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 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  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 hypothalamic- pituitary-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  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