fasd and epigenetics

1. Aboriginal FASD and CNP WorkshopToronto, 6th. March, 2013 Barry Stanley. www.barrystanleyfasd.com

2. DEFINITIONS PRENATAL – Existing or Occurring Before Birth Phenotype - The observable physical or biochemical characteristics of an organism, as determined by both genetics and environment Diagnosis – The identification of the nature of a disease or injury by history, examination and laboratory data. Genotype – The genetic makeup of an organism or a group of organisms. GENETICS – The study of heredity and the variation of inherited characteristics. EPIGENETICS – The study of changes in gene function [expression] That do not involve changes in DNA sequence. STEM CELL – develop into specialized cells or replenish some specialized cells- can replicate [ reproduce] indefinitiely. PROGINATOR CELL - more specialized- can only replicate a few times. Nucleic Acids – DNA and RNA Nucleotides – are what the Nucleic Acids are formed from.

3. ALCOHOL • -use – 12,000 Years • Negative effects –individual and • society. • Rare references to effects • of PAE – 4,000 years, until • the last 300 years Generations – approx. 600 - 12,000 years 200 – 4,000 years

4. Epigenetcs, Alcohol and FASD “Now is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning. Winston Churchill

5. ALCOHOL – 2013 • Reflects the historical perspective • Research on alcohol and alcohol related issues • cost – millions annually. • all related to the developed brain. • negligibly less on PAE exposure. • the role of PAE still largely ignored by the alcohol research community the medical profession and governments. • Pubmed • - 138,000 results for “publications on alcohol” • - 35,300 results for “publications on alcoholism • - 397 results for “publications on Fetal Alcohol Spectrum Disorder • - 2,550 results for “publications on Fetal Alcohol Syndrome” • - 2,320 results for “publications on Prenatal Alcohol Exposure”. • ”

6. Genetics – D.N.A. DNA Structure The long, stringy DNA that makes up genes is spooled within chromosomes inside the nucleus of a cell. (Note that a gene would actually be a much longer stretch of DNA than what is shown here.) DNA consists of two long, twisted chains made up of nucleotides. Each nucleotide contains one base, one phosphate molecule and the sugar molecule deoxyribose. The bases in DNA nucleotides are adenine, thymine, cytosine and guanine.

7. Genetics – R.N.A. Ribonucleic acid [RNA] is a ubiquitous family of large biological Molecules that perform multiple vital roles in the coding, decoding, Regulation, and expression of genes. Together with DNA, RNA Comprises the nucleic acids, which along with proteins, constitute Three major macromolecules essential for all known forms of life.

8. Increasing awareness of the Consequences of Prenatal Alcohol Exposure • BEFORE our understanding of Epigenetics • > Clinical presentation and Psychological Assessments • > Gross anatomy and imaging. • > Female consumption > FASD [FAS, pFAS, ARND] • Now with our understanding of Epigenetics • > Micro-anatomy and advanced imaging. • > Cellular level studies – animal models • > Genetics and Epigenetics • > Female and Male alcohol consumption, • present and previous generations.

9. PLASTICITY AND SOME OF THE REGIONS OF THE BRAIN EFFECTED BY PAE

10. Brain Size and Cortical Thicknessand the Glial Cell

11. Corpus Callosum

12. Amygdalae

13. Thalamus

14. Hypothalamus

15. Hypothalamic-Pituitary-Adrenal Axis

16. Hippocampus

17. Prefrontal Cortex

18. Cerebellum

19. Basal Ganglia

20. Thymus

21. Cell Structure, Function andNeurotransmitters-some of the effects of PAE

22. Methylation, Acetylationleading to • impaired IGF receptor function • glial and astrocyte cell dysfunction > impaired neuron migration • impaired development of neurotransmitter receptors • glucose uptake and transport • suppression of antioxidants -accumulation of free radicles • impaired cell membrane function > calcium ion exchange • abnormal protein formation > ubiquitous effects on brain function • reduced proliferation of neural progenitor cells • abnormalities of endocrine function and neuroendocrine regulation • impaired immune function and stress response > deficiencies in number • and function of white blood cells • cell death > impaired apoptosis and necrosis

23. Neurotransmitters, Neuromodulator Systems and Hormones • - Dysregulation of Insulin Growth Factors • - NMDA glutamate receptors > synaptic plasticity and memory systems • GABA [a,b,c] gamma-aminobutyric acid > C.N.S. inhibitory [and excitatory during development] neurotransmitter > cell membrane function • - Reduced CholineAcetyltransferase > decreased acetylcholine > Hippocampus > memory – Neuromodulator > platicity, arousal, reward, sensory perceptions and • sustained attention. • Hydroxylase > mood, appetite, sleep, memory, learning • - Decreased Dopamine receptor function > reward learning, reward seeking. Decreased levels of Dopamine in the Prefrontal Cortex. • - Hypothalamic-Pituitary Axis > differing activation > stress responsiveness. Male/Female differential stress responsiveness > protective role of estrogens. • Inhibition of Serotonin synthesis and expression of serotonin precursor, tryptophan

24. Neurotrophic Factors and Adult Neurogenesis Proteins that control the development, survival and function of nerve cells [ neurons ] They trigger the development of neurons from progenitor cells Neuronal progenitors persist in the adult brain, but die. Neurotrophic factors might be used to develop those cells for repair of damaged nerve cells.

25. FASD and COMORBIDITY and Diagnosis Attention, Mood and Personality Disorders Addictions Cancer Infectious Diseases

26. EPIGENETICS and FASD

27. EPIGENETICS and FASD

28. EPIGENETICS and FASD

29. Preconception - paternal, 9 weeks exposure and maternal - 10 weeks exposure Preimplantation – fertilized egg > implantation > first two weeks of pregnancy - > placenta > growth retardation Gastrulation – 3rd to 8th week of pregnancy > most sensitive – stem cells > cellular differentiation – birth defects. transient exposure to alcohol during the pre-implantation and early gastrulation periods of development may have permanently altered gene expression patterns in basic cell-signaling pathways involved in limbic/ neuroendocrine development, resulting in reprogramming of the hypothalamic-pituitary-adrenal (HPA) axis and stress- related autonomic and behavioral reactivity in these infants. On/off switch effect

30. Perinatal Adaptation – fetal susceptibility and protection • second and third trimesters – • separate from early embryogenesis • Adaption increases fetus survival but leads to adult disease – through the • epigenetic regulation of gene expression – rheostat effect, rather than off/on • switch effect. • Fetal insults – anoxia, nutritional > maternal or utero-placental insufficiency • > Adult metabolic disorders, cardiovascular disease, insulin resistance and obesity. • Consequently the later effects of PAE will tend to vary ?

31. more likely to be mechanistically important in the epigenetic regulation of perinatal adaptability. CANDIDATE GENES AND MARKERS

32. > The brain is a complex system PAE creates a complex chaotic system Manipulation of a complex system by a simple system leads to unintended consequences The more complex the system is the greater the unintended consequences

33. Epigenetics explains the many puzzling and contradictory observations about FASD. • The brain dysfunctions of PAE are only part of the disease effect of PAE • The factor of the mother drinking in a pregnancy no longer stands alone. • The term “prenatal” for any given pregnancy has to include alcohol exposure from both parents, including previous generations. • The nomenclature of FASD needs to be changed to reflect our understanding of epigenetics without diminishing acknowledgment and treatment of FASD, as occurs at present. • Disorders of mood and personality need to be redefined in the context of environmental factors that cause changes in gene expression- alcohol being a major factor. • Society needs to be aware that the manipulation of gene expression will result in harmful unintended consequences. • CONCLUSIONS