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This study evaluated the in vivo effects of aqueous extracts from Pteridium aquilinum rhizomes and freeze-dried fiddleheads in a transgenic mouse model of human papillomavirus type 16 (HPV16)-induced cancer. Rhizome extract was administered in drinking water at concentrations of 0.0125, 0.025, and 0.05 g\/mL for 28 days across six experimental groups (n = 5): G1 (wild-type, control), G2 (wild-type, 0.05 g\/mL), G3 (HPV, control), G4 (HPV, 0.0125 g\/mL), G5 (HPV, 0.025 g\/mL), and G6 (HPV, 0.05 g\/mL). Freeze-dried fiddleheads were incorporated into the diet at concentrations of 12.5%, 25%, and 50%, also using six groups (n = 5). Humane endpoints, body weight, and food and water consumption were monitored weekly. The rhizome extract was associated with more pronounced biological effects compared to fiddleheads, particularly at the histological and molecular levels. Conversely, freeze-dried fiddleheads were better tolerated. The results indicate that rhizomes were associated with great biological impact under the present experimental conditions, particularly in HPV16 transgenic mice, highlighting a potential synergistic effect with HPV. The potential risks associated with Pteridium aquilinum consumption, as well as preparation methods, should be carefully considered, even for rhizomes which are often regarded as less harmful than other plant parts.<\/jats:p>","DOI":"10.3390\/biology15120976","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"976","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Toxicological Activities of Pteridium aquilinum Rhizomes and Fiddleheads in HPV16-Transgenic Mice"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3909-5903","authenticated-orcid":false,"given":"Beatriz","family":"Medeiros-Fonseca","sequence":"first","affiliation":[{"name":"Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Pathology and Laboratory Medicine Department\/Clinical Pathology\/Porto Comprehensive Cancer Center Raquel Seruca (Porto. 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and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Agrarian School of Viseu, Polytechnic Institute of Viseu, Quinta da Alagoa-Estrada de Nelas Ranhados, 3500-606 Viseu, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-4867","authenticated-orcid":false,"given":"Helena","family":"Vala","sequence":"additional","affiliation":[{"name":"Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"CERNAS-IPV Research Centre, Instituto Polit\u00e9cnico de Viseu, Campus Polit\u00e9cnico, Repeses, 3504-510 Viseu, 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CCC), 4200-072 Porto, Portugal"},{"name":"Research Department of the Portuguese League Against Cancer Regional Nucleus of the North (LPCC-NRN), 4200-177 Porto, Portugal"},{"name":"Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), 4050-313 Porto, Portugal"},{"name":"Biomedical Research Center (CEBIMED), Faculty of Health Sciences of Fernando Pessoa University (UFP), 4249-004 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9519-4044","authenticated-orcid":false,"given":"Paula A.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Department of Veterinary Sciences, University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2151-2449","authenticated-orcid":false,"given":"Rui M.","family":"Gil da Costa","sequence":"additional","affiliation":[{"name":"Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production (Inov4Agro), University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"},{"name":"Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)\/Pathology and Laboratory Medicine Department\/Clinical Pathology\/Porto Comprehensive Cancer Center Raquel Seruca (Porto. CCC), 4200-072 Porto, Portugal"},{"name":"Laboratory for Process Engineering, Environment, Biotechnology and Energy (LEPABE), Associate Laboratory in Chemical Engineering (ALiCE), Faculty of Engineering, University of Porto (FEUP), 4200-465 Porto, Portugal"},{"name":"Agrarian School of Viseu, Polytechnic Institute of Viseu, Quinta da Alagoa-Estrada de Nelas Ranhados, 3500-606 Viseu, Portugal"},{"name":"Department of Pathology, State University of Maranh\u00e3o (UEMA), S\u00e3o Lu\u00eds 65055-310, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1556\/avet.57.2009.1.18","article-title":"A biological hazard of our age: Bracken fern [Pteridium aquilinum (L.) Kuhn]\u2014A review","volume":"57","author":"Vetter","year":"2009","journal-title":"Acta Vet. 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