Transcript Fetal Growth and Developmentx

Fetal Growth and Development
Fetal Growth and Development, AnS 536
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To Grow
• Grow:
– To become larger. To increase in size or amount
• Growth:
– The progressive act of growing
‘At the moment we are
born, we are dying’
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Fetal Growth
• Affected by numerous factors
– Genetics
• Potential- genetic code
• Transcription- phenotype
– Physical environment
• Uterine Capacity- restrictor
• Nutrient availability- metabolism
– Interaction between the two
• Hormones
• Growth factors
• Transcription factors
PROTEIN
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Establishing DNA
• Success of reproduction begins prior to
fertilization
– Quality of gametes produced by the parents
• At fertilization, comingling of gametes
establishes the genetic makeup of the new
offspring
– Basis for all further protein production from the
fetus
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Genetic Influence
• Once fertilization occurs, and the new DNA is
assembled, the cell begins its process of mitotic
divisions, building up the cells that will eventually
cleave and differentiate into the organ systems of the
body.
• Mitotic divisions are generally not influenced by maternal
or environmental changes.
• Cells are in stage of strict proliferation and cleavage into
non specific cells.
– Cleavage driven by space within the zona pellucida
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Genetic Potential
Short, fine
boned
4.5% butterfat, 3.5%
total protein
3.9% butterfat, 3.3%
total protein
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http://www.subzeroicecream.com/a-day-in-the-life-of-a-dairy-cow/
Tall, heavy
frame
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Transcription of DNA
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http://www.csus.edu/indiv/l/loom/lect8.htm
Blastocyst, Cell Differentiation
• Continued mitotic divisions and cleavage of cells
form the blastocyst.
– Blastocyst is the cellular mass that will hatch from the
zona pellucida and implant in the endometrium
• Implantation into the endometrium facilitated by
trophoblast cells
– Trophoblasts differentiate into villous cells of the
placenta, attach to the uterus to establish blood flow
between fetal and maternal tissues.
– Trophoblasts also modify maternal arteries through
reduction of resistance, and increasing blood flow.
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Trophoblasts
• Different types of trophoblast cells have
specific jobs in association with the maternal
tissue
• Cytotrophoblast cells: sites of hormone influence from
hCG, placental lactogen, placental GH, estrogen, and
progesterone
• Syncytiotrophoblast cells: line the placental trophoblast
villi, in direct contact with the uterus.
– The purpose appears to primarily be the movement of amino
acids and other nutrients across the uterus and into the
placenta
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Comparative Fetal Growth Rates
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Fetal Growth- Placenta
• As previously discussed in this class, importance of
placental establishment during pregnancy cannot be
underestimated
• Once the trophoblasts have established vascularization
in the uterus and created path for nutrient and signal
transport, placental growth can begin
– Placental growth is influenced by uterine environment
• Estrogen influence on placental size also has indirect influences on
fetal growth.
• Increases in volumes of allantoic and amniotic fluids occur with
gestational fluctuations in estrogen levels.
– In swine, two peaks of placental growth have been characterized during
gestation, (Knight et al., 1977)
– Electrolytes appeared to create a “short circuit”. Increase in ion gradient
favors the flow of electrolyte ions from the maternal to fetal side of the
chorion (Knight et al., 1977)
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Fetal Growth-Tissue Development
• Fetal growth and development is parallel to placental
growth
• Proper development of the fetus during gestation is
assessed through comparison of fetal size at
gestational age time points.
– These assessments are made based on comparisons of
individual growth potential and population averages
– This subjective scale of measurement is utilized as a
predictor for preterm pregnancies, and a diagnostic
consideration for determining growth abnormalities.
– In essence, the proper establishment of the placenta has
great influence over the growth of the fetal tissues, and
their size at the appropriate gestational ages
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Tissue Development- Humans
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Tissue Development- Cattle
Gestational Age (days)
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30-60
60-90
Description of Development
The extremities develop. The pharyngeal cleft closes, the sternum still has a
longitudinal fissure in the middle, closing toward the end of the eighth week. The
length of the fetus is 48 mm In the ninth week its length is 8 cm.
Four stomachs may be recognized. The fetus measures 14 cm. in length. The scrotum
is present.
Hoofs distinct: they are firm, non-transparent. The fetus is about 24 cm. long and
weighs up to 2 kg.
90-150
First tactile hairs appear on the lips, chin, upper eyelid, and orbital arch. The teats are
plainly visible. The testicles descend into the scrotum. The fetus, is about 35-46 cm.
long and weighs 2.5 to 3 kg.
150-180
Hairs appear at the end of the tail; also hairs about the coronet and on the spots
where the horns appear. The fetus is about 60 cm. long.
180-240
The back begins to be covered with hair, also along the edges of the ears. The length
of the fetus toward the 32d week is 65 cm, and toward the end of this month 75 cm.
240-Term
Whole body is covered with hair and increases greatly in size. Maturation of the fetus
in preparation for birth nearing term. The fetus measures from 80 to 100 cm.
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Fetal Growth- Uterine Capacity
• Influenced by
– Physical maternal size
• Maturity of mother, or parity
– Placental size and density
– Litter bearing or twinning vs. singleton
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Uterine Capacity- Growth Restriction
Example
•
Average US birth weight between 1985-1990: 6.8-7.1 lbs.
• Genetic Potential: Paternal side
– Siblings size at birth: 7-8.5lbs, 19”-21”
– Sibling current W/H: 145-210 lbs, 5’-6”- 6’0” (Ave.-Lrg. body
frame)
• Uterine Capacity (Restriction of growth)
– Baby (at birth): 7lbs 2oz, 19.5”
– Mom: 5’3”, 95lbs (Sml. body frame)
• Gained only 25lbs during 9mo. Pregnancy
• ~25lbs total gain – (~7lbs fetus+~7lbs placenta)= 11 lbs.
extra.
• No more room for fetus to grow!
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Fetal Growth- Uterine Capacity
• Uterine capacity increases with parity due to
stretching of the uterine muscle and birth
canal
• Possible other physical changes occur
– Increase in abdominal size, age
• Sows vs. gilts
– After day 35 of gestation, IUGR can be noticed in piglet growth
and development, due to restriction of uterine capacity and
limited vascular flow
• Cows vs. heifers
• Sheep- twinning
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Fetal Growth- Nutrient Availability
• Nutritional regulation of growth is both a
reaction to environmental conditions and
acting on genetic potential
• Environmental situations of nutrient
availability are due to maternal intake of the
appropriate nutrients
– Amino acids, glucose, triglycerides
– Vitamins, minerals, water
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Fetal Growth- Nutrient Availability
• Maternal blood glucose
– Increases in maternal blood glucose (instance of
hyperglycemia) are often linked to reductions in
insulin secretion
• Increased availability of the glucose from the maternal
blood gets taken up by the placenta and the uterus
• Results in a larger fetus
– Decreases in blood glucose (maternal
hypoglycemia)
• result in a smaller fetus, with a higher uptake and
demand for glucose
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Fetal Growth-Nutrient Availability
• Changes to placental uptake of glucose can
also influence fetal growth
– Placental uptake of glucose normally between 4060% of all glucose taken up by the conceptus
– Increases in uptake create in increase in glucose
gradient from the maternal to fetal tissues.
• Compensatory for fetal needs of glucose to make up for
increased placental uptake.
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Fetal Growth
• The process of fetal growth and development is
dynamic and fluid throughout gestation
• Growth of the fetus is encouraged and regulated
by a number of redundant and conflicting factors
• Most easily controlled influences of fetal growth
continue to be genetics and environment
• Next time: Expressing the phenotype
– Interaction with genetics and environment
• Hormones
• Growth factors
• Transcription factors
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Fetal Growth and Development
Part 2
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Fetal Growth
• Affected by numerous factors
– Genetics
• Potential- genetic code
• Transcription- phenotype
– Physical environment
• Uterine Capacity- restrictor
• Nutrient availability- metabolism
– Interaction between the two
• Hormones
• Growth factors
• Transcription factors
PROTEIN
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Tissue Accretion
• Cell growth= tissue gain
• Formation of organ systems occurs through
the building of tissue
Cell
Cell
Cell
Cell
Cell
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Tissue development- Mouse
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Hormone Secretion
Placental growth
Cell Proliferation
Fertilization
Implantation
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Growth Factors and Hormones
• Cells are influenced by growth factors differently
depending on their state of development
• Progesterone : Estrogen ratio
• Insulin, drive nutrients into tissues
– Placental growth
– Adipose
– Muscle
• Growth Hormone and IGF axis
• Glucocorticoids
• Amino acids: protein receptors and signaling
compounds
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IGF
• Insulin-like Growth factor: influence somatic cell growth
and proliferation
– IGF-I: cell proliferation directly, fetal growth (paternal)
– IGF-II: both placental and fetal growth (maternal)
• Interaction of IGF and Growth Hormone (GH), termed the IGF/GH
axis
– Secretion of IGF is driven by syncytiotrophoblast cells
• Triggered by growth hormone (GH) and placental lactogen
• Greatest during early pregnancy (time of high level of cell
proliferation)
• Associated with increasing growth in all tissues during development
– Fibroblasts and myoblasts in the establishment of skeletal
muscle
– Increasing hyperplasia
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IGFBP
• IGF binding proteins (IGFBP): regulate IGFs
– Growth restrictor
– Serum concentrations determined by maternal
genetics and environment
• All fetal and placental tissues have exhibited
receptors for IGF signals, and most also have
sources of IGFBPs within the tissues
• Secretion of IGFBP is greatest as the fetus
approaches term
– Decrease hyperplasia, increase hypertrophy
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Glucocorticoids
• Glucocorticoids are associated with cell maturation
– Improve surfactant when given to premature neonates
• Increasing the ratio of lecithin to shyingomyelin in amniotic fluid,
subsequent surfactant
• Influence of glucocorticoids prior to birth have been linked
to reduced fetal growth and premature increases in
maturity of fetal development
– Thought to suppress the influence of IGF axis (Bloomfield, et al.,
2001)
• Glucocorticoids are involved in a variety of life processes
– Appear more beneficial to cells that have been differentiated, as
opposed to cells that are still within a proliferative state
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Glucocorticoids
• Glucocorticoids are regulated during fetal
development
– 11β-HSD, a regulatory protein known as the
placental glucocorticoid barrier
– This protein is secreted heavily during early
gestation
– Measured changes in maternal glucocorticoid
levels have apparently little to no effect on the
fetus that in adequate secretion of the 11β-HSD
protein
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Amino Acids
• Necessary in the creation of these transporters for moving other
molecules into conceptus
– Lack of functional transporters can lead to deficiency, despite availability
• Taurine, essential for fetal development
• Without a functioning transporter, a fetus can be taurine deficient
• Functional amino acids (FAA): primarily transport proteins
FAA
Function
Arginine
Cell division, the healing of wounds, removing ammonia from the body, immune
function, and the release of hormone
Cysteine
Enzymes and oxidation, donates electron for breakdown of molecules
Leucine
Leucine is utilized in liver, adipose, muscle. Leucine is the only dietary amino acid
that has the capacity to stimulate muscle protein synthesis
Glutamine
Protein synthesis, regulation of acid-base balance, cellular energy- glucose
uptake, nitrogen donation for anabolic reactions, Carbon donation, nontoxic
transporter of ammonia in the blood circulation
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Amino Acids
• Expression of transport amino acids increases
throughout gestation, as the demand for
increased nutrient transport increases
• Reduced concentrations of polyamines have
been associated with IUGR in fetuses
• Reduction in amino acids important and
biosynthesis can have the greatest overall
effect on fetal growth
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Wu, G., Bazer, F. W., Cudd, T. A., Meininger, C. J., & Spencer, T. E. (2004).
Maternal Nutrition and Fetal Development, (13), 2169–2172.
Fatty Acids
• Fatty acid metabolism is driven by protein carrier
transport.
• Important mostly in the development of brain and nerve
tissues.
• Lipoprotein lipase (LPL)
– Active role in metabolism of triglycerides taken up by the
conceptus from the maternal blood
• Hydrolyzes lipoproteins
• Promotes the cellular uptake of chylomicrons, cholesterol-rich
lipoproteins, and free fatty acids
– Lack of enzyme is associated with reduced growth and
preterm births
• Formation of sterols: Steroid hormones
• Cell membrane development: phosolipid membrane
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Glucose
• Fetus has minimal capacity for
gluconeogenesis
• Glucose uptake is regulated by GLUT
(glutamine) transporters and glucose
gradient
– Cellular energy: glycolysis
and ATP production
– ATP: the elixir of life
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Immune response & Growth
• Nitric oxide (NO): biosynthetic compound, primary
functions in association with muscle contraction and by
product of immune response in adults
– Synthesized from L-arginine
– Macrophages
• Fetal development: Capable of inhibiting the development
of adipocytes
– Stimulating oxidation of fatty acids and glucose within muscle
– NO may have a greater influence in the differentiation of
somatic stem cells into secondary muscle fibers (Wu et al.,
1998).
• FAA’s such as arginine, regulate the partitioning of nutrients, favoring
muscle growth over that of adipocyte accretion
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Immune response & Growth
• The influence of NO on the differentiation of muscle cells
and the formation of secondary muscle cells can have
lasting effects postnatally.
– The development of muscle tissue is well characterized and
provides a clear picture of the effect of nutrients, endocrine
signaling, and genetic potential on the development of the
fetus.
• Fetal muscle development, and subsequent postnatal
growth, is
– influenced by the number of myofibers, which are produced
during proliferation of designated somatic cells
• Extreme genetic example: ‘double’ muscling, Belgian Blue
• NO: increased muscle differentiation, decreased muscle fiber
numbers, increased muscle fiber size, decreased accretion of adipose
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Abnormal Development
• “Cloned cattle fetuses with the same nuclear
genetics are more variable than contemporary halfsiblings resulting from artificial insemination and
exhibit fetal and placental growth deregulation
even in the first trimester.”
– Lee et al., 2004
• Nuclear Transfer calves, clones, as compared to in
vitro fertilization (IVF) and artificial insemination
(AI)
– NT fetuses have a notoriously reduced survival rate
– Fetal and placental growth measured at d 50, 100, and
150 post implantation
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Basic Cloning Process,
Nuclear DNA Transfer
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Fetal Growth- Abnormal Development
• Increased fetal size and slightly advanced
development was noted within the NT
fetuses.
• Tendency for the placental tissues to have a
greater weight and density
• No growth factors were measured
– Suggested by the investigators that the lack of
opposing IGF signals may be to blame.
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Fetal Growth- Abnormal Development
• Moore and Haig (1991) suggest that different IGF
signals are controlled by different parental
genomic mechanisms.
– IGF-I promotes fetal growth, Paternal alleles
– IGF-II regulates growth of the placenta, Maternal
alleles
• In the case of the NT calf or cloned calf, are IGF
signals not regulatory of each other?
– Due to the replication of a complete genome
sequence, instead of the formation of a parental mix?
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Fetal Growth- Abnormal Development
Normal
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NT Fetus
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