Abstract 2404: Paternal intake of an obesity-inducing diet before conception modulates the risk of pancreatic cancer in offspring in a mouse model

Pancreatic cancer is a mostly untreatable malignancy, with 5-year survival rates of about 5%. Life-style and dietary factors have been associated with pancreatic cancer risk. Particularly, the consumption of high-fat diets and obesity (and underlying metabolic dysfunction) have been linked to increased susceptibility to this cancer. Recent studies have shown that the paternal diet and life-style can have a significant influence on offspring’s health via epigenetic information transmitted in the germ-line. Paternal overweight before conception has been shown to increase offspring’s susceptibility of developing metabolic diseases and some types of cancer. Here, we evaluated the effects of paternal overweight in the susceptibility of pancreatic cancer in offspring using the P48Cre/+ /KrasG120/+ mouse model of pancreatic cancer. LSL-KrasG120/+ and P48Cre/+ male mice were fed either an obesity-inducing (OID) or control (CO) diet for 8 weeks from weaning to sexual maturity. After this period, OID-fed and CO-fed male mice were housed together with 7 week-old female mice, with free access to CO diet, for 3 days. Pregnant dams were kept on the CO diet during pregnancy and after giving birth. Pups were weaned from mothers at 21 days of age, fed a standard chow diet for the extent of the study and weighed weekly. The offspring of CO or OID fathers were used to study body weight, metabolic parameters and pancreatic cancer development. Fathers fed an OID gained significantly more weight (CO 15.7±1.0g; OID 19.7±1.3g, p=0.02) and had higher leptin levels (p=0.04), compare to CO group fathers. Body weight analyses of OID and CO offspring, showed gender-specific effects. While the OID female offspring had higher weight at birth (p=0.005) and at weaning (p=0.02), compare to CO group, no significant differences were observed between the CO and OID male offspring. Those gender-specific differences were also observed in metabolic parameters such GTT with the OID male, but not female, offspring showing impaired glucose tolerance (p=0.0004) compared to CO. While the monitoring period is still ongoing, 8-week old OID offspring present gender-specific differences in susceptibility to pancreatic cancer: Males OID offspring have higher number/area (481±25; 2.6±0.3) of pancreatic intraepithelial neoplasia (PanIn), compared to CO (359±61; 2.0±0.5). On the other hand, female OID offspring have similar levels of PanIn, but have higher incidence of PDACs compare to CO. In conclusion, an ancestral history of overweight through the paternal lineage may be associated with an increased susceptibility to pancreatic cancer development in adulthood. The mechanisms mediating this effect remain to be elucidated. Citation Format: Raquel Santana Da Cruz, Johan Clarke, Ali Baird, Hong Cao, Carlos Benitez, M. Idalia Cruz, Sonia De Assis. Paternal intake of an obesity-inducing diet before conception modulates the risk of pancreatic cancer in offspring in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2404. doi:10.1158/1538-7445.AM2017-2404