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Polyethylene (PE), widely used in food-contact materials, can carry bisphenol A (BPA), an endocrine disruptor with oxidative and neuroactive properties. Although both MPs and BPA can cross biological barriers, their acute effects on the prefrontal cortex (PFC) remain poorly understood. The aim of the study was to evaluate the acute impact of orally administered free BPA, free MPs, and BPA adsorbed onto PE MPs (PE\u2013BPA) on oxidative stress, inflammation, and gene expression in the PFC of Wistar rats. Animals received a single dose of BPA, PE\u2013BPA, PE alone, or vehicle. Methods: Biochemical and transcriptional analyses were performed to evaluate the antioxidant and inflammatory responses as well as the potential changes in synaptic-related gene expression. Results: BPA-containing treatments produced selective early molecular responses. Catalase (CAT) and glutathione S-transferase (GST) activities were significantly increased in the PE\u2013BPA group, with GST being also elevated in the BPA-alone group, whereas superoxide dismutase (SOD), myeloperoxidase (MPO), and malondialdehyde (MDA) levels did not significantly change. Transcriptional analyses revealed upregulation of the antioxidant genes Nrf2 and CAT in the PE\u2013BPA group. Co-exposure to BPA and MPs also altered synaptic markers, including decreased brain-derived neurotrophic factor (BDNF) and Sert along with increased Nr2A expression, while inflammatory gene expression remained unaffected. Conclusions: These findings indicate that acute co-exposure to BPA and PE microplastics elicits early antioxidant activation and selective synaptic-related transcriptional changes in the PFC, suggesting that MPs may modulate BPA-associated molecular responses in the brain.<\/jats:p>","DOI":"10.3390\/nu18121892","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:08Z","timestamp":1781229128000},"page":"1892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral Administration of Polyethylene Microplastics Induces BPA-Associated Antioxidant Activation and Synaptic-Related Transcriptional Responses in the Rat Prefrontal Cortex"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3260-3075","authenticated-orcid":false,"given":"Maria del Mar","family":"Ribas-Taberner","sequence":"first","affiliation":[{"name":"Research Group on Community Nutrition & Oxidative Stress, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"},{"name":"Health Research Institute of Balearic Islands (IdISBa), E-07120 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4155-7780","authenticated-orcid":false,"given":"Maria Magdalena","family":"Quetglas-Llabr\u00e9s","sequence":"additional","affiliation":[{"name":"Research Group on Community Nutrition & Oxidative Stress, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"},{"name":"Health Research Institute of Balearic Islands (IdISBa), E-07120 Palma, Illes Balears, Spain"},{"name":"CIBERobn (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, E-28029 Madrid, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2718-2535","authenticated-orcid":false,"given":"Llucia","family":"Garc\u00eda-Moll","sequence":"additional","affiliation":[{"name":"Flow Injection and Trace Analysis Group (FI-TRACE), Department of Chemistry, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6143-1574","authenticated-orcid":false,"given":"Manuel","family":"Jim\u00e9nez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Health Research Institute of Balearic Islands (IdISBa), E-07120 Palma, Illes Balears, Spain"},{"name":"Research Group on Neurophysiology, Department of Biology, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6146-8692","authenticated-orcid":false,"given":"Joan","family":"Truyols-Vives","sequence":"additional","affiliation":[{"name":"Molecular Biology, Health Geography, and One Health Research Group (MolONE), Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7498-6090","authenticated-orcid":false,"given":"Silvia","family":"Tejada","sequence":"additional","affiliation":[{"name":"Health Research Institute of Balearic Islands (IdISBa), E-07120 Palma, Illes Balears, Spain"},{"name":"CIBERobn (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, E-28029 Madrid, Madrid, Spain"},{"name":"Flow Injection and Trace Analysis Group (FI-TRACE), Department of Chemistry, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"},{"name":"Research Group on Neurophysiology, Department of Biology, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1924-7727","authenticated-orcid":false,"given":"Miguel D.","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Health Research Institute of Balearic Islands (IdISBa), E-07120 Palma, Illes Balears, Spain"},{"name":"Molecular Biology, Health Geography, and One Health Research Group (MolONE), Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"},{"name":"Renal Lithiasis and Pathological Calcification Group (LiRCaP), Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Mir\u00f3","sequence":"additional","affiliation":[{"name":"Health Research Institute of Balearic Islands (IdISBa), E-07120 Palma, Illes Balears, Spain"},{"name":"Flow Injection and Trace Analysis Group (FI-TRACE), Department of Chemistry, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"},{"name":"Molecular Biology, Health Geography, and One Health Research Group (MolONE), Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8656-6838","authenticated-orcid":false,"given":"Antoni","family":"Sureda","sequence":"additional","affiliation":[{"name":"Research Group on Community Nutrition & Oxidative Stress, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"},{"name":"Health Research Institute of Balearic Islands (IdISBa), E-07120 Palma, Illes Balears, Spain"},{"name":"Molecular Biology, Health Geography, and One Health Research Group (MolONE), Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"},{"name":"Renal Lithiasis and Pathological Calcification Group (LiRCaP), Research Institute of Health Sciences (IUNICS), University of the Balearic Islands, E-07122 Palma, Illes Balears, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Campanale, C., Massarelli, C., Savino, I., Locaputo, V., Uricchio, V.F., and Campanale, C. 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