Abstract
While many studies have shown that maternal weight and nutrition in pregnancy affects offspring’s breast cancer risk, no studies have investigated the impact of paternal body weight on daughters’ risk of this disease. Here, we show that diet-induced paternal overweight around the time of conception can epigenetically reprogram father’s germ-line and modulate their daughters’ birth weight and likelihood of developing breast cancer, using a mouse model. Increased body weight was associated with changes in the miRNA expression profile in paternal sperm. Daughters of overweight fathers had higher rates of carcinogen-induced mammary tumors which were associated with delayed mammary gland development and alterations in mammary miRNA expression. The hypoxia signaling pathway, targeted by miRNAs down-regulated in daughters of overweight fathers, was activated in their mammary tissues and tumors. This study provides evidence that paternal peri-conceptional body weight may affect daughters’ mammary development and breast cancer risk and warrants further studies in other animal models and humans.
Highlights
While many studies have shown that maternal weight and nutrition in pregnancy affects offspring’s breast cancer risk, no studies have investigated the impact of paternal body weight on daughters’ risk of this disease
Recent studies suggest that the male germline can be epigenetically reprogrammed due to life-style and environmental exposures in humans[27] and animals[9,10]
We found that paternal overweight around the time of conception was associated with epigenetic changes in the father’s germline and with higher birth weight, altered mammary gland development and increased mammary cancer risk in their female offspring
Summary
Effect of dietary consumption on paternal body weight and sperm miRNA expression profile. In order to determine the effects of high birth weight and ancestral overweight on mammary gland development, we analyzed normal mammary tissue of female offspring after puberty onset, on post-natal day (PND) 50. This is when the mammary tissue is most susceptible to carcinogen induced initiation of breast cancer in rodents. We observed no change in the expression of ER- α, but detected higher levels of MAPK activity in OID mammary tissue than in the controls Neither of those pathways was altered in OID mammary tumors (Figure S2).
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