Transgenerational animal models of nutritional impact on cancer predisposition

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The objective of the current study is to investigate the effect of maternal high fat diet and changes in metabolic bioenergetics on prostate gland development and susceptibility to prostate cancer in the male offspring. We hypothesize that a high fat maternal diet prior to and throughout pregnancy alters epigenomic marks leading to abnormal expression of key genes involved in the development of the prostate gland, which predispose the offspring to develop prostate cancer. Our rationale is that if maternal diet and metabolic bioenergetics alter the process of tumor development and progression in the prostate, then further studies exploring the mechanism of this process may elucidate new therapies and recommendations for the prevention and treatment of prostate cancer. To test our hypothesis the following aims will be pursued: Specific Aim 1: To examine prostate gland development and imprinted gene expression in control vs high fat fed offspring, from mothers given a high fat diet for 1 month prior to conception and throughout pregnancy.+ Specific Aim 2: To examine the incidence and timing of tumor development in offspring of control vs high fat fed mothers by administration of diethylstilbestrol (DES) to neonatal male mice on postnatal days 1-5. Specific Aim 3: To examine the effects of a high fat diet on tumor development in an established model for prostate cancers. The high fat diet experiment will be performed in mice with prostate specific knockout of PTEN vs controls (Pten[loxp/lop];PB-Cre4*) vs Pten*'*;PBCre4-). This proposal is innovative in that although data show that dietary changes during pregnancy can result in epigenetic changes in the offspring and that some of these epigenetic changes have been linked to prostate cancer, the connection between maternal diet and prostate cancer has never been explored. It is anticipated that the maternal diet of high fat will accelerate this process and decrease the latency period to the development of cancer. If successful in complefing our aims this work will advance our understanding of how changes in maternal diet and metabolic bioenergefics in utero have transgenerational effects on the predisposition and development of prostate cancer.