It has been proposed that the risk of some chronic diseases in adult life, including cancer, is influenced by exposures acting in early development. Epidemiologic as well as animals studies show that high birth weight-a proxy measure of the in utero nutritional environment-is associated with an overall increase in cancer risk in humans, including cancers of the gastrointestinal track such as pancreatic cancer. Using rodent models, we have shown that prenatal exposure to a high-fat diet increases birth weight and cancer risk in the adult offspring long after the exposure. Others have shown that inadequate parental nutrition and body weight before conception and during pregnancy leads to pancreatic dysfunction in the offspring. One of the proposed mechanisms by which ancestral/prenatal dietary exposures could be linked to cancer phenotypes in the adult offspring is epigenetic reprogramming. We have shown that show that parental consumption of high fat diet reprograms the normal miRNA expression profile in the offspring's pancreas, including miRNAs shown to be altered in pancreatic cancers. Objective/hypothesis: An association between ancestral/prenatal dietary exposures and disease risk, including cancer, been demonstrated by epidemiologic and animal studies. The goal of this proposal is to investigate whether parental consumption of obesity-inducing diet (OID) before conception (fathers) and during pregnancy (mothers) will epigenetically reprogram the offspring's pancreas and increase their risk of pancreatic cancer. We postulate that parental consumption of OID before conception (fathers) and during pregnancy (mothers) will lead to epigenetic reprogramming (DNA methylation and miRNA expression) of the offspring's pancreas and increase their risk of pancreatic cancer.
Specific Aims :
Aim 1 : Determine whether mothers' consumption of OID during pregnancy is associated with increased pancreatic cancer risk in their offspring in adulthood.
Aim 2 : Determine whether consumption of OID by fathers before conception is associated with increased pancreatic cancer risk in their offspring in adulthood.
Aim 3 :
Aim 3 : Determine whether parental consumption of OID leads to epigenetic reprogramming (DNA methylation and miRNA expression) in normal pancreas tissue of their offspring. Study Design: The p48Cre/+ /LSL-KrasG12D/+ mouse model of pancreatic cancer will be used in our experiments. In experiment 1, pregnant females will be fed AIN93G diets containing either 17% (control) or 58% energy from fat (Obesity-Inducing-Diet, OID), respectively, for the extent of pregnancy (21 days). In experiment 2, male mice will be fed a control or OID diet from weaning (3 weeks of age) until sexual maturity (8 weeks of age); at this point all male mice will be switched to contro diet and housed together with female mice. Pregnant dams in experiment 2 will be fed the control diet for the extent of pregnancy (21 days) and after giving birth. Pups born in both experiments will be weaned on postnatal day 21 and fed the AIN93G control diet for the duration of the experiment. Offspring's pancreatic tissues will be collected on post-natal day (PND) 50 and again at 12 months of age. Pancreatic tissue from the p48Cre/+ /LSL-KrasG12D/+ of mice collected at 12 months will be evaluated for pancreatic in situ carcinoma (PanIN) and Pancreatic ductal carcinomas (PDAC) by a pathologist to determine the effects of parental OID consumption on offspring's pancreatic tumor development. Littermates lacking either the p48Cre or LSL-KrasG12D allele will be used as controls. Pancreatic tissue collected on PND50 will be used to for microRNA profiling and global methylation analysis to determine the effects of parental OID consumption on epigenetic programming of the offspring's pancreas.
A better understanding of how parental nutrition can affect the risk of pancreatic cancer in their offspring could have great public health implications for pancreatic cancer prevention. Knowledge of how dietary factors before conception and during pregnancy affect fetal programming of the pancreas could lead recommendations to parents to help to decrease cancer risk in their offspring, tests to identify individuals at risk for pancreatc cancer due to ancestral exposures and exposures in fetal life. Monitoring at-risk individuals closely would allow detection of pancreatic tumors in their earliest, most-treatable stages.
| Fontelles, Camile Castilho; da Cruz, Raquel Santana; Hilakivi-Clarke, Leena et al. (2018) Investigation of Paternal Programming of Breast Cancer Risk in Female Offspring in Rodent Models. Methods Mol Biol 1735:207-220 |
