Maternal exposures to environmental factors during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. Here we investigate whether feeding pregnant rats a high-fat (HF)-or ethinyl-oestradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. We show that mammary tumourigenesis is higher in daughters and granddaughters of HF rat dams and in daughters and great-granddaughters of EE2 rat dams. Outcross experiments suggest that the increase in mammary cancer risk is transmitted to HF granddaughters equally through the female or male germ lines, but it is only transmitted to EE2 granddaughters through the female germ line. The effects of maternal EE2 exposure on offspring's mammary cancer risk are associated with changes in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and oestrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through epigenetic means.
Bibliographical noteFunding Information:
This study was supported by the American Cancer Society (116602-PF-09-018-01-CNE to S.deA.), the National Institutes of Health (R03CA150040 to S.deA.; U54CA100970, U54CA149147 and P30CA051668 to L.H.-C.; R21GM085665 and CA160036 to Y.W.; R01CA069065, R01ES017594, P30CA054174 and U54CA113001 to T.H.-M.H.) and by generous gifts from the Cancer Therapy and Research Center Foundation at University of Texas Health Science Center, San Antonio, to T.H.-M.H. We thank Dr Jianhua Xuan of Virginia Tech and Dr Guoqiang Yu of Stanford University for suggestions to the data analysis, and Dr Pasi Pollanen of University of Helsinki, Finland, and Robert Clarke of Georgetown University for suggestions to the manuscript. We also thank the following Lombardi Cancer Center Shared Resources (SR) for their assistance: Animal SR, Histopathology and Tissue SR and Genomics and Epigenomics SR.