of di-2-ethylhexyl phthalate (DEHP), we performed network toxicology and molecular docking analyes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In NHANES, longer weekday outdoor time was associated with higher odds of DR (OR = 3.18, 95% CI: 1.36\u20137.95), whereas higher serum epi-25-hydroxyvitamin D3 levels were associated with lower odds of DR (OR = 0.80, 95% CI: 0.64\u20130.97). In the clinical cohort, less electronic device use was correlated with lower odds of DR (OR = 0.67, 95% CI: 0.43\u20130.98), while cataract was strongly associated with DR (OR = 11.0, 95% CI: 1.77\u201399.8). Urinary phthalate assessment showed inverse associations of mono-isobutyl phthalate (MiBP) and a mixed phthalate index with DR. Network toxicology identified 123 overlapping target genes, with enrichment in AGE-RAGE signaling and apoptosis-related pathways. Molecular docking predicted stable binding of MiBP to SRC, BCL2, and MAPK1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrative analysis identifies novel clinical and environmental correlates of DR and suggests a possible link between phthalate exposure and DR-related pathways. These findings highlight the potential relevance of environmental exposures in DR risk and offer a basis for further mechanistic and preventive research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1792532","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:42:33Z","timestamp":1778647353000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From risk factors to molecular targets: clinical associations and molecular docking insights into phthalate-associated diabetic retinopathy"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhiwei","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Taizhou Municipal Hospital, Taizhou University Affiliated Municipal Hospital, Taizhou","place":["Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Medicine, Taizhou University, Taizhou","place":["Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caidi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Taizhou Municipal Hospital, Taizhou University Affiliated Municipal Hospital, Taizhou","place":["Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaobei","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Taizhou Municipal Hospital, Taizhou University Affiliated Municipal Hospital, Taizhou","place":["Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, Beijing Zhongwei Medical Research Center","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qile","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Biology, Oasis Road Research Center","place":["Watertown, MA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haijian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Taizhou Municipal Hospital, Taizhou University Affiliated Municipal Hospital, Taizhou","place":["Zhejiang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Beijing Zhongwei Medical Research Center","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/j.ecl.2021.05.005","article-title":"Prevention of microvascular complications of diabetes.","volume":"50","author":"Crasto","year":"2021","journal-title":"Endocrinol Metab Clin North Am"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.3390\/cells12091342","article-title":"Retinal cell damage in diabetic retinopathy.","volume":"12","author":"Zhou","year":"2023","journal-title":"Cells."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1016\/j.ophtha.2021.04.027","article-title":"Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis.","volume":"128","author":"Teo","year":"2021","journal-title":"Ophthalmology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"7083","DOI":"10.3390\/jcm13237083","article-title":"Incidence of diabetic retinopathy in individuals with type 2 diabetes: a study using real-world data.","volume":"13","author":"Hern\u00e1ndez-Teixid\u00f3","year":"2024","journal-title":"J Clin Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.ajo.2024.07.028","article-title":"Factors affecting global adherence for the uptake of diabetic retinopathy screening: a systematic review and meta-analysis.","volume":"268","author":"Rahmati","year":"2024","journal-title":"Am J Ophthalmol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"S252","DOI":"10.2337\/dc25-S012","article-title":"12. Retinopathy, neuropathy, and foot care: standards of care in diabetes-2025.","volume":"48","year":"2025","journal-title":"Diabetes Care."},{"key":"B7","doi-asserted-by":"publisher","first-page":"503","DOI":"10.3949\/ccjm.91a.24028","article-title":"Diabetic retinopathy: screening, prevention, and treatment.","volume":"91","author":"Chong","year":"2024","journal-title":"Cleve Clin J Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"106670","DOI":"10.1016\/j.phrs.2023.106670","article-title":"Diabetic retinopathy in the pediatric population: pathophysiology, screening, current and future treatments.","volume":"188","author":"Invernizzi","year":"2023","journal-title":"Pharmacol Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/j.survophthal.2024.07.001","article-title":"Diabetic retinopathy: new concepts of screening, monitoring, and interventions.","volume":"69","author":"Sinclair","year":"2024","journal-title":"Surv Ophthalmol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.3390\/nu14061252","article-title":"The effect of diet and lifestyle on the course of diabetic retinopathy-a review of the literature.","volume":"14","author":"Bryl","year":"2022","journal-title":"Nutrients."},{"key":"B11","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s00592-019-01454-y","article-title":"Frequent physical activity is associated with reduced risk of severe diabetic retinopathy in type 1 diabetes.","volume":"57","author":"Tikkanen-Dolenc","year":"2020","journal-title":"Acta Diabetol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"167904","DOI":"10.1016\/j.scitotenv.2023.167904","article-title":"Efficient analysis of toxicity and mechanisms of environmental pollutants with network toxicology and molecular docking strategy: acetyl tributyl citrate as an example.","volume":"905","author":"Huang","year":"2023","journal-title":"Sci Total Environ."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1111\/jdi.13480","article-title":"Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy.","volume":"12","author":"Lin","year":"2021","journal-title":"J Diabetes Investig"},{"key":"B14","doi-asserted-by":"publisher","first-page":"966714","DOI":"10.3389\/fpubh.2022.966714","article-title":"Associations between psycho-behavioral risk factors and diabetic retinopathy: NHANES (2005-2018).","volume":"10","author":"Sun","year":"2022","journal-title":"Front Public Health."},{"key":"B15","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1007\/s00592-023-02226-5","article-title":"Retinal neurodegeneration in diabetic retinopathy with systemic hypertension.","volume":"61","author":"Sung","year":"2024","journal-title":"Acta Diabetol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/s00592-022-02007-6","article-title":"Quantification of risk factors for diabetic retinopathy progression.","volume":"60","author":"Tarasewicz","year":"2023","journal-title":"Acta Diabetol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1097\/CM9.0000000000001364","article-title":"Relationship of serum vitamin D levels with diabetic microvascular complications in patients with type 2 diabetes mellitus.","volume":"134","author":"Zhao","year":"2021","journal-title":"Chin Med J"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e000058","DOI":"10.1136\/bmjdrc-2014-000058","article-title":"Lower levels of 25-hydroxyvitamin D3 are associated with a higher prevalence of microvascular complications in patients with type 2 diabetes.","volume":"3","author":"Zoppini","year":"2015","journal-title":"BMJ Open Diabetes Res Care"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e40099","DOI":"10.1097\/MD.0000000000040099","article-title":"Leisure screen time and diabetic retinopathy risk: a Mendelian randomization study.","volume":"103","author":"Tang","year":"2024","journal-title":"Medicine"},{"key":"B20","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1507\/endocrj.EJ22-0431","article-title":"Association of mobile phone usage time with incidence of diabetic retinopathy in type 2 diabetes: a prospective cohort study.","volume":"70","author":"Zhang","year":"2023","journal-title":"Endocr J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"109556","DOI":"10.1016\/j.envint.2025.109556","article-title":"Association between endocrine disrupting chemicals exposure and the risk of all-cause mortality in individuals with diabetes mellitus or its complications: a prospective cohort study.","volume":"200","author":"Zhang","year":"2025","journal-title":"Environ Int"},{"key":"B22","doi-asserted-by":"publisher","first-page":"110580","DOI":"10.1016\/j.mce.2019.110580","article-title":"The effects of acute BPA exposure on skeletal muscle mitochondrial function and glucose metabolism.","volume":"499","author":"Ahmed","year":"2020","journal-title":"Mol Cell Endocrinol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.etap.2012.12.016","article-title":"Effect of Bisphenol-A on insulin signal transduction and glucose oxidation in liver of adult male albino rat.","volume":"35","author":"Jayashree","year":"2013","journal-title":"Environ Toxicol Pharmacol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1955","DOI":"10.1007\/s00204-020-02729-y","article-title":"Exposure to inorganic arsenic and its methylated metabolites alters metabolomics profiles in INS-1 832\/13 insulinoma cells and isolated pancreatic islets.","volume":"94","author":"Li","year":"2020","journal-title":"Arch Toxicol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3895","DOI":"10.1097\/JS9.0000000000002394","article-title":"Exploring the toxicological network in diabetic microvascular disease.","volume":"111","author":"Song","year":"2025","journal-title":"Int J Surg"},{"key":"B26","doi-asserted-by":"publisher","first-page":"153847","DOI":"10.1016\/j.tox.2024.153847","article-title":"Analysis of environmental pollutant Bisphenol F elicited prostate injury targets and underlying mechanisms through network toxicology, molecular docking, and multi-level bioinformatics data integration.","volume":"506","author":"Huang","year":"2024","journal-title":"Toxicology"},{"key":"B27","doi-asserted-by":"publisher","first-page":"118030","DOI":"10.1016\/j.ecoenv.2025.118030","article-title":"Efficient evaluation of osteotoxicity and mechanisms of endocrine disrupting chemicals using network toxicology and molecular docking approaches: triclosan as a model compound.","volume":"293","author":"Wang","year":"2025","journal-title":"Ecotoxicol Environ Saf."},{"key":"B28","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/s40779-025-00674-4","article-title":"Risk factor control in relation to mortality and life expectancy among people with type 2 diabetes: results from 3 nationwide cohort studies.","volume":"12","author":"Qiu","year":"2025","journal-title":"Mil Med Res"},{"key":"B29","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s40779-025-00658-4","article-title":"Trace element-dictated exosome modules and self-adaptive dual-network hydrogel orchestrate diabetic foot regeneration through complement-mitochondria-autophagy circuitry.","volume":"12","author":"Wang","year":"2025","journal-title":"Mil Med Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s40779-025-00615-1","article-title":"The national and provincial prevalence and non-fatal burdens of diabetes in China from 2005 to 2023 with projections of prevalence to 2050.","volume":"12","author":"Zhou","year":"2025","journal-title":"Mil Med Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"270","DOI":"10.2337\/dc22-0513","article-title":"Vitamin D status, vitamin D receptor polymorphisms, and risk of microvascular complications among individuals with type 2 diabetes: a prospective study.","volume":"46","author":"Chen","year":"2023","journal-title":"Diabetes Care"},{"key":"B32","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.jfo.2023.01.024","article-title":"Vitamin D deficiency and diabetic retinopathy risk.","volume":"46","author":"Navaei","year":"2023","journal-title":"J Fr Ophtalmol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e3447","DOI":"10.1002\/dmrr.3447","article-title":"Protective role of vitamin D against oxidative stress in diabetic retinopathy.","volume":"37","author":"Valle","year":"2021","journal-title":"Diabetes Metab Res Rev"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e0237149","DOI":"10.1371\/journal.pone.0237149","article-title":"Association between daily sunlight exposure duration and diabetic retinopathy in Korean adults with diabetes: a nationwide population-based cross-sectional study.","volume":"15","author":"Lee","year":"2020","journal-title":"PLoS One."},{"key":"B35","doi-asserted-by":"publisher","first-page":"101424","DOI":"10.1016\/j.eclinm.2022.101424","article-title":"Associations of sedentary time and physical activity with adverse health conditions: outcome-wide analyses using isotemporal substitution model.","volume":"48","author":"Cao","year":"2022","journal-title":"EClinicalMedicine"},{"key":"B36","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.pop.2021.11.001","article-title":"Risk factors and lifestyle interventions.","volume":"49","author":"Salzberg","year":"2022","journal-title":"Prim Care."},{"key":"B37","doi-asserted-by":"publisher","first-page":"dyae056","DOI":"10.1093\/ije\/dyae056","article-title":"Long-term exposure to ambient air pollution and risk of microvascular complications among patients with type 2 diabetes: a prospective study.","volume":"53","author":"Wang","year":"2024","journal-title":"Int J Epidemiol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1186\/s12903-024-04316-4","article-title":"Association of phthalate metabolites with periodontitis: a population-based study.","volume":"24","author":"Bian","year":"2024","journal-title":"BMC Oral Health"},{"key":"B39","doi-asserted-by":"publisher","first-page":"116866","DOI":"10.1016\/j.ecoenv.2024.116866","article-title":"Elucidating the mechanism of plasticizers inducing breast cancer through network toxicology and molecular docking analysis.","volume":"284","author":"He","year":"2024","journal-title":"Ecotoxicol Environ Saf."},{"key":"B40","doi-asserted-by":"publisher","first-page":"113930","DOI":"10.1016\/j.ecoenv.2022.113930","article-title":"Association of urinary phthalate metabolites with renal function among 9989 US adults.","volume":"242","author":"Wang","year":"2022","journal-title":"Ecotoxicol Environ Saf"},{"key":"B41","doi-asserted-by":"publisher","first-page":"119878","DOI":"10.1016\/j.lfs.2021.119878","article-title":"Rutin prevents cardiac oxidative stress and inflammation induced by bisphenol A and dibutyl phthalate exposure via NRF-2\/NF-\u03baB pathway.","volume":"284","author":"Oluranti","year":"2021","journal-title":"Life Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"3258","DOI":"10.1021\/acs.est.8b05729","article-title":"Phthalates and phthalate alternatives have diverse associations with oxidative stress and inflammation in pregnant women.","volume":"53","author":"van","year":"2019","journal-title":"Environ Sci Technol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"169513","DOI":"10.1016\/j.scitotenv.2023.169513","article-title":"Association of co-exposure to polycyclic aromatic hydrocarbons and phthalates with oxidative stress and inflammation.","volume":"912","author":"Lu","year":"2024","journal-title":"Sci Total Environ."},{"key":"B44","doi-asserted-by":"publisher","first-page":"122714","DOI":"10.1016\/j.envpol.2023.122714","article-title":"Phthalate exposure and risk of metabolic syndrome components: a systematic review.","volume":"340","author":"Perez-Diaz","year":"2024","journal-title":"Environ Pollut"},{"key":"B45","doi-asserted-by":"publisher","first-page":"123933","DOI":"10.1016\/j.lfs.2025.123933","article-title":"Dysregulation of the TNF-\u03b1-OTUD3-PPAR\u03b3 signaling axis exacerbates retinal oxidative stress and inflammation in diabetic retinopathy.","volume":"380","author":"Zhang","year":"2025","journal-title":"Life Sci"},{"key":"B46","doi-asserted-by":"publisher","first-page":"3194","DOI":"10.1007\/s10753-025-02259-8","article-title":"Inhibition of cullin3 neddylation alleviates diabetic retinopathy by activating Nrf2 signaling to combat ROS-induced oxidative stress and inflammation.","volume":"48","author":"Chen","year":"2025","journal-title":"Inflammation."},{"key":"B47","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.lfs.2017.12.001","article-title":"Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress.","volume":"193","author":"Dehdashtian","year":"2018","journal-title":"Life Sci"},{"key":"B48","doi-asserted-by":"publisher","first-page":"6103","DOI":"10.3390\/ijms26136103","article-title":"Maternal phthalate exposure and allergic diseases in children: a meta-analysis and network toxicology.","volume":"26","author":"Xiang","year":"2025","journal-title":"Int J Mol Sci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1097\/js9.0000000000001857","article-title":"Analysis of toxicity and mechanisms of DEHP in prostate cancer with network toxicology and molecular docking strategy.","volume":"111","author":"Yin","year":"2025","journal-title":"Int J Surg."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2896185","DOI":"10.1155\/2022\/2896185","article-title":"Identification of potential molecular targets and active ingredients of mingmu dihuang pill for the treatment of diabetic retinopathy based on network pharmacology.","volume":"2022","author":"Zhou","year":"2022","journal-title":"Biomed Res Int"},{"key":"B51","doi-asserted-by":"publisher","first-page":"111651","DOI":"10.1016\/j.cbi.2025.111651","article-title":"The association between exposure to phthalates and cardiovascular disease: a comprehensive study utilizing NHANES data from 2005 to 2018 and network toxicology.","volume":"420","author":"Gong","year":"2025","journal-title":"Chem Biol Interact"},{"key":"B52","doi-asserted-by":"publisher","first-page":"tfaf090","DOI":"10.1093\/toxres\/tfaf090","article-title":"Integrative network toxicology, molecular dynamics and transcriptional analysis elucidate DEHP-induced cardiovascular dysfunction.","volume":"14","author":"Guo","year":"2025","journal-title":"Toxicol Res"},{"key":"B53","doi-asserted-by":"publisher","first-page":"118132","DOI":"10.1016\/j.ecoenv.2025.118132","article-title":"Exploring the link between Di-2-ethylhexyl phthalate (DEHP) exposure and muscle mass: a systematic investigation utilizing NHANES data analysis, network toxicology and molecular docking approaches.","volume":"295","author":"Hao","year":"2025","journal-title":"Ecotoxicol Environ Saf"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1792532\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:42:45Z","timestamp":1778647365000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1792532\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":53,"alternative-id":["10.3389\/fmed.2026.1792532"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1792532","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]},"article-number":"1792532"}}