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“Prenatal and Postnatal Epigenetic Programming ( PreP and PEP):

“Prenatal and Postnatal Epigenetic Programming ( PreP and PEP): Implications for GI, Immune and Neuronal Function in Autism”. Richard Deth, PhD Northeastern University Boston, MA. Overview Oxidation and antioxidant metabolism Autism: An epigenetic disorder

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“Prenatal and Postnatal Epigenetic Programming ( PreP and PEP):

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  1. “Prenatal and Postnatal Epigenetic Programming (PreP and PEP): Implications for GI, Immune and Neuronal Function in Autism” Richard Deth, PhD Northeastern University Boston, MA

  2. Overview • Oxidation and antioxidant metabolism • Autism: An epigenetic disorder • Prenatal epigenetic programming (PREP) • Postnatal epigenetic programming (PEP) • Brain-specific redox features • Redox signaling in the immune response • Gluten and casein-derived opiate peptides

  3. Viewing Life Through Redox Glasses • Oxidation: Loss of an electron • Reduction: Gain of an electron

  4. Life: The evolved ability to resist oxidation Death: The inevitable outcome of oxidation Evolution: Gradual acquisition and manifestation of novel adaptive strategies to survive oxidation Development: Programmed and progressive changes in gene expression, driven by changes in oxidation status, via epigenetic mechanisms

  5. As oxygen became more plentiful, evolution was driven by the ability to adapt and to resist oxidation. Earliest life appears arose at hydrothermal vents emitting hydrogen sulfide. H2S From Paul G. Falkowski; Science311 1724 (2006)

  6. EVOLUTION = LAYER UPON LAYER OF USEFUL ADAPTIVE RESPONSES TO OFFSET THE THREAT OF OXIDATION The ability to control oxidation is at the core of evolution Each addition is strengthened because it builds on the solid core already in place.

  7. Ergo: • Life, from beginning to end, depends upon sufficient levels of antioxidant. • Disorders and diseases commonly reflect an interference • with the capacity to resist oxidation. • Agents or organisms which interfere with antioxidant capacity • will disrupt normal development and cause diseases. • Metabolic treatments that restore and sustain antioxidant • capacity will be effective in reversing many disorders and diseases.

  8. The available level of antioxidant (GSH) controls the level of aerobic metabolism and ATP formation = Redox Signaling Selenoproteins Antioxidant Supply Glucose NADPH Glutathione NADH+ O2 + 4H+ 2H2O + ATP formation Reactive Oxygen Species ROS [Antioxidant] Oxidative Cellular Damage No Damage Glutathionylation of Complex I

  9. Water Oxygen e.g ROS Reducing equivalents are passed from selenium to sulfur and from sulfur to oxygen e- Sulfur e.g. GSH e- NADPH Selenium e.g. Thioredoxin Reductase Hydrogen (Reducing Equivalent) Illustrations from: Bentor, Yinon. Chemical Element.com

  10. 28%↓ 36%↓ 38%↓ Autism is associated with inadequate levels of glutathione and impaired methylation

  11. Eleven studies showing significantly lower GSH in autism

  12. The available level of intracellular cysteine is rate-limiting for GSH synthesis GLUTATHIONE (GSH) Glycine γ- Glutamylcysteine Glutamate [Cysteine]

  13. Cysteine for glutathione synthesis can be provided by either transsulfuration of homocysteine or by uptake from outside the cell NEURONAL CELL

  14. Absorption and distribution of cysteine/cystine

  15. The GI tract is a critical site for immune cell activation, especially during postnatal development. Decreased cysteine uptake can promote oxidative stress and inflammation, resulting in epigenetic effects which can last throughout life. Postnatal Epigenetic Programming (PEP) Prenatal Epigenetic Programming (PREP)

  16. Adenosine Methionine Synthase ATP PP + Pi Oxidative Stress A reversible reaction! SAH HCY ( - ) ( - ) MethylTHF ( + ) ~1,000 MethylationReactions via 209 MTases • METHYLATION IS INHIBITED BY OXIDATIVE STRESS THF Vitamin B12 (Cobalamin) MET SAM ( ) SAM SAH Global methylation = DIETARY PROTEIN

  17. Methylation of DNA and histones is fundamental to epigenetic regulation of gene expression during development

  18. Regulation of gene expression during development X Transcription Factor Regulation: Growth Factors Start site for mRNA synthesis Neurotransmitters Hormones TF CpG CpG TF binding region Gene sequence DNA RNA polymerase mRNA Transcription Translation Protein (e.g. enzyme) Epigenetic Regulation: Me SAM Me MBDP (e.g. MeCP2) HMT Histone proteins Me Me SAM CpG CpG DNMT Me X No mRNA Me TF binding region DNA DNA + Histone = Heterochromatin Genes are silenced and transcription is blocked

  19. Epigenetic changes in gene expression are the Primary mechanism underlying development

  20. Epigenetic marks change in response to the environment and contribute to adaptive capabilities gained through evolution

  21. Essentially: • Epigenetics = A memory system • linked to gene expression • responsive to redox status • driver of development • active in all cell types • active at all ages • capable of transgenerational effects • Agents which interrupt antioxidant • and/or methylation pathways will • interfere with the many roles of • epigenetic regulation.

  22. PrEP PEP Postnatal Epigenetic Programming Prenatal Epigenetic Programming Maternal Metabolism Maternal Nutrition Maternal Toxic Exposures Placental Function Genetic Factors Breast Milk (Formula) Toxic Exposures Physical Experiences Emotional Experiences BIRTH

  23. GI tract absorption of cysteine is critical for postnatal epigenetic programming (PEP)

  24. Odds of autism decrease with increasing duration of breastfeeding

  25. Data from Waly et al. (In Prep)

  26. Folate and B12 Levels are Markedly Lower Data from Waly et al. (In Prep)

  27. Thus malnutrition-based autism in Oman shares a similar metabolic profile to autism in the U.S. i.e. Oxidative stress and impaired methylation are fundamental features of autism Data from Waly et al. (In Prep)

  28. Growth factors stimulate cysteine uptake, providing a powerful mechanism to regulate redox and methylation Glial Cells (Astrocytes) Neurotrophic Growth Factors Cysteinylglycine Cysteine GSH EAAT3 GSH GSSG ( + ) PI3-kinase γ-Glutamylcysteine Cysteine EAAT3 Cystathionine Adenosine SAH HCY ( - ) MethylTHF • >150 • Methylation • Reactons Methionine Synthase THF SAM MET ATP PP+Pi

  29. FOOD-DERIVED OPIATE PEPTIDES

  30. A1 casein contains HIS at position 67 and is readily hydrolyzed to BCM7 A2 casein contains PRO at position 67 and is resistant to hydrolysis

  31. IC50 values 62 nM 14 nM 16 nM 4 nM 7.022 nm

  32. Bovine casomorphin 7 decreases cysteine, glutathione, and methionine levels in neuronal cells. Homocysteine and cystathionine levels are increased. • This is consistent with: • 1. Decreased cysteine uptake • 2. Decreased GSH synthesis • 3. Lower activity of methionine • synthase • 4. Increased transsulfuration

  33. Opiate peptides can inhibit cysteine uptake and promote oxidative stress GI Tract Blood Brain GI Blood Epithelial Brain Gluten/Casein Cell Barrier Astrocytes ↓GSH ↓GSH ↓Cystine Cysteine Cysteine ↓Cysteine - ↓Cysteine ( ) Opiate Peptides ↓Cystine ↓Cystine Gluten/Casein ( - ) Opiate Peptides ↓Cysteine ↓GSH Oxidative Stress ↓ Methylation Wheat/Milk Neurons ↓Cysteine ↓Cystine Liver

  34. Effects of morphine and bovine and human casomorphin-7 peptides on redox/methylation gene expression in human neuronal cells

  35. Breast Milk Constituents Can Exert Epigenetic Effects BREAST MILK Casein Growth Factors DHA GI Peptidases Beta Casomorphin Modulation of GI cysteine uptake Systemic availability of cysteine Δ Cellular Redox Status Δ Methylation Status Δ Gene Expression Brain GI Tract Immune System

  36. Terminal Ileum is critical site for absorption of cysteine and selenocysteine via the EAAT3 transporter

  37. Terminal ileum is also critical for vitamin B12 and folic acid absorption

  38. Antioxidant Availability (i.e. cysteine and GSH) Metabolic Activity (Antioxidant demand) Homeostatic Equilibrium ↑Metabolic Activity (Higher antioxidant demand) ↓Antioxidant Availability (Low cysteine and GSH) Adaptive Epigenetic Changes Oxidative Stress →

  39. Autism-associated changes in gene expression in terminal ileum Data from Drs. Steve Walker and Arthur Krigsman

  40. A preliminary qRT-PCR evaluation of redox/methylation-related gene expression In blood-derived RNA of autistic vs. control subjects

  41. The brain extracellular environment (CSF) has more than 10-fold less cysteine than plasma!! Blood-Brain Barrier BRAIN BLOOD Neurons Astrocytes [GSH] = 0.21mM [GSH] = 0.91mM [GSH] = 3.5 μM [CYS] [CYS] =22 μM [CYS] [CysGly] [GSH] CSF [GSH] = 0.3 μM [CYS] = 2.2μM 12-fold lower 10-fold lower Data from: Castagna et al. Neurology, 45:1678-83 (1995) and Sun et al. J Biol Chem, 281:17420-31 (2006).

  42. Redox and Methylation Pathways in Neurons

  43. Methionine synthase mRNA in cortex progressively decreases with increasing age in normal subjects 28 weeks of fetal development 400-fold

  44. The level of methionine synthase mRNA is reduced by 50% in postmortem brain of autistic subjects vs. age-matched controls

  45. Redox signaling plays a central role in the immune response Dendritic cells release GSH, similar to astocytes in brain Effector T-cells take up cysteine, similar to neurons in brain Antibody production Antigen EAAT3 provides Cysteine uptake Regulatory T-cells compete with Teff for cysteine and restrict the immune response

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