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Biological Effects of Alcohol on the Fetus

Competency #4Midwest Regional Fetal Alcohol Syndrome Training Center

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Competency 4: Biological Effects of Alcohol on the Fetus

• This competency describes how alcohol affects the nervous system of the developing embryo and fetus, and how alcohol gets to the fetal brain and other organs.

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What is a ‘Drink’?2-4

Standard DrinkStandard Drink

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Alcohol Metabolism and Pharmacology

• Absorption• Distribution• Metabolism and elimination

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Absorption

• Woman takes a drink→introduced into the stomach→absorption/metabolism of the molecule (C2H5OH) occurs rapidly

• Peak blood ethanol concentrations attained approx 1 hour after consumption

• Women attain consistently higher blood ethanol concentrations than men following equivalent amounts of ethanol consumption

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Distribution

• Compartmentalization Because of alcohol’s rapid solubility in water, it can

easily cross cell membranes into the cell (which is 98% water)

Alcohol is less soluble into lipids and compartments with substantial lipids

• Placental effects and fetal distribution The placenta acts as a selective barrier Alcohol is easily passed by diffusion from the

maternal blood into the fetal blood

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Stomach

Brain

Liver

Kidneys

Fetus

Muscles

Nerves

Placenta

Brain

Heart

Organs

Breast

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Metabolism and Elimination

• Alcohol is metabolized by enzymes as it is available by concentration

• Most ethanol is metabolized in the liver – via three pathways Alcohol dehydrogenase (ADH) Microsomal ethanol oxidizing system (MEOS) Catalase (peroxisomal)

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Alcohol Metabolism

• MaternalLiverMEOS

• Embryonic• Fetal

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Metabolism and Elimination

• Metabolism occurs primarily through the ADH pathway; chronic exposure might enhance or induce other pathways

• All metabolism pathways lead to acetaldehyde, which is then metabolized by acetaldehyde dehydrogenase (ALDH); ALDH metabolizes acetaldehyde to acetate, which is then metabolized into carbon dioxide and water

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Metabolism and Elimination

• Genetic or polymorphic variants of the ALDH gene might influence ethanol metabolism in some populations.

• The placenta does not metabolize ethanol well; the capacity for ethanol metabolism by the embryo/fetus increases with gestational age.

• An embryo or early fetus lacks the enzymes for metabolism, thus the mother must metabolize most of the alcohol. Removal of the alcohol in the embryo/fetus occurs by simple diffusion back to the mother.

• Embryonic alcohol levels might be higher in the embryo than in the mother and be present for a more prolonged, variable time due to limited embryonic metabolism.

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Effects of Alcohol on the Fetus

• Miscarriage• Premature Birth• Low Birth Weight • Development Complications• FASD

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Effects of Alcohol on the Fetus

• Central Nervous System• Craniofacial defects• Growth retardation• Cardiovascular defects• Renal defects• Skeletal defects

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Sensitivity to Alcohol During Development

When is the embryo or fetus most susceptible to alcohol exposure?

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Development of the Embryo

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Alcohol’s Effects on the Brain

(ethanol/ethyl alcohol)

H H H–C–C–OH

H H

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Alcohol’s Effects on Neurons

What are primary mechanisms by which alcohol damages the brain cells during development?

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Neuronal Responses to Alcohol Exposure

• Neurogenesis – neuron ‘birth’• Migration• Growth & Differentiation• Synaptogenesis• Apoptosis• Plasticity

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Neurogenesis

• Neuron generation occurs rapidly in the developing embryo and fetus

• Alcohol exposure during this process affects cell numbers, which might result in cognitive and behavioral deficits

• This has been shown through animal models and models using cultured neurons

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Migration

• Cellular migration, and migration of the cell process, occurs to form nerve pathways

• Migration of the processes occurs using molecules in the membrane that follow substrates in the tissue are are supported by chemicals – nerve growth factors

• Neurites are guided to their destinations following chemical substrates for which the neurites have an affinity

• Subsequent neurites follow using cell adhesion molecules (CAM) to co-locate to the appropriate destination forming a “nerve”

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Growth and Differentiation of Neurons

• Newly formed neurons undergo maturation or differentiation. Associated with differentiation is the genetic

expression of appropriate neurotransmitters for synaptic function, growth, and migration of the processes (neurites) to their respective locations and migration of the cell to its appropriate location (brain nuclei).

• Each of these processes is vulnerable to the effects of ethanol exposure.

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Synaptogenesis

• Once at its destination, the neurite must form a synapse.

• The connection between two nerves, or between nerve and another cell) allows communication between the nerves (or nerve and cell). This is a critical junction at which various components must be present for proper operation.

• Alcohol exposure during this period might disturb the mechanisms on which synaptogenesis depends.

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Synaptogenesis

Alcohol effects on:• Neurotransmitter Receptors• Signal Transduction Mechanisms

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Apoptosis

• Apoptosis refers to the process of programmed cell death

• Alcohol exposure might enhance or modify apoptosis, resulting in more extensive cell death than what was biologically programmed

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Plasticity

• Plasticity refers to a nerve cell’s ability to grow back and re-establish meaningful connections after it is damaged, such as by trauma

• One maturation occurs, most neuros are post-mitotically static and less able to regenerate their function

• Alcohol exposure during development seems to decrease the ability of the nervous system to regenerate

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Neuromorphological Effects

What are the primary cellular or molecular mechanisms by which alcohol damages the brain cells during development?

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Neurodevelopmental Effects of Alcohol

• Multifactorial:Cellular effects

- Mechanisms such as neurogenesis, etc.- Membrane effects

Metabolic Factors- Growth factors & adhesion molecules- Free radical generation

Gene expression- DNA/RNA Regulation

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Craniofacial Malformations

Short palpebral fissures

Smooth philtrum

Hypoplastic midface

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Brain Damage From In Utero Alcohol Exposure

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Brain Regions Affected

The Cerebral Cortex

The Hippocampus and Cerebellum

The Corpus Callosum

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Differences in Brain Size

Cerebrum

Cerebellum

*** **

Cerebrum Cerebellum

75

80

85

90

95

100

PEA

FAS <p 0.001

p < 0.010% o

f Con

trol

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Cognitive and Behavioral Impairments

• Memory• Attention• Learning

VerbalVisual-Spatial

• Reaction Time• Executive Functions

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Cognitive

• The effects of alcohol might cause organic disturbance to the formation and function of the brain and its cellular components

• Streissguth et al. found the average IQ of 178 individuals with FAS was 79 (range 20-120) which is below the general population range of 85-115

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Psychiatric/Behavioral

• Behavioral deficits Attention and memory

problems, hyperactivity

• Memory and learning impairments Verbal learning Visual-spatial learning Attention Reaction time Executive functions

• Secondary conditions Mental health problems Disrupted school

experiences Trouble with the law Confinement and/or

incarceration Inappropriate sexual

behavior Alcohol or other drug

problems

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Severity

• Severity depends on alcohol:DosagePattern of exposureTiming of exposureDuration of exposure

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Genotype and FAS

Is genotype important in predicting fetal alcohol syndrome?

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Genetic Variants and Markers

• Alternate forms of the ADH gene have been demonstrated to metabolize alcohol differently ADH2*3 allele of the ADH gene demonstrated to

protect against adverse prenatal effects of alcohol among Blacks/African Americans

Protective effect of ADH2*3 allele believed to be associated with rapid metabolism of alcohol to acetyaldehyde

• This effect cannot be considered proven

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‘Safe’ Levels

Is there a level of alcohol that is ‘safe’ to drink during pregnancy?

•Less than 1 drink per day can result in:• Enduring growth retardation

• Neurobehavioral deficits

• Organ malformations

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Postnatal Exposure to Alcohol

Can alcohol affect the baby’s development after birth such as during breast feeding?

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C. Nature of the Agent

•Ability to cross the placentaMolecular size / weight

- Smaller molecules cross easierCharge

- Highly charged molecules cross less wellLipophilic / lipophobic

- Cell membranes contain large amounts of lipids. Lipophilic compounds cross the placenta better

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Nature of the Agent

•Mechanism of actionvasoconstrictor / vasodilatoralters DNAchanges rate of cell growthmodulates apotosis

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Ethanol

• Small molecule• Not highly charged• Dissolves well in water or lipid

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D. Other Influencing Factors

• DosageIncreasing dosage associated with greater

effects

• DurationLonger duration associated with greater

effects

• Pattern of exposureBinge exposures are more significant than

chronic exposures

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Dosage

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E. Genetic Susceptibility to Teratogens

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Fetal Hydantoin Syndrome

• Characteristic craniofacial features• Growth disturbance• Neurodevelopmental delays• Limb anomalies• Nail hypoplasia• Hirsutism

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In utero Dilantin exposure

• 1/3 infants have Fetal Hydantoin syndrome, 2/3 do not

• Can’t explain by dose, frequency or timing

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F. Paternal Exposures

• No convincing data exists to document any paternal exposures can be specifically teratogenic

• However, paternal exposures (male mediated effect) may contribute

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Male Mediated Effects

• Decreased Fertility• Sperm transfer to eggs• Irradiation to paternal gonads may induce

chromosome breakage • Increased Genetic Mutations• Trans-placental transfer after conception

ie the father as the teratogen May see increased BDs with certain paternal

occupations (artists, hair dressers, landscapers/groundskeepers)

• Contributing to Maternal use

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Why are only some babies born with FAS?

• No differences in types of alcohol

• Timing of exposure• Amount / duration of exposure• Drinking pattern• Maternal genetic factors• Fetal genetic susceptibility• Co – teratogens

nutrition

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Collectively, scientific studies clearly indicate that

NO alcohol during pregnancy remains the best medical advice!

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Summary

• Cellular Actions & Mechanisms

• Timing During Development

• Brain Areas Affected

• Postnatal Effects