{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T12:40:09Z","timestamp":1791549609279,"version":"4.3.4"},"reference-count":37,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Paracetamol is a well-known analgesic drug. Studies linked gestational paracetamol use to disorders like autism and attention-deficit\/hyperactivity disorder. This study aimed to evaluate the role of prenatal paracetamol exposure in 1-month-old offspring rats. Sixteen pregnant albino rats were divided into four groups: group I received saline; group II received sodium valproate 600 mg\/kg i.p. on embryonic day 13; group III received paracetamol 100 mg\/kg i.p. daily from embryonic day 13 to 21; group IV received paracetamol 300 mg\/kg i.p. on embryonic day 13. Offspring were assessed for behavioral test parameters. Animal brains underwent histopathological and immunohistochemical analysis for brain-derived neurotrophic factor (BDNF). Offspring in groups II (valproic acid) and IV (single paracetamol dose) showed differences in neurobehavioral test parameters, supported by cerebellar and hippocampal pathology. BDNF-stained cerebellum and hippocampus sections from the valproic group and the single paracetamol group revealed focal staining in granular cerebellar cells and pyramidal hippocampal cells. These findings indicate that prenatal exposure to high doses of paracetamol induces neurodevelopmental pathology. The safety of paracetamol use during pregnancy requires further evaluation.<\/jats:p>","DOI":"10.3390\/cimb48070714","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:34:44Z","timestamp":1783996484000},"page":"714","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gestational Paracetamol (Acetaminophen) Toxicity Induces Behavioral and Structural Brain Defects in Rats"],"prefix":"10.3390","volume":"48","author":[{"given":"Linah H.","family":"Ali","sequence":"first","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanaa A.","family":"Khalaf","sequence":"additional","affiliation":[{"name":"Medical Histology and Cell Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Histology, Hours University, New Damietta City 8027101, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameera S.","family":"Hamed","sequence":"additional","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2510-7229","authenticated-orcid":false,"given":"Ahmad M.","family":"Helaly","sequence":"additional","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4656-9956","authenticated-orcid":false,"given":"Aya E.","family":"Maghrabia","sequence":"additional","affiliation":[{"name":"MERC, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doaa","family":"Ghorab","sequence":"additional","affiliation":[{"name":"Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal A.","family":"El Bakary","sequence":"additional","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41574-021-00553-7","article-title":"Paracetamol use during pregnancy\u2014A call for precautionary action","volume":"17","author":"Bauer","year":"2021","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.siny.2017.07.006","article-title":"Perinatal and neonatal use of paracetamol for pain relief","volume":"22","author":"Allegaert","year":"2017","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Devkota, R., Khan, G.M., Alam, K., Regmi, A., and Sapkota, B. (2016). Medication utilization pattern for management of pregnancy complications: A study in Western Nepal. BMC Pregnancy Childbirth, 16.","DOI":"10.1186\/s12884-016-1068-8"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1093\/ije\/dyp151","article-title":"Use of acetaminophen during pregnancy and risk of adverse pregnancy outcomes","volume":"38","author":"Rebordosa","year":"2009","journal-title":"Int. J. Epidemiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1001\/jamapediatrics.2013.4914","article-title":"Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders","volume":"168","author":"Liew","year":"2014","journal-title":"JAMA Pediatr."},{"key":"ref_6","first-page":"548","article-title":"Over-the-Counter Medications in Pregnancy","volume":"90","author":"Servey","year":"2014","journal-title":"Am. Fam. Physician"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/humupd\/dmaa042","article-title":"Over-the-counter analgesics during pregnancy: A comprehensive review of global prevalence and offspring safety","volume":"27","author":"Zafeiri","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.jri.2012.10.014","article-title":"Acetaminophen and pregnancy: Short- and long-term consequences for mother and child","volume":"97","author":"Thiele","year":"2013","journal-title":"J. Reprod. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1111\/bcp.13656","article-title":"Long-term adverse effects of paracetamol\u2014A review","volume":"84","author":"McCrae","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/ppe.12568","article-title":"Prenatal paracetamol exposure and neurodevelopmental outcomes in preschool-aged children","volume":"34","author":"Wood","year":"2020","journal-title":"Paediatr. Perinat. Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e20163840","DOI":"10.1542\/peds.2016-3840","article-title":"Prenatal Exposure to Acetaminophen and Risk of ADHD","volume":"140","author":"Ystrom","year":"2017","journal-title":"Pediatrics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/MCG.0000000000000378","article-title":"Risk Factors, Clinical Presentation, and Outcomes in Overdose With Acetaminophen Alone or With Combination Products: Results From the Acute Liver Failure Study Group","volume":"50","author":"Serper","year":"2016","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.yhbeh.2018.01.003","article-title":"Prenatal paracetamol exposure and child neurodevelopment: A review","volume":"101","author":"Bauer","year":"2018","journal-title":"Horm. Behav."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00228-011-1112-6","article-title":"Systematic review of safety in paediatric drug trials published in 2007","volume":"68","author":"Choonara","year":"2012","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/ajmg.c.30097","article-title":"Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome","volume":"142C","author":"Capone","year":"2006","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1093\/ije\/dyt282","article-title":"Maternal lifestyle and environmental risk factors for autism spectrum disorders","volume":"43","author":"Lyall","year":"2014","journal-title":"Int. J. Epidemiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.reprotox.2015.05.007","article-title":"Prenatal factors associated with autism spectrum disorder (ASD)","volume":"56","author":"Ornoy","year":"2015","journal-title":"Reprod. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1111\/dmcn.12745","article-title":"Use of paracetamol during pregnancy and child neurological development","volume":"57","author":"Sawchik","year":"2015","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/sj.npp.1300767","article-title":"Environmental enrichment reverses behavioral alterations in rats prenatally exposed to valproic acid: Issues for a therapeutic approach in autism","volume":"31","author":"Schneider","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106856","DOI":"10.1016\/j.nbd.2025.106856","article-title":"Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function","volume":"207","author":"Brown","year":"2025","journal-title":"Neurobiol. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1523\/JNEUROSCI.1835-22.2023","article-title":"CSMD3 Deficiency Leads to Motor Impairments and Autism-Like Behaviors via Dysfunction of Cerebellar Purkinje Cells in Mice","volume":"43","author":"Xi","year":"2023","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.bj.2021.11.011","article-title":"Effects of physical exercise on children with attention deficit hyperactivity disorder","volume":"45","author":"Chan","year":"2022","journal-title":"Biomed. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1007\/s12035-014-8956-6","article-title":"The Physiology of BDNF and Its Relationship with ADHD","volume":"52","author":"Liu","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Posadas, I., Santos, P., Blanco, A., Mu\u00f1oz-Fern\u00e1ndez, M., and Ce\u00f1a, V. (2010). Acetaminophen induces apoptosis in rat cortical neurons. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015360"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40478-015-0184-4","article-title":"Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid","volume":"3","author":"Nicolini","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Miranda, M., Morici, J.F., Zanoni, M.B., and Bekinschtein, P. (2019). Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00363"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/ame2.12363","article-title":"Neurotrophins and neural stem cells in posttraumatic brain injury repair","volume":"7","author":"Guo","year":"2024","journal-title":"Anim. Models Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cardenas-Aguayo, M.d.e.l.C., Kazim, S.F., Grundke-Iqbal, I., and Iqbal, K. (2013). Neurogenic and neurotrophic effects of BDNF peptides in mouse hippocampal primary neuronal cell cultures. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053596"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"626","DOI":"10.2174\/1871527317666180720163221","article-title":"Serum Tryptophan, Tryptophan Catabolites and Brain-derived Neurotrophic Factor in Subgroups of Youngsters with Autism Spectrum Disorders","volume":"17","author":"Ormstad","year":"2018","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1093\/ije\/dyt183","article-title":"Prenatal paracetamol exposure and child neurodevelopment: A sibling-controlled cohort study","volume":"42","author":"Brandlistuen","year":"2013","journal-title":"Int. J. Epidemiol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hong, S.C., Han, J.Y., and Choi, S.K. (2026). Acetaminophen use in pregnancy and autism: Separating controversy from scientific evidence. Obstet. Gynecol. Sci., Epub ahead of printing.","DOI":"10.5468\/ogs.26022"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/S2215-0366(20)30312-6","article-title":"Environmental risk factors, protective factors, and peripheral biomarkers for ADHD: An umbrella review","volume":"7","author":"Kim","year":"2020","journal-title":"Lancet. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1001\/jamapsychiatry.2019.3259","article-title":"Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit\/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood","volume":"77","author":"Ji","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"177481","DOI":"10.1016\/j.ejphar.2025.177481","article-title":"Mitigating effects of H3 receptor antagonism on cerebellar autophagic pathways and behavioral phenotypes in BTBR T+ tf\/J mouse model of autism spectrum disorder","volume":"997","author":"Eissa","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107279","DOI":"10.1016\/j.ntt.2023.107279","article-title":"Gestational paracetamol exposure induces core behaviors of neurodevelopmental disorders in infant rats and modifies response to a cannabinoid agonist in females","volume":"99","author":"Klein","year":"2023","journal-title":"Neurotoxicology Teratol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Jones, J.P., Williamson, L., Konsoula, Z., Anderson, R., Reissner, K.J., and Parker, W. (2024). Evaluating the Role of Susceptibility Inducing Cofactors and of Acetaminophen in the Etiology of Autism Spectrum Disorder. Life, 14.","DOI":"10.20944\/preprints202406.0154.v1"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.etap.2013.11.004","article-title":"Paracetamol impairs the profile of amino acids in the rat brain","volume":"37","author":"Piechal","year":"2014","journal-title":"Environ. Toxicol. Pharmacol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/714\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T03:18:17Z","timestamp":1783999097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/7\/714"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cimb48070714"],"URL":"https:\/\/doi.org\/10.3390\/cimb48070714","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}