Endocrine Abstracts

Metabolic disorders, such as overweight and obesity, are serious health societal challenges due to their high incidence rates. Obesity leads to metabolic dysregulation, promoting hormonal imbalance, oxidative stress, and a chronic inflammation state. Eating habits towards the intake of highly caloric fat-rich regimes induce epigenetic changes in the information transgenerationally transmitted. Furthermore, obesity promotes carcinogenesis. It is known that the prostate is sensitive to the metabolic and hormonal alterations promoted by obesity. Prostate Cancer (PCa) is the second most common cancer and the fifth leading cause of death among men. The diagnosis is generally based on the detection of PSA (prostate-specific antigen) and digital rectal examination. Further, PCa biomarkers, like homeobox Hox-B13 (HOXB13), are used for tissue diagnosis. Due to the close relationship between obesity and PCa development, as well as the emerging evidence on the inheritance of obesity-related factors, it has been debated if there are inheritable obesity-related changes that trigger PCa. Still, to date, no data has been clearly reported showing the inheritance of obesity-related factors that could also promote the development of PCa. In this work, we studied the expression of HOXB13, a PCa biomarker, on the prostate of the progeny of fathers lean, obese, and subjected to diet correction after high-fat diet. To test this, a transgenerational animal model (Mus musculus) was established, where F0 mice were exposed to three different diets: standard, high-fat (HFD), and diet correction (60 days HFD, plus 120 days standard diet), ad libitum for 200 days post wearing. Two more generations were bred, F1 and F2, between males and lean females. We evaluated several PCa biomarkers expression on the prostates (Androgen receptor, HOXB13, Ki-67). Among these, HOXB13 presented a decreased expression on the prostates of F1 mice whose diet was corrected from HFD to standard. HOXB13 decreased expression is associated with carcinogenesis since it promotes lipid accumulation, which is a carcinogenesis hallmark. Obesity has already been correlated to altered DNA methylation patterns in several tissues, including the prostate. Concurrently, HOXB13 promoter hypermethylation decreases HOXB13 expression. These results suggest that the offspring of obese fathers subjected to diet correction have an increased risk of developing PCa. We propose that a diet correction from HFD to a standard diet may not be sufficient to revert the effects of HFD on DNA methylation and that this epigenetic alteration is being transmitted from the F0 to F1 animals as detected in HOXB13 expression.