Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

Mammary gland from F1 CO female offspring exhibited enhanced development when transplanted into OID females [OID(CO-MG)], as shown by higher mammary gland area, epithelial branching and epithelial elongation, compared to CO females that received a CO mammary gland [CO(CO-MG)]. Similarly, mammary tumors from F1 CO female offspring transplanted into OID females [OID(CO.T)] displayed improved growth with higher proliferation index and lower apoptotic rates. We also found that granddaughters (F2) from the OID grand-paternal germline showed accelerated tumor growth compared to COxCO granddaughters (F2). Transmission of breast cancer predisposition to the F2 generation through OID male germline was associated with alterations in sperm tRNA fragments (tRF) in both F0 and F1 males. Male mice (F0) were fed either a control (CO) diet or an obesity-inducing diet (OID) for seven weeks and then mated with female mice (F0) reared on a CO diet only. The resulting offspring (F1), also fed exclusively with CO diet, were either used for mammary gland or tumor transplantation surgeries or to generate the F2 generation. To induce the mammary tumors, F1 and F2 female offspring were treated with 7,12 dimethylbenz[a]anthracene (DMBA). Total RNA extracted from F0 or F1 male’s sperm was used for small RNA-Seq analysis.