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Developmental Origins of Obesity: The Role of Epigenetics

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This presentation will:
- Review the concept of ‘fetal programming’
- Demonstrate that early life nutritional events may serve as molecular memory of individual in utero experiences
- Show how changes persist following multiple rounds of cell division
- Highlight extrinsic (recapitulation) & Intrinsic (genetic) mechanisms that strongly suggest Intergenerational transmission of traits via epigenetics in humans
- Look at how to best move forward as a scientific and clinical community

Published in: Health & Medicine
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Developmental Origins of Obesity: The Role of Epigenetics

  1. 1. Zach Ferraro, PhD, CEP CIHR Postdoctoral Fellow Chronic Disease Program, Ottawa Hospital Research Institute (OHRI) Clinical Research Associate, Division of Maternal-Fetal Medicine, The Ottawa Hospital CON Obesity Summit 2015 Toronto, ON April 29th, 2015 website: www.DrFerraro.ca twitter: @DrFerraro email: zach.ferraro@gmail.com Developmental Origins of Obesity: Inheritance or recapitulation?
  2. 2. Objectives  Review the concept of ‘fetal programming’  Early life nutritional events may serve as molecular memory of individual in utero experiences  Following multiple rounds of cell division  Highlight extrinsic (recapitulation) & Intrinsic (genetic) mechanisms  Intergenerational epigenetics in humans  Moving forward
  3. 3. Birthweight & Metabolic Syndrome Risk Dutch ‘hunger winter’ 1945 Pettitt DJ. Curr Diab Rep 2001; 1: 78–81; Von Hagens, 2005 Body Worlds; Ong KK. Horm Res 2006; 65: 65–69. SGA & LGA neonates Cardiometabolic Disease
  4. 4. Developmental Origins of NCDs  Nutrition  Weight gain  Smoking  Stress  Toxins  Physical activity  Aging
  5. 5. Gluckman, PD et al. Nat. Rev. Endocrinol. 5, 401-408 (2009). Environmental sensitivity of epigenome throughout life PA? PA? PA? PA?  Plasticity has high energetic cost & is limited to early development  Reengineering tissue/body after phenotype developed is costly
  6. 6. DEVELOPMENTAL PLASTICITY AND CHRONIC DISEASE RISK Gluckman et al. NEJM 2008 Jul 3;359(1):61-73. M Desai et al. International Journal of Obesity (2015) 633 – 641 transmission recapitulation
  7. 7. Epigenetics  “interactions of genes with their environment which bring the phenotype into being” - Conrad Waddington  Mitotic or meiotic heritable alterations in gene expression potential that occur without alterations in DNA sequence Ozanne, S. E. Nat. Rev. Endocrinol. 11, 67–68 (2015) Waddington, C. H. Organizers and Genes (Cambridge U Press, 1940) M Desai et al. International Journal of Obesity (2015) 633 – 641
  8. 8. Regulatory mechanisms  DNA methylation: CH3-attached to CpG islands regulate gene activity. Renders the DNA inaccessible and suppresses gene expression  Histone (covalent) modifications: methylation (Me) or acetylation (Ac) of histones determines the activity of the DNA wrapped around them  microRNA (miRNA): noncoding (19-22 nucleotides) molecules that silence RNA & post-transcriptional regulation of gene expression, bind to complementary sequences in the 3′ end of mRNA and reduce the rate of protein synthesis Gluckman et al. NEJM 2008 Jul 3;359(1):61-73.
  9. 9. DNA Methylation  Dynamic in embryogenesis  Pre-implantation, DNA hypo-Me, > DNA-Me over time  Differentiation & organogensis  Mediated by DNMT  Silenced expression  Role of in utero nutrition/CH3 donors Clarke HJ. Biochem Cell Biol 1992; 70: 856–866; Weaver JR et al. Mamm Genome 2009; 20: 532–543; Desai et al. IJO (2015) 633-41; sciblogs.co.nz; www.discoverymedicine.com
  10. 10. Transgenerational mechanisms Inheritance  Transmitted through genes that are passed from parents to children  The reception of genetic qualities by transmission from parent to offspring Recapitulation  The repetition of an evolutionary or other process during development  Re-occurrence in an individual organism's development (phenotype) resembling the series of ancestral types from which it descended so offspring retraces the phylogeny of its group  Largely environmental  Nutrition  Smoking/Alcohol/Drugs  Physical activity  Stress  Exposure to endocrine disruptors  Etc. R. Waterland (personal communication); Waterland, Annu. Rev. Nutr. 2014;34:337–55; http://ghr.nlm.nih.gov/glossary=geneticinheritance
  11. 11. Maternal Diet in Pregnancy Classic example of CH3-dependent Epigenetic Modification  BPA ↓ methylation of agouti gene  When mothers fed BPA their babies were yellow & obese  When moms fed BPA + CH3-rich foods the offspring were brown & healthy  Supplementation counteracted exposure  Demonstrates how environmental exposure in utero can alter phenotypes in isogenetic pairs Waterland, Annu. Rev. Nutr. 2014;34:337–55 http://learn.genetics.utah.edu/content/epigenetics/nutrition/
  12. 12. Inheritance: direct (epigenetics) vs. indirect (recapitulation)  ‘Soft’ inheritance or recapitulation operates indirectly, via re-creation in each generation of the conditions, which generate certain phenotypic effects in offspring  Extrinsic process  For instance, small mothers might generate small offspring through:  ↓ uterine size in each generation  Behaviours (e.g., smoking or food preference)  Factors that have familial component
  13. 13. Examples Trangenerational Inheritance  Genetically driven  Intrinsic process Recapitulation of Phenotype  Environmentally driven  Early acquisition of language  Extrinsic process R. Waterland (personal communication); Waterland, Annu. Rev. Nutr. 2014;34:337–55 ; M Desai et al. International Journal of Obesity (2015) 633 – 641; P. D. Gluckman et al., (2010). Journal of Developmental Origins of Health and Disease, 1, pp 618
  14. 14. Bariatric BPD surgery ↓ F1 Obesity  N= 49 moms who lost 36% body weight sustained for 12yr & n=111 children (54 BMS and 57 AMS) aged 2.5–26  AMS children: ↓ birth weight ↓ macrosomia ↔ LBW 3x ↓ severe obesity at f/u Extrinsic process  Epigenetic alteration in somatic tissues with required repeat exposures each generation  Altered maternal phenotype via nutrient restriction Smith, 2009. J Clin Endocrinol Metab, 94(11):4275–4283
  15. 15. Human evidence of transmission: Famine & Overnutrition  In the Dutch Famine (1944–1945) cohort, 60 yo adults prenatal exposure to famine showed hypo- Me of whole blood IGF2 gene  Hyper-Me of 2 obesity-related non-imprinted genes (IL-10, leptin) vs. unexposed, same-sex siblings  Hypo-He at IGF2 DMR associated with paternal obesity  reprogramming of imprint marks during spermatogenesis
  16. 16. Human evidence of transmission: GWG  (CpG) Dinucleotide site Me in newborn cord blood DNA from 88 participants Avon Longitudinal Study of Parents and Children  >GWG in T1 (0-18 wks) associated with ↑ DNA-Me in 4 CpG sites at MMP7, KCNK4, TRPM5 and NFKB1 genes  Newborns of mom with excess GWG ↑ DNA-Me at MMP7 CpG site vs. IOM-recommended GWG
  17. 17. A clean slate?  Following fertilisation, global DNA methyl tags are erased  By blastocyst stage (implantation), the genome is hypomethylated  After blastocyst hatching, DNA methylation levels are re-established in a lineage specific manner  trophectoderm-derived cells remain hypo-Me vs. inner-cell mass-derived cells  Placenta is likely to show the > evidence of environmental ‘footprint’ or ‘memory’ of environmental insult during pregnancy  tissue most exposed to environmental factors during pregnancy Placenta 33 (2012) 959-970
  18. 18. Persistent epigenetic marks  -CH3 marks not completely erased in early development & gametogenesis  -CH3 sites preserved, replicated & DNA + histones passed along during cell division  Effects stem cell fate & gene expression throughout life Fan S et al. Biochem Biophys Res Commun 2009; 383: 421–425; Flanagan JM et al. Am J Hum Genet 2006; 79: 67–84;Trasler JM. Mol Cell Endocrinol 2009; 306: 33–36; Desai et al. IJO (2015) 633 – 641
  19. 19. Animal evidence of inheritance Glucose intolerance & Obesity Jimenez-Chillaron et al. Diabetes 58:460–468, 2009.  C & UN F1 females were mated at age 2 months with nonsibling F1-C or F1-UN males to generate 4 experimental groups  Adverse neonatal exposure (UN) leads to F1, F2 & likely F3 obesity & IGT despite ad libitum feeding during second pregnancy  Different aspects of these phenotypes transmitted via maternal lineage (obesity), the paternal lineage (LBW), or both (glu intolerance) 6mo males 4mo males
  20. 20. Animal evidence of inheritance Glucose intolerance & Obesity Jimenez-Chillaron et al. Diabetes 58:460–468, 2009.  C & UN F1 females were mated at age 2 months with nonsibling F1-C or F1-UN males to generate 4 experimental groups  Adverse neonatal exposure (UN) leads to F1, F2 & likely F3 obesity & IGT despite ad libitum feeding during second pregnancy  Different aspects of these phenotypes transmitted via maternal lineage (obesity), the paternal lineage (LBW), or both (glu intolerance) 6mo males 4mo males IGT in F1 & F2 generations is linked to impaired beta-cell function partly explained by dysregulation of Sur1 expression
  21. 21. Germline transmission  Suboptimal diet (UN) during fetal development altered germ-cell DNA methylome of male offspring when nourished normally from weaning  Prenatal UN compromises male germline epigenetic reprogramming & permanently alters sperm DNA-Me in adult offspring  DNA-Me in late-gestation somatic tissues of subsequent generation was not observed  Altered gene expression in F2  Gamete methylation may be ‘memory’ early in utero & developmental exposures Radford, E. J. et al. Science 345, 1255903 (2014); Ozanne, S. E. Nat. Rev. Endocrinol. 11, 67–68 (2015)
  22. 22. Human evidence of inheritance Dutch hunger winter  Offspring born during the famine were smaller than average and risk of having smaller babies persisted 2 generations (F1 & F2) Emanuel I, Filakti H, Alberman E, Evans SJ. Intergenerational studies of human birthweight from the 1958 birth cohort. 1. Evidence for a multigenerational effect. Br J Obstet Gynaecol 1992; 99: 67–74; Desai et al. IJO (2015) 633-41.
  23. 23. Human evidence of inheritance Dutch hunger winter  Offspring born during the famine were smaller than average and risk of having smaller babies persisted 2 generations (F1 & F2) Emanuel I, Filakti H, Alberman E, Evans SJ. Intergenerational studies of human birthweight from the 1958 birth cohort. 1. Evidence for a multigenerational effect. Br J Obstet Gynaecol 1992; 99: 67–74; Desai et al. IJO (2015) 633-41.  Programmed obesity via alterations in DNA methylation  Histone modifications & changes in chromatin structure not demonstrated in humans
  24. 24. Conflicting evidence  Maternal diet during the F0 pregnancy affected the F2 BW, independent of the F1 BW Lumey LH. Paediatr Perinat Epidemiol 1992; 6: 240–253; Stein & Lumey. Hum Biol 2000; 72: 641–654; Desai et al. IJO (2015) 633-641.  BW of women with T1 exposure ↑154 g & BW of women T3 exp ↓ 251 g vs. BW of unexposed  Maternal prenatal famine exposure does not affect the association between maternal and offspring BW VS.
  25. 25. Conflicts cont’d Maternal Effect Persists into F2?  F1 women exposed to famine as fetuses had F2 babies with ↑ neonatal adiposity & poor adult health No Maternal, but Paternal effect?  No transgenerational effects if the grandmother had been UN  ↑ adiposity in offspring of prenatally UN fathers Painter et al. BJOG 2008; 115: 1243–1249; Veenendaal et al. BJOG 2013; 120: 548–553; Desai et al. IJO (2015) 633–41.
  26. 26. Conflicting results  Different data collection methods  Early studies based on record retrieval and relied on parents' recall of their offspring's size at birth and later health status  Phone surveys  Questionnaires  Interviews  Newer studies, the offspring were directly contacted to assess their body composition & health Desai et al. IJO (2015) 633–641.
  27. 27. Human evidence lacking  “True transgenerational transmission [in humans] should be demonstrable by effects [+/-] induced in F0 persisting to the F3 generation, but such long-term studies are expensive and not frequently performed” Sir Peter Gluckman Gluckman, PD et al. (2009). Nat. Rev. Endocrinol. 5, 401-408. Gluckman, PD et al. (2010). J DOHD, 1, p 6-18. PA? PA? PA? PA?
  28. 28. In utero milieu, fetal plasticity & chronic disease risk Gluckman et al. NEJM 2008 Jul 3;359(1):61-73. M Desai et al. International Journal of Obesity (2015) 633 – 641 Role of nutrition
  29. 29. In utero milieu, fetal plasticity & chronic disease risk Gluckman et al. NEJM 2008 Jul 3;359(1):61-73. M Desai et al. International Journal of Obesity (2015) 633 – 641 transmission recapitulation Maternal nutrition affects F1 gene methylation a. Immune response b. Adipogenesis c. Lipogenesis = metabolic abnormalities
  30. 30. In utero milieu, fetal plasticity & chronic disease risk Gluckman et al. NEJM 2008 Jul 3;359(1):61-73. M Desai et al. International Journal of Obesity (2015) 633 – 641 transmission recapitulation
  31. 31. Predictive adaptive response  Human example  Thickened heel pads on the feet of infants at birth  prediction is reliable & assimilated into genomic determinants  No evolutionary explanation for these which does not involve an anticipatory component  Classic example of a developmental process fixed in the genome, yet it is a predictive response  Exact mechanisms remains to be establish P. D. Gluckman, M. A. Hanson and T. Buklijas (2010). A conceptual framework for the developmental origins of health and disease. Journal of Developmental Origins of Health and Disease, 1, pp 618
  32. 32. Moving forward…  Quantify the influence of genotype, ENV, & intxn with human epigenome  Most compare DNA methylation to phenotype independently of genotype  Genotype is an essential factor in these relationships  Assess the degree to which env influences are moderated by genotype Teh, 2014 Genome Research 24:1064–1074
  33. 33. Acute exercise remodels promoter–Me in human muscle  Effects of chronic exercise?  Muscle  Germ cells  Behavioural-induced changes persistent across generations?  Effect of postnatal intervention on offspring ‘exposed’ to suboptimal env? Barres et al., 2012. Cell Metabolism 15, 405–411.
  34. 34. Conclusions  Phenotype transmission demonstrated  Animals (DNA-Me & Histone Mods)  Humans (DNA-Me + familial components)  How does under- & over-nutrition produce similar phenotypes?  Predictive adaptive response?  How does an acute insult persist across generations?  Need to establish causal relationships between loci-specific epigenetic marks in response to adverse ENV & metabolic adult disease phenotypes  Are epigenetic marks ‘erasable’ with intervention?  Can the beneficial effects be inherited?  Similar or different mechanisms?  Developmental origins of health and disease
  35. 35. Thank you. Acknowledgements:  CIHR Allied care provider Fellowship, Human Development, Child & Youth Health  Dr. Erin Keely – The Ottawa Hospital Endocrinology/Metabolism  Dr. Kristi Adamo & Lab group – CHEO  Dr. Laura Gaudet – The Ottawa Hospital MFM  Dr. Mark Walker – The Ottawa Hospital MFM  Dr. Karen Fung Kee Fung – The Ottawa Hospital MFM  Dr. Felipe Moretti – The Ottawa Hospital MFM  The late Dr. Andree Gruslin – The Ottawa Hospital MFM/OHRI  Adamo Lab Staff & Students – CHEO  CON & CON-SNP staff, students, & volunteers  Everyone in attendance For more discussion follow me on twitter: @DrFerraro

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