Maternal diet during gestation affect prostatic tissue component in SHR/Izm offspring
Authors: Shibamori Kosuke , Kyoda Yuki , Shindo Tetsuya , Hashimoto Kohei , Kobayashi Ko , Tanaka Toshiaki , Suzuki Hiromu , Masumori Naoya 
Published: November 2023

Background

Numerous studies have investigated the associations between maternal nutritional status and various diseases, with the underlying mechanism often attributed to epigenetic changes. However, limited research has been conducted on the relationship between maternal nutrition and benign prostatic hyperplasia (BPH). In this study, we aimed to explore the potential association between maternal nutrition and BPH using an animal experiment and evaluating the findings through fluorescent immunostaining and genetic analysis.

Methods

Female spontaneously hypertensive rats (SHR/Izm) were randomly assigned to three groups at the start of pregnancy: a standard diet group (SD; 17% protein, 7% fat), a low‐protein diet group (LPD; 6% protein, 7% fat), and a high‐fat diet group (HFD; 22% protein, 35% fat). The diets were maintained throughout gestation. After giving birth, both the mothers and their pups were exclusively fed a standard diet. Male pups were euthanized at 48 weeks, and their prostates were removed. The composition of the ventral prostate (VP) was evaluated using fluorescent immunostaining with antibodies for cytokeratin, vimentin, and Ki‐67. Microarray analysis, real‐time RT‐PCR, and DNA methylation analysis using pyrosequencing were performed. Statistical analysis was conducted using one‐way ANOVA and Tukey's multiple comparison test, with a significance level set at p < 0.05.

Results

Pups in the LPD group exhibited significant underweight from birth (1 day; SD vs. LPD vs. HFD: 4.46 vs. 4.08 vs. 4.35, p = 0.04) until weaning (21 days; SD vs. LPD vs. HFD: 30.8 vs. 27.4 vs. 29.2, p = 0.03). However, they exhibited catch‐up growth, and there was no significant difference at 48 weeks (p = 0.84). The epithelial area in the ventral prostate was significantly increased in the LPD group (SD vs. LPD vs. HFD: 39% vs. 48% vs. 37%, p = 0.01), while the stromal area was significantly increased in the HFD group (SD vs. LPD vs. HFD: 11% vs. 11% vs. 15%, p < 0.01). Gene ontology analysis of the gene expression microarray showed increased activity in developmental processes (SD vs. LPD: p = 6.3E‐03, SD vs. HFD: p = 7.2E‐03), anatomical structure development (SD vs. LPD: p = 6.3E‐03, SD vs. HFD: p = 5.3E‐03), and cell differentiation (SD vs. LPD: p = 0.018, SD vs. HFD: p = 0.041) in both the LPD and HFD groups. Real‐time RT‐PCR revealed high expression levels of the transcription factors NFκB (p < 0.01) and Smad3 (p < 0.01) in both the LPD and HFD groups. XIAP, an apoptosis inhibitor, was increased in the LPD group (p = 0.02). The TGF beta pathway, associated with epithelial mesenchymal transition (EMT), and vimentin (p < 0.01) were upregulated in the HFD group. Pyrosequencing DNA methylation analysis of the TGF beta pathway indicated hypomethylation of TGFb1, TGFbR1, and Smad3 in all groups, although there were no significant differences.

Conclusions

Our findings suggest that both maternal undernutrition and obesity influence the prostatic development of offspring. Maternal consumption of a low protein diet promotes epithelial hyperplasia through the upregulation of apoptosis inhibitors, while a high fat diet leads to increased stromal growth through the induction of EMT.