fasd epigenetics

Aboriginal FASD and CNP Workshop Toronto, 6th. March, 2013

Barry Stanley. www.barrystanleyfasd.com

PRENATAL – ExisMng or Occurring Before Birth Phenotype -‐ The observable physical or biochemical characterisMcs of an organism, as determined by both geneMcs and environment Diagnosis – The idenMficaMon of the nature of a disease or injury by history, examinaMon and laboratory data. Genotype – The geneMc makeup of an organism or a group of organisms. GENETICS – The study of heredity and the variaMon of inherited characterisMcs. EPIGENETICS – The study of changes in gene funcMon [expression] That do not involve changes in DNA sequence. STEM CELL – develop into specialized cells or replenish some specialized cells-‐ can replicate [ reproduce] indefiniMely. PROGINATOR CELL -‐ more specialized-‐ can only replicate a few Mmes. Nucleic Acids – DNA and RNA NucleoMdes – are what the Nucleic Acids are formed from.

DEFINITIONS

ALCOHOL

-‐use – 12,000 Years -‐ NegaMve effects –individual and society. Rare references to effects of PAE – 4,000 years, unMl the last 300 years

GeneraMons – approx.

600 -‐ 12,000 years 200 – 4,000 years

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

ALCOHOL – 2013

Reflects the historical perspecMve

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 sMll largely ignored by the alcohol research community the medical profession and governments.

Pubmed -‐ 138,000 results for “publicaMons on alcohol” -‐ 35,300 results for “publicaMons on alcoholism -‐ 397 results for “publicaMons on Fetal Alcohol Spectrum Disorder -‐ 2,550 results for “publicaMons on Fetal Alcohol Syndrome” -‐ 2,320 results for “publicaMons on Prenatal Alcohol Exposure”.

”

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 nucleo@des. Each nucleo@de contains one base, one phosphate molecule and the sugar molecule deoxyribose. The bases in DNA nucleo@des are adenine, thymine, cytosine and guanine.

GeneMcs – D.N.A.

GeneMcs – R.N.A.

Ribonucleic acid [RNA] is a ubiquitous family of large biological Molecules that perform mulMple vital roles in the coding, decoding, RegulaMon, and expression of genes. Together with DNA, RNA Comprises the nucleic acids, which along with proteins, consMtute Three major macromolecules essenMal for all known forms of life.

Increasing awareness of the Consequences of

Prenatal Alcohol Exposure •  BEFORE our understanding of EpigeneMcs

•  > Clinical presentaMon and Psychological Assessments

•  > Gross anatomy and imaging.

•  > Female consumpMon > FASD [FAS, pFAS, ARND]

•  Now with our understanding of EpigeneMcs

•  > Micro-‐anatomy and advanced imaging.

•  > Cellular level studies – animal models

•  > GeneMcs and EpigeneMcs •  > Female and Male alcohol consumpMon,

•  present and previous generaMons.

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

Brain Size and CorMcal Thickness and the Glial Cell

Corpus Callosum

Human brain 8

The corpus callosum, a nerve bundle connecting the two cerebral hemispheres, with thelateral ventricles directly below

The two cerebral hemispheres areconnected by a very large nerve bundlecalled the corpus callosum, whichcrosses the midline above the level ofthe thalamus. There are also two muchsmaller connections, the anteriorcommissure and hippocampalcommissure, as well as manysubcortical connections that cross themidline. The corpus callosum is themain avenue of communication

between the two hemispheres, though. It connects each point on the cortex to the mirror-image point in the oppositehemisphere, and also connects to functionally related points in different cortical areas.

In most respects, the left and right sides of the brain are symmetrical in terms of function. For example, thecounterpart of the left-hemisphere motor area controlling the right hand is the right-hemisphere area controlling theleft hand. There are, however, several very important exceptions, involving language and spatial cognition. In mostpeople, the left hemisphere is "dominant" for language: a stroke that damages a key language area in the lefthemisphere can leave the victim unable to speak or understand, whereas equivalent damage to the right hemispherewould cause only minor impairment to language skills.A substantial part of our current understanding of the interactions between the two hemispheres has come from thestudy of "split-brain patients"—people who underwent surgical transection of the corpus callosum in an attempt toreduce the severity of epileptic seizures. These patients do not show unusual behavior that is immediately obvious,but in some cases can behave almost like two different people in the same body, with the right hand taking an actionand then the left hand undoing it. Most such patients, when briefly shown a picture on the right side of the point ofvisual fixation, are able to describe it verbally, but when the picture is shown on the left, are unable to describe it, butmay be able to give an indication with the left hand of the nature of the object shown.

Amygdalae

Thalamus

Hypothalamus

Hypothalamic-‐Pituitary-‐Adrenal Axis

Hippocampus

Prefrontal Cortex

Cerebellum

Basal Ganglia

Thymus

Cell Structure, FuncMon and Neurotransmifers

-‐some of the effects of PAE

MethylaMon, AcetylaMon leading to

  impaired IGF receptor funcMon   glial and astrocyte cell dysfuncMon > impaired neuron migraMon   impaired development of neurotransmifer receptors   glucose uptake and transport   suppression of anMoxidants -‐accumulaMon of free radicles   impaired cell membrane funcMon > calcium ion exchange   abnormal protein formaMon > ubiquitous effects on brain funcMon   reduced proliferaMon of neural progenitor cells   abnormaliMes of endocrine funcMon and neuroendocrine regulaMon   impaired immune funcMon and stress response > deficiencies in number and funcMon of white blood cells   cell death > impaired apoptosis and necrosis

Neurotransmifers, Neuromodulator Systems and Hormones

-‐ DysregulaMon of Insulin Growth Factors -‐ NMDA glutamate receptors > synapMc plasMcity and memory systems -‐ GABA [a,b,c] gamma-‐aminobutyric acid > C.N.S. inhibitory [and excitatory during development] neurotransmifer > cell membrane funcMon -‐ -‐ Reduced Choline Acetyltransferase > decreased acetylcholine > Hippocampus > memory – Neuromodulator > plaMcity, arousal, reward, sensory percepMons and sustained afenMon. Hydroxylase > mood, appeMte, sleep, memory, learning -‐ Decreased Dopamine receptor funcMon > reward learning, reward seeking. Decreased levels of Dopamine in the Prefrontal Cortex. -‐ Hypothalamic-‐Pituitary Axis > differing acMvaMon > stress responsiveness. Male/Female differenMal stress responsiveness > protecMve role of estrogens. -‐ InhibiMon of Serotonin synthesis and expression of serotonin precursor, tryptophan

Neurotrophic Factors and Adult Neurogenesis

Proteins that control the development, survival and funcMon 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.

FASD and COMORBIDITY and Diagnosis

AfenMon, Mood and Personality Disorders AddicMons Cancer InfecMous Diseases

EPIGENETICS and FASD

PreconcepMon -‐ paternal, 9 weeks exposure and maternal -‐ 10 weeks exposure

PreimplantaMon – ferMlized egg > implantaMon > first two weeks of pregnancy -‐ > placenta > growth retardaMon

GastrulaMon – 3rd to 8th week of pregnancy > most sensiMve – stem cells > cellular differenMaMon – 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

Perinatal AdaptaMon – fetal suscepMbility and protecMon  second and third trimesters –  separate from early embryogenesis

AdapMon increases fetus survival but leads to adult disease – through the epigeneMc regulaMon of gene expression – rheostat effect, rather than off/on switch effect. Fetal insults – anoxia, nutriMonal > maternal or utero-‐placental insufficiency > Adult metabolic disorders, cardiovascular disease, insulin resistance and obesity.

 Consequently the later effects of PAE will tend to vary ?

more likely to be mechanisMcally important in the epigeneMc regulaMon of perinatal adaptability.

CANDIDATE GENES AND MARKERS

> The brain is a complex system

PAE creates a complex chaoMc system

ManipulaMon of a complex system by a simple system leads to unintended consequences

The more complex the system is the greater the unintended consequences

 EpigeneMcs explains the many puzzling and contradictory observaMons about FASD.  The brain dysfuncMons 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 generaMons.   The nomenclature of FASD needs to be changed to reflect our understanding of epigeneMcs 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 manipulaMon of gene expression will result in harmful unintended consequences.

CONCLUSIONS

fasd epigenetics

Health & Medicine