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The (epi)genetic influences of obesity may be transgenerationally transmitted, potentially impacting PCa susceptibility in the offspring of fathers with obesity. Thus, we studied the impact of early-life or lifelong exposure to a high-fat diet (HFD) on PCa biomarkers [Homeobox B13 (HOXB13) and the Androgen Receptor (AR)] and their correlation with obesity-related markers. Furthermore, we focused on the offspring\u2019s PCa biomarkers outcomes and explored their potential link with paternal diet. A transgenerational <jats:italic>Mus musculus<\/jats:italic> model was established, with F0 males exposed to different diets (200 days): standard chow, lifelong HFD (HFD), and transient diet (60 days HFD, plus 140 days of standard chow) (HFD<jats:sub>t<\/jats:sub>). <jats:italic>AR<\/jats:italic> expression in the prostates was unaffected, whereas <jats:italic>HOXB13<\/jats:italic>, Fat Mass and Obesity Associated gene (<jats:italic>FTO)<\/jats:italic>, and Tumor Necrosis Factor-Alpha (<jats:italic>TNF-\u03b1)<\/jats:italic> expression decreased in the F1 HFD<jats:sub>t<\/jats:sub> group. <jats:italic>HOXB13<\/jats:italic> and <jats:italic>AR<\/jats:italic> prostate expression were positively correlated. There was also a positive correlation between <jats:italic>FTO<\/jats:italic> prostate expression and PCa biomarkers, and between <jats:italic>TNF-\u03b1<\/jats:italic> expression and <jats:italic>FTO<\/jats:italic> and PCa biomarkers. <jats:italic>HOXB13<\/jats:italic> promoter methylation levels were unaffected, however, were positively correlated with <jats:italic>FTO<\/jats:italic> and <jats:italic>HOXB13<\/jats:italic> expression. Finally, protein nitration remained unchanged in the prostates, while lipid peroxidation was increased in the F0 HFD group and decreased in the F1 and F2 HFD and HFD<jats:sub>t<\/jats:sub> groups. Our study highlights the intergenerational interplay between obesity-related factors and PCa biomarkers, suggesting that offspring of male progenitors subjected to HFD may face an increased risk for elevated PCa biomarkers expression.<\/jats:p>","DOI":"10.1007\/s00394-025-03737-3","type":"journal-article","created":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T04:39:19Z","timestamp":1749271159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Increased susceptibility to prostate cancer biomarkers in the offspring of male mouse progenitors with lifelong or early life exposure to high-fat diet"],"prefix":"10.1007","volume":"64","author":[{"given":"Mariana","family":"Santos-Pereira","sequence":"first","affiliation":[]},{"given":"Sara C.","family":"Pereira","sequence":"additional","affiliation":[]},{"given":"B\u00e1rbara","family":"Matos","sequence":"additional","affiliation":[]},{"given":"Margarida","family":"Fardilha","sequence":"additional","affiliation":[]},{"given":"Pedro F.","family":"Oliveira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-783X","authenticated-orcid":false,"given":"Marco G.","family":"Alves","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,6,7]]},"reference":[{"key":"3737_CR1","unstructured":"Organization WH (2000) Obesity: preventing and managing the global epidemic. 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