Transgenerational Effects of Diet: Implications for Cancer Prevention Overview and Conclusions

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1 Transgenerational Effects of Diet: Implications for Cancer Prevention Overview and Conclusions John Milner, Ph.D. Director, USDA Beltsville Human Nutrition Research Center Beltsville, MD

2 AICR s 2013 Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 7-8, 2913 Hyatt Regency Bethesda Name of Speaker: John Milner No Relevant Financial Relationship to disclose except for unrelenting passion for promoting research that relates to diet and health, especially cancer prevention!

3 Transgenerational Response, Diet and Cancer Lillycrop and Burdge (2014) Adv Nutr and Cancer 159: ) There is growing evidence that the environment, particularly variations in diet, during specific developmental periods can induce changes in the epigenome, which are then stably maintained throughout life influencing susceptibility to cancer in later life!

4 The World Is Changing: Not Always for The Better! Projected Deaths (Million) Health, history and hard choices: Funding dilemmas in a fast changing world, Aug 2006 Is there anything that can be done to prevent this from occurring??

5 Transgenerational Epigenetic Effects on Phenotypic Variation and Disease Risk (J. H. Nadeau, Pacific NW Res. Inst). Nelson and Nadeau (2012) Under some conditions, these transgenerational genetic effects can be as frequent and strong as conventional inheritance, and can persist for multiple generations. Growing evidence suggests that RNA mediates these heritable epigenetic changes. The primary challenge now is to identify the molecular basis for these effects, characterize mechanisms and determine whether transgenerational genetic effects occur in humans. Complex Issue! Methylation of CpG islands Changes in the histone code MicroRNA profiling Polycomb Normal mirna Cancer mirna mirna gene CpG island promoter mirna gene CpG island promoter MCpppG MCpppG AAAAA AAAAA Translation Parasramka et al., (2012) Mol Carcinog 51:213-30

6 Effects of Methyl Donor Nutrition on Transgenerational obesity (RAWaterland, Baylor College of Medicine) Hochberg et al (2012) Endocr Rev. 32: Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.

7 LTR Hypomethylated Maternal Supplements with zinc, methionine betaine, choline, folate, B 12 Or Genistein LTR Hypermethylated Bis-Phenol Yellow Mouse High risk cancer, diabetes, obesity & reduced lifespan + Genistein Agouti Mouse Lower risk of cancer, diabetes, obesity and prolonged life Cooney et al. J Nutr 132:2393S (2002); Dolinoy et al. Envir. Health Perspect 114: 567 (2006) Waterland et al Int J. Obes 32:1373 (2008), Romagnolo et al Adv Nutr. 3: 749 (2012)

8 Environmental challenge Maternal protein restriction induces transgenerational epigenetic & phenotypic changes in the offspring (Karen Lillycrop, U. Southampton) Sustained challenge Transient challenge P L O P L O P L O Transient nutritional challenge F0 F1 F2 F3 Generation Sustained nutritional challenge Persistence Persistence Loss The improvement in some traits by the F3 generation, suggests a mechanism by which a single phenotypic trait induced in the F1 generation may eventually be resolved longevity of traits trait and exposure dependent Adjustment phenotypes and epigenotypes do not appear to be stable between generations suggests a mechanism for phenotypic shift over several generations when a population is presented with a sustained environmental change

9 Authors Yr Dietary Change Phenotype Generation Beach et al Mouse F0 zinc deprivation/f1 and F2 no intervention Depressed immune function F2/F3 Burdge et al Rat (Wis) F0 high-energy diet/f1 high-energy diet Methylation status F2/F3 Drake et al Rat (Wis) F0 dexamethasone/f1 and F2 no intervention Birthweight, glucose tolerance and hepatic enzyme activity F2 not F3 Benyshek et al Rat (SD) F0 low-protein diet/f1 and F2 energy restricted Insulin/glucose metabolism F2/F3 Benyshek et al Rat (SD) F0 Low protein/f1 and F2 energy restricted Insulin/glucose metabolism F2 not F3 Harrison and Langley- Evans 2009 Rat (Wis) F0 protein restriction/f1 and F2 no intervention Systolic blood pressure, nephron number, body composition F2 not F3 Dunn and Bale 2011 Mouse F0 high fat/f1 and F2 no intervention Bodyweight and glucose tolerance F2/F3 Frantz et al Mouse F0 low protein/f1 and F2 no intervention Insulin secretion and pancreatic beta cell mass Aiken and Ozanne (2013) Hum. Reprod. Update Sept 29 Epub F2/F3

10 Other Environmental Factors Have a Role! (D. Crews U. Texas) Epigenetics and the Concatenation of Exposures Transgenerational inheritance (germline modification from exposure to fungicide in F0) alters how descendants respond to challenges in own lifetime (stress during adolescence). Lineage Stress

11 Many Factors Can Influence Transgenerational Responses Aiken and Ozanne (2013) Hum. Reprod. Update Sept 29 Epub

12 Concern Worldwide with Obesity Age-adjusted prevalence of obesity, by sex and race and Hispanic origin, among adults aged 20 and over: United States, CDC/NCHS, National Health and Nutrition Examination Survey,

13 Methylating nutrients fed the F0 boars (per kg diet). Estimates of effects on carcass traits of F2 pigs Braunschweig et al. (2012) PLoS ONE 7(2): e30583.

14 Future is to Move to Personalized Nutrition Using information about a person's genetic makeup to tailor strategies for the detection, treatment, or prevention of disease. Using molecular profiling technologies to assess DNA, RNA, protein, and metabolites to tailor medical care. Approach has the promise of delivering the right dose for food to the right indication to the right patient at the right time.

15 Implications: Now and Beyond?? Are there ways to balance growth, development and disease resistance (obesity, heart disease and cancer) or are they independent processes?? Why in controlled conditions in preclinical models is there variation? What other processes are setting the tone for this variation in response? Can selected foods be used to offset the ill-consequences/adaptations associated with environmental contaminations? Could some environmental contaminants actually be beneficial rather than harmful?? Which food components are most important to stabilize Epigenetic Processes? Are the Effects of Human Milk Consumption on Cancer Risk Really an In Utero Effect on Epigenetic Processes?