Maternal high fat diet during pregnancy induces similar miRNA changes in F1 generation male germ cells and F3 generation female mammary glands (LB309)

Abstract

Maternal dietary exposures during pregnancy can initiate epigenetic inheritance of increased breast cancer risk, perhaps including changes in miRNAs. In this study, we investigated whether the epigenetic inheritance occurs through paternal lineage by studying changes in miRNAs in the male germ cells. Pregnant C57BL/6NTac mothers were fed either a control (CON, 6% corn oil) or isocaloric high n‐6 polyunsaturated fat (HF) diet (18% corn oil) between gestation days 8 and 21. Offspring in the subsequent generations (F1‐F3) were not exposed to any further dietary modifications and were kept on CON diet. F3 female HF offspring exhibited significantly higher mammary tumor incidence (50% had mammary tumors) than the control offspring (32%). We extracted germ line RNA from the sperm cells of 50‐day‐old F1 male offspring and RNA from the mammary glands of F3 female offspring. Expression levels of miRNAs were examined between CON and HF sperm cells and between CON and HF exposed mammary glands. A total of 10 miRNAs were significantly different (p<0.05) in the germ cells of F1 male offspring and 25 miRNAs were different in the mammary glands of F3 females. In addition, four miRNAs were down‐regulated in both F1 male germ cells and F3 mammary glands in the HF offspring: miR‐451, miR‐486, miR‐877, and snoRNA‐202. Down‐regulation of miR‐451 and miR‐486 have been linked to increased susceptibility to many cancers, including breast cancer. Further, recent findings suggest that snoRNAs are new players in cancer. Our study shows that miRNA modifications in F1 generation male germ cells, caused by in utero exposure to a high fat diet, might be carried through to their granddaughters in the F3 generation.Grant Funding Source: Supported by NCI RO1