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. 2017 May 10;12(5):e0175764.
doi: 10.1371/journal.pone.0175764. eCollection 2017.

Exposure to Maternal Obesogenic Diet Worsens Some but Not All Pre-Cancer Phenotypes in a Murine Genetic Model of Prostate Cancer

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Free PMC article

Exposure to Maternal Obesogenic Diet Worsens Some but Not All Pre-Cancer Phenotypes in a Murine Genetic Model of Prostate Cancer

Theresa Okeyo-Owuor et al. PLoS One. .
Free PMC article

Abstract

Prostate cancer research has been predominantly focused on adult exposures and risk factors. However, because the prostate develops during gestation and early life, exposure to external factors, such as obesity, during development could affect the prostate cancer progression in adults. Our previous work demonstrated that exposure to a high fat/high sugar (HF/HS) diet during gestation and until weaning stimulated prostate hyperplasia and altered the Pten/Akt pathway in adult mice fed a normal diet after weaning. Here, we asked whether maternal exposure to HF/HS would worsen prostate phenotypes in mice lacking Pten, a widely accepted driver of prostate cancer. We found that, at six weeks of age, both Chow (control)-and HF/HS-exposed Pten knockout mice showed evidence of murine PIN that included ducts with central comedo necrosis but that the HF/HS exposure did not influence murine PIN progression. The Pten knockout mice exposed to HF/HS in utero had significantly more mitotic cells than Pten knockouts exposed to Chow diet. In the Pten null background, the maternal HF/HS diet enhanced proliferation but did not have an additive effect on Akt activation. We observed neuroendocrine differentiation in Pten knockout mice, a phenotype that had not been previously described in this model.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Experimental set-up.
Four-week-old Ptenloxp/loxp female mice were fed either a Chow or HF/HS diet for four weeks and then mated to Ptenloxp/loxp;PBCre4+ males. Male offspring were fed a Chow diet after weaning (three weeks) and until sacrifice at six weeks of age.
Fig 2
Fig 2. Metabolic consequences of HF/HS diet in nine-week-old Ptenloxp/loxp dams.
Dot plots show quantitation of body weight (A), percent fat mass (B), percent lean mass (C), percent water (D), glucose tolerance (E), and insulin sensitivity (F). n > 3 mice per group, *P<0.05 as calculated by student’s t-test.
Fig 3
Fig 3. HF/HS diet exposure increases mitotic figures in prostates of Pten knockout males.
(A) Representative H&E staining of dorsolateral prostates (DLPs) from six-week-old WT and Pten knockout offspring from to Chow or HF/HS-fed dams. Black arrows indicate expansile central comedo necrosis. Scale bars = 500 μm in main panel and 100 μm in inset. (B) Quantification of ducts with expansile central necrosis (% of total ducts per prostate section). (C) Representative H&E staining of DLP sections. Arrows indicate mitotic figures. Scale bars = 100 μm. (D) Numbers of prostate cells undergoing mitosis per 10 high-powered fields in Pten knockout mice exposed to Chow or HF/HS. Same letters mean there’s no significant difference between conditions, different letters represent statistically significant differences. N >10 mice; P<0.05 as calculated by Wilcoxon rank sum test, plotted using median and range.
Fig 4
Fig 4. HF/HS diet exposure stimulates increased proliferation in male offspring.
(A) Representative pHH3 and Ki67 staining of prostates from Pten knockout mice exposed to maternal Chow or HF/HS diet Red—pHH3, Green—Ki67, Blue—DAPI (nuclei). Scale bars = 25 μm. (B and C) Quantification of pHH3- (B) and Ki67- (C) positive cells normalized to total number of cells per image. Same letters mean there’s no significant difference between conditions, different letters represent statistically significant differences. n = 10 images per mouse from n = 5 mice per experimental group; P<0.05 as calculated by 2-way analysis of variance followed by Tukey’s multiple comparison’s test.
Fig 5
Fig 5. HF/HS diet exposure does not affect phospho-Akt and Akt expression in Pten knockout males.
Representative images of phospho-Akt (Ser-473) (a-d), Akt (e-h) and Pten (i-l) staining of prostates from WT and Pten knockout mice exposed to maternal Chow or HF/HS diet. Red—Pten, phospho-Akt, Green—Akt, Blue—DAPI, scale bar = 50 μm.
Fig 6
Fig 6. Features of neuroendocrine differentiation observed in Pten kockout males.
Representative H&E and synaptophysin staining of prostates from WT and Pten knockout. The WT and Pten knockout mice exposed to maternal HF/HS diet showed similar findings as their Chow counterparts and these findings are summarized in Table 1. Black arrows show areas of NED. Scale bar = 100 μm.

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