DAY 6 TO WEEK 8
9 WEEKS - BIRTH
PRE-IMPLANTATION PERIOD FIRST WEEK OF LIFE
EMBRYONIC PERIOD/ WEEKS 2-8
A. FETAL MEMBRANES ARE ESTABLISHED
B. GERM LAYERS LAID DOWN IN EMBRYONIC DISC
C. RAPID GROWTH
D. BEGINNING OF ALL INTERNAL AND EXTERNAL STRUCTURES DEVELOP
E. ORGANOGENESIS: ALL ORGAN SYSTEMS HAVE BEGUN FORMING BY END OF WK 8
D. MAJOR EXTERNAL FEATURES ARE RECOGNIZABLE
E. CRITICAL PERIOD OF DEVEOPMENT
FETAL PERIOD/ 9 WEEKS TO BIRTH
A. SYSTEMS DEVELOP FURTHER
B. DEVELOPMENTAL CHANGES ARE NOT SO DRAMATIC
C. RATE OF BODY GROWTH IS REMARKABLE
During the embryonic period, all organ development begins. Also, during this time, the human is most sensitive to teratogens.
Hensen's node helps set up left-right axis
LEFT RIGHT AXIS FORMATION
How Does the Embryo Know Its Left From Its Right?
THIS SLIDE SHOWS THE NODE – AN AREA IMPORTANT IN BREAKING SYMMETRY AND DEFINING THE L-R AXIS
Nodal Cilia Beat in a Right to Left Direction
Circular power stroke right-left
motors: kinesin (red) and dynein (pink)
KO mouse, no cilia-no left-right axis
Primary Cilia in The Node are Needed for Left Right Asymmetry
Nodal Flow Generates Left Right Asymmetry
A = time lapse image showing nodal vesicular parcel (NVP) at 2 second intervals moving left to right
B= Time lapse images showing release through smash phase for NVP
C= diagram of nodal flow
Nodal Flow Generates Left Right Asymmetry models
PKD1L1 Polycystic kidney disease like protein
SHH = sonic hedgehog . signaling molecule (protein) instagates reactions.
SOME OF THE MOLECULAR PLAYERS IN NODAL FLOW
Nodal turns on Pitx2 (transcription factor) left side
Lefty inhibits snail
snail (transcription factors) right side
What Happens When Nodal Flow Does Not Occur??
Situs inversus (organs not in normal place)
THE PURPOSE OF FOLDING IS TO TRANSFORM THE FLAT THREE ALYERED EMBRYONIC DISK INTO A CYLINDER (WHICH IS WHAT ARE BODIES ARE)
Longitudinal Folding – From Langman
TRANSVERSE FOLDING- from Langman
CARNEGIE STAGES FOR HUMAN EMBRYOS
MRI Imaging of Human Embryos
EXAMPLES OF HUMAN EMBRYOS MADE WITH MRI MICROSCOPE
CAN SEE THEM IN 3D
CAN BE ROTATED
CAN LOOK AT SECTIONS THRU EMBRYOS
NOTICE DETAIL IN IMAGES - CAN YOU ID STRUCTURES?
MUCH BETTER QUALITY THAN ULTRASOUND
FIGS SHOW SECOND AND THIRD TRIMESTER
PHENOMENAL WEIGHT GAIN ESPECIALLY IN LAST FEW WEEKS OF PREGNANCY
ORGAN SYSTEMS NOT ONLY DEVELOP BUT ALSO BEGIN TO FUNCTION DURING FETAL PERIOD
Characterized by rapid growth
Week 9: head=1/3 total length of fetus.
Organ systems begin to function prenatally.
By the end of gestation, the fetus drinks about a pint of amniotic fluid every day.
Sense of taste: depending on what's in the amniotic fluid, fetus may drink more or less
Kidneys make about 450 mL of "urine" every day. The urine excretes into the amniotic cavity and recycles again and again. Much more dilute than adult urine.
If the kidneys don't produce enough urine, there's oligohydramnios (not enough amniotic fluid which can lead to abnormal limb development)
Endocrine glands functine prenatally. Fetus decides when to be born.
Respiratory system is the last to finish development.
Dipalmitoyl lecithin spreads water in the lungs which leads to proper functioning. hyaline membrane disease (infanant cannot breathe) without dipalmitoyl lecithin
Fetal Growth Curve
Fetal body scale changes over time
Changes in Relative Size of the Head
HYALINE MEMBRANE DISEASE
1. 500 ML AMNIOTIC FLUID SWALLOWED/DAY AT END OF PREGNANCY 2. MOST ELECTROLYTES, WATER, GLUCOSE, UREA, STEROID HORMONES ARE ABSORBED BY SMALL INTESTINE
3. REPLACES WATER LOST THROUGH URINATION
4. CONTROLS VOLUME OF AMNIOTIC FLUID
5. SENSE OF TASTE DEVELOPS PRENATALLY
1. PLACENTA = EXCRETORY ORGAN DURING PREGNANCY
2. KIDNEY PRODUCES URINE - RELEASED INTO AMNIOTIC FLUID - ABOUT 450 ML A DAY AT END
3. IF NO KIDNEY - AMOUNT OF AMNIOTIC FLUID IS LOW = OLIGOHYDRAMNIOS
1. FUNCTION BY 9-10 WEEKS
2. GENERAL SAME FUNCTIONS AS IN ADULT
3. MAY INITIATE LABOR
1. RHYTHMIC BREATHING BEFORE BIRTH - PRACTICE MOVEMENTS
2. SURFACTANT NEEDED FOR PROPER INFLATION OF LUNGS AT BIRTH
METHODS TO STUDY FETUS
1. PLACENTAL FUNCTION - HCG CAN BE MONITORED EASILY - IF LOW COULD BE A THREATENED PREGNANCY
2. AMINO - DONE AFTER 14 WEEKS -LATE IN PREGNANCY - ENOUGH AMNIOTIC FLUID
THEN CELLS MUST BE GROWN - SEVERAL WEEKS TO GET RESULT
1. A-FETOPROTEIN IN FLUID CAN INDICATE OPEN NEURAL TUBE DEFECT
2. SEX CAN BE DETERMINED
3. RECOMBINANT PROBES - MUSC DYSTROPHY, HEMOPHILA, HUNTINGTON’
3. CVB CAN BE DONE EARLY IN FIRST TRIMESTER
1. TAKE PLUG OF CELLS FROM CHORION
2. DO NOT NEED TO CULTURE SO CAN GET RESULT FAST
3. CAN NOT DETECT NTD W/ CVB
4. CAN DO OTHER DNA TESTS
5. MAY BE SLIGHTLY MORE RISK OF SPON ABORTION FOLLOWING CVB
4. BLASTOCYST ANALYSIS BEFORE IMPLANTATION
1. SETS PRENATAL TESTING CLOCK BACK TO 8CELL STAGE
2. FERTILIZE EGGS IN VITRO AND REMOVE A BLASTOMERE BY PIPETTE
3. EXAMINE DNA FOR MUTANT GENES
4. USED PROBES FOR CYSTIC FIBROSIS
5. PUT ONLY GOOD EMBRYOS BACK IN MOTHER’S UTERUS
6. COST = $2000 FOR BABI, BUT LESS THAN CARE OF CHILD WITH SERIOUS DISEASE
5. ULTRASOUND VALUABLE - CAN DIAGNOSE A LOT OF PROBLEMS
1. SIMPLE, RAPID, NO HARM, NO DISCOMFORT TO MOTHER
Placenta function: take blood or amniotic fluid sample, look for biomarkers
hCG goes up during pregnancy, if it's too high, it can indicate a hydatidaform mole
Amniocentesis (about 30 mL taken from uterus)
1. take the fluid and analyze it. If alpha fetaprotein is too high, the neural tube isn't closed
2. culture cells, check DNA. can check for trisomy 21, huntington's disease, etc.
Cannot perform until about 14 weeks. There's also a danger that the needle may induce spontaneous abortion
Chorionic Villus Biopsy: some cells are taken from the placenta. May be done in embryonic stage, much earlier than fetus. disadvantates: needle may induce spontaneous abortion.
METHODS TO STUDY FETUS CONTINUED
BABI--> take out one blastomere
the tests are expensive. anywhere from 20,000 to 100,000
2 vs 3-Dimensional Ultrasound
3D high res render surface of fetus
4D adds time (video)
OCCURS 266 DAYS OR
38 WEEKS AFTER
LENGHT = 360mm
WEIGHT = 3400g
LOW BIRTH WEIGHT BABIES
SMALL FOR DATES
Premature birth: before 37 weeks of gestation.
PB accounts for 35% of deaths in first year of life.
Costs exceed $26 billion/year
Risk factors include multiple pregnancies – twins, triplets etc, gentialurinary infection, smoking, extreme body weight;
Also depression, stress, poor diet, periodontal disease..
Short cervical length consistent predictor of premature birth – sometimes can suture around cervix
If newborn weighs under 2,500 grams, low birth weight
INTRAUTERINE GROWTH RETARDATION
1. REDUCED BLOOD FLOW - HYPOTENSION, RENAL DISEASE, KNOT IN CORD
2. DYSFUNCTION - NOT NORMAL PLACENTA, SMALL, BRUISED, UNDER DEVELOPED, RETARDS GROWTH
3. MULTIPLE PREGNANCY
1. SMALL MOTHERS HAVE SMALL BABIES
2. SMALL BABIES RUN IN SOME FAMILIES
3. CHROMOSOMAL ABERRATIONS - DOWN’S SYNDROME, TRISOMY 18
1. MALNUTRITION - FAMINES, POOR DIET
2. CIGARETTE SMOKING - FETAL TOBACCO SYNDROME
3. DRUGS - LSD, HEROINE, MORPHINE, AMPHETAMINES, ETOH
SMALL BABIES WHETHER PREMATURE OR SFD ARE MORE VULNERABLE AND LESS LIKELY TO SURVIVE!!
Placental factors: underdeveloped, twins/triplets, bruised, knots in cord
Genetic factors: small women-->small babies
Environmental factors: smoking-->small babies (active or passive smoking), alcohol is toxic to neural crest cells. recreational drugs, etc.
Fetal surgeries have been done for more 20 year – but dangerous
May be used to treat spina bifida or diaphragmatic hernias (improperly formed diaphragm-guts in thoracic cavity...fatal condition normally)
But risky for both mother and fetus
Because this is very dangerous- is only done in rare case
For example – has been used to treat diaphragmatic hernia, but dangerous and may not be very effective
Also may be used to treat spina bifida but again controversial
Best use is when fetal surgery accompanies delivery.
E.g. fetus has tumor in thorax that will prevent breathing
remove tumor using fetal surgery just before delivery, then baby can breath when born
Called exit surgery.
Likely fetal surgery will become obsolete
Replaced by stem cell and gene therapy.
E.g. stem cells could be used to treat sickle cell anemia.
Fetal Origins of Adult Health and Disease– a new science
New branch of medicine
Recognizes that what we are as adults and our adult health can be linked to the conditions we were exposed to in utero
Recognized only recently
Intensively researched during last 10 years
Heart disease – early onset associated with birth weight – smaller babies tend to have increased risk for heart disease
Obesity – If mothers are obese during pregnancy, their children will tend to be obese. If mothers fat is surgical removed to restore normal weight- he subsequent children are more likely to also have normal weight
Diabetes – diabetic mother – has high glucose- this disrupts fetal metabolism- predisposes her children to type II diabetes
Air- cord blood is loaded with the air pollutants a mother breathes. New borns have PAH (polycyclic aromatic hydrocarbons) in blood. Evidence they have already affected DNA even before birth
Stress- If mothers are stressed during pregnancy – they are more likely to have anxious children and children with schizophrenia
What happens in utero affects the rest of life. some adult diseases originate in utero
Barker Theory-makes conditions come on sooner than they otherwise would.
IF metabolism is set slower in utero, it stays slow the rest of life-->tendency towards obesity
The Barker Theory
Reduced fetal growth is strongly associated with a number of chronic conditions later in life. These chronic conditions include coronary heart disease, stroke, diabetes, and hypertension.
Also called Thrifty phenotype.
This increased susceptibility results from adaptations made by the fetus in an environment limited in its supply of nutrients.
Like between fetal birth weight and later early onset of adult disease first made by David Barker 20 years ago
Poorest areas in England and Wales had highest rates of heart disease. Found birth weights lower in poorer regions. Strong correlation between birth weight and later heart disease.
Not taken seriously at first but now many studies have been done confirming his observations. Why- if resources are limited in utero, fetus may not be able to develop all organs fully, may also put resources in to brain at expense of the heart and other organs. Later in life, the deficiencies may take their toll.
Developmental Origins of Adult Health and Disease
The DOHaD hypothesis states that exposure to an unfavorable environment during development (either in utero or in the early postnatal period) programs changes in fetal or neonatal development such that the individual is then at greater risk of developing adulthood disease.
Flip side of this hypothesis
Exposure to a good environment in utero will favor development of a healthy adult
Could be very important in public health – an improvement of quality of life
Pregnant women may make simple adjustments during pregnancies and help their fetus develop in a way that helps them remain healthy longer in adulthood.
Specific Example - Possible relationship between uterine environment and development of type II diabetes
How could a fetus reset its metabolism (or anything else) in a way that would affect it as an adult?
The answer may lie in epigenetics
= Study of gene activity that do not involve changes in the genetic code but still get passed down to successive generations.
Patterns of gene expression governed by the epigenome- which marks genes telling them if they should turn off or on
Or if they should be highly or lowly expressed.
Involves mitotically and meiotically inheritable changes in gene expression that do not involve a change in the DNA sequence itself.
Often accomplished by methylating select regions of DNA (as we saw in genomic imprinting)
Regulatory Proteins Have Two Functions
1. SWITCH SPECIFIC GENES ON OR OFF
A gene regulatory protein attaches to a specific sequence of DNA on one or more genes. Once there, it acts like a switch, activating genes or shutting them down.
2. RECRUIT ENZYMES THAT ADD AND REMOVE EPIGENETIC TAGS
Gene regulatory proteins also recruit enzymes that add or remove epigenetic tags. Enzymes add epigenetic tags to the DNA, the histones, or both. Epigenetic tags give the cell a way to "remember" long-term what its genes should be doing.
Epigenetic silencing of a gene often involves methylating the DNA in that gene
methylation can turn off a gene
regulatory protein-temporary; methylation-permanent
what you eat can affect the methylation of DNA. gene expression is then affected.
Experiences Are Passed on to Daughter Cells
As cells grow and divide, cellular machinery faithfully copies epigenetic tags along with the DNA.
This is especially important during embryonic development, as past experiences inform future choices.
A cell must first "know" that it is an eye cell before it can decide whether to become part of the lens or the cornea.
The epigenome allows cells to remember their past experiences long after the signals fade away.
DNA METHYLATION – USUALLY OF CYSTEINE
folic acid, betaine, choline, B vitamins can all methylate DNA
DNA METHYLATION CAN BE STUDIED USING AGOUTI MICE
Experiment showing how BPA in diet can effect coat color (DNA methylation and gene expression)
Can effects of BPA be reversed by diet?
Don’t Count Dad Out
So if a pregnant mother's diet can affect the child's epigenetic outcome, can dad's diet do the same? Quite possibly, according to scientists who delved into the well-kept, historical records of annual harvests from a small Swedish community. These records showed that food availability between the ages of nine and twelve for the paternal grandfather affected the lifespan of his grandchildren. But not in the way you might think.
Food abundance for the grandfather was associated with a reduced lifespan for his grandchildren.
Shortage of food for the grandfather was associated with extended lifespan of his grandchildren.
Food abundance, on the other hand, was associated with a greatly shortened lifespan of the grandchildren.
Early death was the result of either diabetes or heart disease.
Could it be that during this critical period of development for the grandfather, epigenetic mechanisms are "capturing" nutritional information about the environment to pass on to the next generation?
Genomic Imprinting revisited