{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:21:46Z","timestamp":1785424906371,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005716","name":"Babol University of Medical Sciences","doi-asserted-by":"publisher","award":["724132341"],"award-info":[{"award-number":["724132341"]}],"id":[{"id":"10.13039\/501100005716","id-type":"DOI","asserted-by":"publisher"}]},{"award":["724132341"],"award-info":[{"award-number":["724132341"]}],"id":[{"id":"https:\/\/ror.org\/02r5cmz65","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Phthalates are a group of organic compounds widely used for enhancement in flexibility and transparency of polyvinyl chloride (PVC) products. Exposure to phthalate-containing substances has been shown to affect brain function, particularly in learning and memory processes. Quercetin is a plant-derived flavonoid with remarkable anti-oxidant and anti-inflammatory potential. This study investigated the possible protective effects of quercetin on spatial learning and memory, histomorphometric changes, and hippocampal expression of inflammatory cytokines (TNF-\u03b1 and IL-6) in male mice exposed to di(2-ethylhexyl) phthalate (DEHP). Methods: A total of 42 male mice were divided into seven groups. Quercetin was administered orally at doses of 25 and 50 mg\/kg\/day, either alone or in combination with DEHP (200 mg\/kg\/day). Following the final day of the treatment, spatial learning and memory were assessed by the Morris Water Maze test. Hippocampal tissues were sampled for Nissl, H&amp;E, and immunofluorescence staining. Quantitative real-time PCR was used to measure the expression of TNF-\u03b1 and IL-6. Results: The DEHP group exhibited significant impairments in learning and memory, neuronal damage, and cellular disorganization in the hippocampus, along with increased astrocyte activation and elevated expression of TNF-\u03b1 and IL-6. On the other hand, quercetin supplementation significantly reduced these inflammatory markers and histological damages and also improved spatial learning and memory. Conclusions: Overall, quercetin improves cognitive function that is associated with attenuating astrocyte activation and inflammation.<\/jats:p>","DOI":"10.3390\/brainsci16040431","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T14:53:23Z","timestamp":1776696803000},"page":"431","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quercetin Improves Cognitive Function by Ameliorating Histopathological Changes and Inflammation in Di(2-ethylhexyl) Phthalate-Exposed Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Leila","family":"Nadalinezhad","sequence":"first","affiliation":[{"name":"Student Research Committee, Babol University of Medical Sciences, Babol 47176-47745, Iran"},{"name":"Department of Anatomy, Embryology and Histology, Faculty of Medicine, Babol University of Medical Sciences, Babol 47176-47745, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5014-5166","authenticated-orcid":false,"given":"Maryam","family":"Ghasemi-Kasman","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 47176-47745, Iran"},{"name":"Department of Physiology, Faculty of Medicine, Babol University of Medical Sciences, Babol 47176-47745, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Pourghasem","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Histology, Faculty of Medicine, Babol University of Medical Sciences, Babol 47176-47745, Iran"},{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 47176-47745, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9122-7018","authenticated-orcid":false,"given":"Fatemeh","family":"Rabiei","sequence":"additional","affiliation":[{"name":"Student Research Committee, Babol University of Medical Sciences, Babol 47176-47745, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farideh","family":"Feizi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Histology, Faculty of Medicine, Babol University of Medical Sciences, Babol 47176-47745, Iran"},{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 47176-47745, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzin","family":"Sadeghi","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 47176-47745, Iran"},{"name":"Department of Medical Virology and Biotechnology, Faculty of Medicine, Babol University of Medical Sciences, Babol 47176-47745, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Huang, L., Zhu, X., Zhou, S., Cheng, Z., Shi, K., Zhang, C., and Shao, H. (2021). Phthalic Acid Esters: Natural Sources and Biological Activities. Toxins, 13.","DOI":"10.3390\/toxins13070495"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13696","DOI":"10.3390\/ijerph121113696","article-title":"In Utero Exposure to Diethylhexyl Phthalate Affects Rat Brain Development: A Behavioral and Genomic Approach","volume":"12","author":"Lin","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Giuliani, A., Zuccarini, M., Cichelli, A., Khan, H., and Reale, M. (2020). Critical Review on the Presence of Phthalates in Food and Evidence of Their Biological Impact. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17165655"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.envpol.2018.02.088","article-title":"Phthalates contamination in China: Status, trends and human exposure-with an emphasis on oral intake","volume":"238","author":"Wang","year":"2018","journal-title":"Environ. Pollut."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhu, H., and Kannan, K. (2019). A Review of Biomonitoring of Phthalate Exposures. Toxics, 7.","DOI":"10.3390\/toxics7020021"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.reprotox.2022.02.006","article-title":"Exposure to phthalates and female reproductive health: A literature review","volume":"109","author":"Basso","year":"2022","journal-title":"Reprod. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, F., Zhen, H., Cheng, H., Hu, F., Jia, Y., Huang, B., and Jiang, M. (2022). Di-(2-ethylhexyl) phthalate exposure induces liver injury by promoting ferroptosis via downregulation of GPX4 in pregnant mice. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1014243"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"218","DOI":"10.15406\/ppij.2022.10.00390","article-title":"Mechanism involved in cell death induced by DEHP (Di-ethylhexyl phthalate) on primary brain cells from Zebrafish (Danio rerio)","volume":"10","author":"Zayas","year":"2022","journal-title":"Pharm. Pharmacol. Int. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66417","DOI":"10.1007\/s11356-023-26943-0","article-title":"Urinary di-(2-ethylhexyl) phthalate metabolites are independently related to serum neurofilament light chain, a biomarker of neurological diseases, in adults: Results from NHANES 2013\u20132014","volume":"30","author":"Yang","year":"2023","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"610813","DOI":"10.1155\/2015\/610813","article-title":"Interrelation of oxidative stress and inflammation in neurodegenerative disease: Role of TNF","volume":"2015","author":"Fischer","year":"2015","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"766","DOI":"10.2174\/1570159X19666210713122517","article-title":"Effects of Di-2-Ethylhexyl Phthalate on Central Nervous System Functions: A Narrative Review","volume":"20","author":"Safarpour","year":"2022","journal-title":"Curr. Neuropharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1742-2094-7-16","article-title":"Mechanisms of tumor necrosis factor-alpha-induced interleukin-6 synthesis in glioma cells","volume":"7","author":"Tanabe","year":"2010","journal-title":"J. Neuroinflammation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8825387","DOI":"10.1155\/2020\/8825387","article-title":"Quercetin: Its Main Pharmacological Activity and Potential Application in Clinical Medicine","volume":"2020","author":"Yang","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Aghababaei, F., and Hadidi, M. (2023). Recent Advances in Potential Health Benefits of Quercetin. Pharmaceuticals, 16.","DOI":"10.3390\/ph16071020"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liu, A.R., and Ramakrishnan, P. (2021). Regulation of Nuclear Factor-kappaB Function by O-GlcNAcylation in Inflammation and Cancer. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.751761"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Li, Y., Yao, J., Han, C., Yang, J., Chaudhry, M.T., Wang, S., Liu, H., and Yin, Y. (2016). Quercetin, Inflammation and Immunity. Nutrients, 8.","DOI":"10.3390\/nu8030167"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Smith, C.A., and Holahan, M.R. (2014). Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl) phthalate in male Long Evans rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109522"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s10753-015-0227-9","article-title":"Quercetin Protects Mice from ConA-Induced Hepatitis by Inhibiting HMGB1-TLR Expression and Down-Regulating the Nuclear Factor Kappa B Pathway","volume":"39","author":"Li","year":"2016","journal-title":"Inflammation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13542","DOI":"10.3390\/ijerph121013542","article-title":"Altered Hippocampal Lipid Profile Following Acute Postnatal Exposure to Di(2-Ethylhexyl) Phthalate in Rats","volume":"12","author":"Smith","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1177\/0960327115580602","article-title":"Quercetin attenuates di-(2-ethylhexyl) phthalate-induced testicular toxicity in adult rats","volume":"35","author":"Aly","year":"2016","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14676","DOI":"10.1038\/srep14676","article-title":"Cognitive deficits and anxiety induced by diisononyl phthalate in mice and the neuroprotective effects of melatonin","volume":"5","author":"Ma","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"138356","DOI":"10.1016\/j.neulet.2025.138356","article-title":"Arbutin improves spatial learning and memory in a lipopolysaccharide-induced neuroinflammation model via attenuating of astrocytes activation and oxidative stress","volume":"865","author":"Pouramir","year":"2025","journal-title":"Neurosci. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.etap.2013.05.001","article-title":"Neurotoxicity of dibutyl phthalate in brain development following perinatal exposure: A study in rats","volume":"36","author":"Li","year":"2013","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1007\/s00204-015-1539-0","article-title":"Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring","volume":"90","author":"Lee","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Nosratian, N., Ghasemi-Kasman, M., Pourghasem, M., Feizi, F., and Sadeghi, F. (2025). Plumbagin Improves Cognitive Function via Attenuating Hippocampal Inflammation in Valproic Acid-Induced Autism Model. Brain Sci., 15.","DOI":"10.3390\/brainsci15080798"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"115620","DOI":"10.1016\/j.fct.2025.115620","article-title":"Dual-parent di-(2-ethylhexyl) phthalate (DEHP) exposure: A multigenerational assessment of neurocognitive outcomes in male pups","volume":"204","author":"Khalifa","year":"2025","journal-title":"Food Chem. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11849","DOI":"10.1021\/acsomega.0c01818","article-title":"Therapeutic Potential of Quercetin: New Insights and Perspectives for Human Health","volume":"5","author":"Salehi","year":"2020","journal-title":"ACS Omega"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1590\/S1807-59322011001300002","article-title":"Long-term potentiation and long-term depression: A clinical perspective","volume":"66","author":"Bliss","year":"2011","journal-title":"Clinics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5698119","DOI":"10.1155\/2024\/5698119","article-title":"Quercetin Attenuates Oxidative Stress and Apoptosis in Brain Tissue of APP\/PS1 Double Transgenic AD Mice by Regulating Keap1\/Nrf2\/HO-1 Pathway to Improve Cognitive Impairment","volume":"2024","author":"Cheng","year":"2024","journal-title":"Behav. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1039\/D0FO01900C","article-title":"Quercetin improves cognitive disorder in aging mice by inhibiting NLRP3 inflammasome activation","volume":"12","author":"Li","year":"2021","journal-title":"Food Funct."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.bbrc.2017.07.151","article-title":"Quercetin ameliorates learning and memory via the Nrf2-ARE signaling pathway in d-galactose-induced neurotoxicity in mice","volume":"491","author":"Dong","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111443","DOI":"10.1016\/j.brainresbull.2025.111443","article-title":"Nanoliposomal quercetin reduces neuroinflammation and influences TLR4 and microglial activity with potential effects on GABAA2 receptors in a rat model of Huntington\u2019s disease","volume":"229","author":"Alishvandi","year":"2025","journal-title":"Brain Res. Bull."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12270","DOI":"10.1523\/JNEUROSCI.1671-11.2011","article-title":"Memory-guided learning: CA1 and CA3 neuronal ensembles differentially encode the commonalities and differences between situations","volume":"31","author":"Bahar","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Islam, M.S., Quispe, C., Hossain, R., Islam, M.T., Al-Harrasi, A., Al-Rawahi, A., Martorell, M., Mamurova, A., Seilkhan, A., and Altybaeva, N. (2021). Neuropharmacological Effects of Quercetin: A Literature-Based Review. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.665031"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Khan, A., Ali, T., Rehman, S.U., Khan, M.S., Alam, S.I., Ikram, M., Muhammad, T., Saeed, K., Badshah, H., and Kim, M.O. (2018). Neuroprotective Effect of Quercetin Against the Detrimental Effects of LPS in the Adult Mouse Brain. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01383"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s12944-021-01590-x","article-title":"Protective effect of quercetin against the metabolic dysfunction of glucose and lipids and its associated learning and memory impairments in NAFLD rats","volume":"20","author":"Gao","year":"2021","journal-title":"Lipids Health Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ibneur.2023.09.010","article-title":"Comparing the synaptic potentiation in schaffer collateral-CA1 synapses in dorsal and intermediate regions of the hippocampus in normal and kindled rats","volume":"15","author":"Sharifi","year":"2023","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Barnhart, C.D., Yang, D., and Lein, P.J. (2015). Using the Morris water maze to assess spatial learning and memory in weanling mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124521"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Mahyar, M., Ghadirzadeh, E., Nezhadnaderi, P., Moayedi, Z., Maboud, P., Ebrahimi, A., Siahposht-Khachaki, A., and Karimi, N. (2025). Neuroprotective effects of quercetin on hippocampal CA1 neurons following middle cerebral artery ischemia\u2013reperfusion in male rats: A behavioral, biochemical, and histological study. BMC Neurol., 25.","DOI":"10.1186\/s12883-024-04017-z"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1007\/s12264-022-00894-x","article-title":"Monitoring the Activity of Astrocytes in Learning and Memory","volume":"38","author":"Wu","year":"2022","journal-title":"Neurosci. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e57155","DOI":"10.7554\/eLife.57155","article-title":"Activation of astrocytes in hippocampus decreases fear memory through adenosine A(1) receptors","volume":"9","author":"Li","year":"2020","journal-title":"eLife"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Silvestro, S., Bramanti, P., and Mazzon, E. (2021). Role of Quercetin in Depressive-Like Behaviors: Findings from Animal Models. Appl. Sci., 11.","DOI":"10.3390\/app11157116"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/j.bbrc.2020.10.016","article-title":"Dietary quercetin attenuates depressive-like behaviors by inhibiting astrocyte reactivation in response to stress","volume":"533","author":"Zhang","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.biopha.2018.02.125","article-title":"Querectin improves myelin repair of optic chiasm in lyolecithin-induced focal demyelination model","volume":"101","author":"Naeimi","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lee, J., Lee, S., Zhang, H., Hill, M.A., Zhang, C., and Park, Y. (2017). Interaction of IL-6 and TNF-\u03b1 contributes to endothelial dysfunction in type 2 diabetic mouse hearts. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187189"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Khan, H., Ullah, H., Aschner, M., Cheang, W.S., and Akkol, E.K. (2019). Neuroprotective Effects of Quercetin in Alzheimer\u2019s Disease. Biomolecules, 10.","DOI":"10.3390\/biom10010059"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lykowska-Szuber, L., Walczak, M., Skrzypczak-Zielinska, M., Suszynska-Zajczyk, J., Stawczyk-Eder, K., Waszak, K., Eder, P., Wozniak, A., Krela-Kazmierczak, I., and Slomski, R. (2021). Effect of Anti-TNF Therapy on Mucosal Apoptosis Genes Expression in Crohn\u2019s Disease. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.615539"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/4\/431\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T04:16:04Z","timestamp":1777090564000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/4\/431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["brainsci16040431"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16040431","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]}}}