Ancestral Paternal Diet and Risk of Ovarian and Testicular Germ Cell Tumors
Authors: Carney Elissa Justine , de Assis Sonia 
Published: November 2023

BackgroundDietary patterns and sub‐optimal nutrition have been shown to be a critical lifestyle factor impacting cancer risk. An individual's nutrition during critical windows of the lifespan can not only influence their disease outcome but also that of their offspring. Epigenetic alterations have been evidenced as the mechanism for which parental exposures have been associated with disease in the adult offspring. There has is a great deal of evidence for the impact of maternal dietary exposures on offspring's risk of cancer and emerging evidence for the role of paternal diet prior to conception on risk of disease in the offspring. As such, epigenetic information can be transmitted from one generation to another through germline cells which carry environmental epigenetic memory. Here, we investigated whether a paternal sub‐optimal (low protein) diet can epigenetically reprogram the father's own germline and affect their offspring's germ cell development and cancer riskObjectiveThis study seeks to elucidate the effects of paternal sub‐optimal (low protein) nutrition on cancer risk in offspring and associated molecular mechanisms of disease transmission.MethodsMale mice (n=12) were fed either a control diet (18% protein, CON) or a low protein diet (9% protein, LP) from weaning until sexual maturity. CON or LP‐fed males were mated with females reared on a control diet and euthanized for sperm collection once mating was complete. Sperm DNA was used for DNA methylation analysis by MBD‐seq. Mothers (n=12) and offspring were fed a control diet through their entire lifespan. A sub‐set of male and female offspring was euthanized for tissue collection on post‐natal day 50. Another offspring sub‐set is being monitored for germ‐cell development.ResultsOur analysis of sperm DNA showed that the methylome of LP male sperm is altered compared to CON males. In addition, our preliminary findings show that a paternal suboptimal low protein diet increased incidence in ovarian germ cell tumors in daughters (p = 0.01) and these daughters (n=16) showed greater adult net weight gain than those of fathers fed a control diet (p = 0.0168). Given germ cell tumor development is related to regulation of cell differentiation and epigenetic modifications during gonadal development, our current mechanistic studies target the expression of DNA methylation biomarkers (DNMT1A, DNMT3A) as well as differentiation markers targets (Emx2, Lhx9, Sf1, Wt1, and Tcf21).ConclusionsUsing a mouse model, our study provides evidence that paternal lifestyle and dietary consumption, around the time of conception, reprograms their sperm and their daughters’ risk of developing ovarian germ cell tumor. Studies are underway to determine whether the testicular germ cell tumors will be increased the male offspring and which cellular and molecular changes are associated with the increased germ cell tumor in the offspring of LP males.Support or Funding InformationThis work was partially supported by Training Program in Translational Biomedical Science Fellowship. NIH/NCAT 1TL1 TR001431.