Programming and
Assisted Reproductive
Technologies
Modules 18 and 19
AnS 536
Spring 2014
Fetal Programming
 Hypothesis
 The developing fetus responds to nutritional and
oxygen shortages by diverting resources from other
organs to the brain
 Potential adverse affects may occur later in life
 Adaptations include:
 Vascular response
 Metabolic response
 Endocrine response
Fetal Programming
 Exogenous maternal malnutrition during pregnancy
 May cause lifelong, persisting adaptation to the fetus
 Low birth weight
 ↑ Cardiovascular risk
 Non-insulin dependent diabetes
 Critical periods of vulnerability to suboptimal
conditions during development
 Vulnerable periods occur at different times for various
tissues
 Greatest risk: rapidly dividing cells
Fetal Programming
 ‘Fetal origins’ hypothesis
 Poor in utero environment induced by maternal
dietary or placental insufficiency may program
susceptibility later in fetal development and life
 ‘Thrifty phenotype hypothesis’
 If in utero nutrition is poor, then predictive adaptive
responses are made by the fetus to maximize
uptake and conservation of any nutrients available,
resulting in a conservative metabolism
 Problems occur when postnatal diet is adequate
and plentiful and exceeds the range of predicted
adaptive response
Fetal Programming
 Prevalent in developed and developing
countries
 Dutch famine (limited intake of 1680-3360 kJ)
 During late gestation was associated with
increased adult obesity and glucose intolerance
 During early gestation resulted in hypertension
 Disadvantageous populations in USA, South
Africa, the Caribbean, India, and Australia
 Shown cardiovascular risk to be greater in
populations suffering from poor in utero nutrition
Fetal Programming
 Permanent affects of programming
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Modifies susceptibility to disease
Structural changes to organs
Might pass across generations
Different effects on males and females
 Placental effects
 Fetus will attempt to compensate for
maternal deficiencies
Non-genomic
Intergenerational Effects
 Significant evidence that programmed
phenomena can be disturbed in later
generations
 Offspring exposed to a poor uterine environment
 Prenatal programming by nutrition or exercise
(animal models)
 Postnatal programming by nutrition or handling
(animal models)
 Effects:
 Birth weight
 Glucose tolerance
 Hypothalamic-pituitary axis in subsequent generations
Non-genomic
Intergenerational Effects
 Effects on birth weight
 Black and white hooded rats (Steward, 1975)
 Continued poor maternal nutrition produced amplified
effects on birth weight through a number of
generations
 Accidental introduction of less-palatable food in control
animals resulted in a period of self-imposed calorie
restriction
 Evidence that poor nutrition in one generation can
produce effects on birth weight in subsequent
generations
Non-genomic
Intergenerational Effects
 Effects on birth weight, cont…
 First generation pups (Pinto and Shetty, 1995)
 Exercise during pregnancy resulted in low birth
weigh first generation pups
 First generation offspring were sedentary during
pregnancy and second generation offspring were
also found to be growth retarded
 Suggesting adverse intergenerational influence of
maternal exercise stress on fetal growth
Non-genomic
Intergenerational Effects
 Metabolic parameters and blood pressure
 Female rabbits with surgically induced
hypertension were mated with normotensive
males
 Female offspring had increased blood
pressure as adults when compared to the
offspring of sham-operated females
 Blood pressure in male offspring was
unaffected
Non-genomic
Intergenerational Effects
 Postnatal effects
 Second generational alterations on glucose
homeostasis has been seen when overfeeding
takes place in the neonatal period
 In rodents, naturally occurring variations in maternal
behavior is associated with different hypothalamicpituitary-adrenal stress responsiveness in offspring
 Postnatal environmental manipulations to the
hypothalamic-pituitary-adrenal axis stress response
may produce intergenerational effects
Cloning (SCNT)
 Producing genetically identical copies of
a biological entity
 Different types of methods:
 Reproductive
 Natural identical twinning
 Somatic cell nuclear transfer (SCNT)
 Non-reproductive
 Recombinant DNA Technology
 Therapeutic cloning
Cloning (SCNT)
 Challenges
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Low conception rates
Increased birth weights
Increased incidence of genetic abnormalities
Decreased neonatal survival
Increased placentation abnormalities
Decreased life span of animal??
Increased dystocia and prolonged gestation
Decreased genetic variation
Cloning (SCNT)
 Biological mechanisms
 Low conception rates
 Research is being done to explore this reality
 Current methods of cloning are very artificial and vastly
differ from normal in vivo embryo development
 Methods to promote a more similar environment to what
the embryo experiences in vivo
 Increased birth weights
 Possible link to media used in incubating cloned embryos
 Fetal calf serum (FCS) promotes excessive growth of
embryo
Cloning (SCNT)
 Biological mechanisms, cont…
 Increased incidence of genetic abnormalities
 Possible link to problems in cell reprogramming
with SCNT
 Electric charge fuses cells to promote cell
proliferation
 Decreased neonatal survival
 Offspring can be less vigorous initially after birth
 Anemia, enlarged organs, metabolic
disturbances, problems thermoregulating,
hypoxia can all contribute
Cloning (SCNT)
 Biological mechanisms, cont…
 Increased placentation abnormalities
 Mechanisms unknown
 Hydrops amnion is a condition that is seen during gestation
in cattle and sheep
 Fewer attachment sites but increased size of cotyledons as
compared to normal pregnancies in cattle
 Intrauterine Growth Restriction (IUGR)
 Decreased life span of animal ??
 “Dolly” the sheep only lived to 6 years of age
 Controversial studies that cloning affects life span of
offspring
 Decreased telomere length has been associated with a
decreased life span
 Age of animal being cloned may affect life span of offspring
(increased age shortens telomere length)
Cloning (SCNT)
 Biological mechanisms, cont…
 Increased dystocia and prolonged gestation
 Recipient animals carrying cloned animals fail to recognize
the onset of parturition near term or the cloned fetus fails to
induce parturition
 Increased birth weights contribute to dystocia
 Decreased genetic variation
 Selection of cloned animal can potentially promote a
genetically inferior or superior animal
 Breeding pool can be narrowed
 Long term effects?
Cloning (SCNT)
 Management approaches
 Low conception rates
 Matching synchrony of recipient animal with
stage of embryo
 Increased birth weights
 Selecting larger framed, multi-parous recipient
animals
 Awareness of breed of embryo and potential birth
weight
 Caesarian section deliveries
Cloning (SCNT)
 Management approaches, cont…
 Increased incidence of genetic abnormalities
 Humane euthanasia or abortion in severe cases
 Preventing the perpetuation of genetically inferior
animals through selection
 Decreased neonatal survival
 Intensive care and monitoring of animal first
week of life
 Ensuring colostrum uptake
 Temperature regulation
Cloning (SCNT)
 Management approaches, cont…
 Increased placentation abnormalities
 Close monitoring of recipient animals for hydrops
amnion
 Abort early in gestation if necessary
 Pregnancy palpations/ultrasound to determine
fetal well being
 Decreased life span of animal ??
 Age of animal being cloned may affect life span
of offspring (increased age shortens telomere
length)
Cloning (SCNT)
 Management approaches, cont…
 Increased dystocia and prolonged gestation
 Know expected parturition dates
 Induce parturition if necessary
 Caesarian sections
 Decreased genetic variation
 Criteria for animal selection
 Promoting healthy animals – not just based on
phenotype