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• Several studies using animal models have shown that
preimplantation embryos are sensitive to environmental
conditions that can affect future growth and developmental
potential both pre- and postnatally.
Epigenetics
• All cells in the body have a phenotype that is a culmination of
the cell’s gene structure, epigenetic marks and environmental
influences.
• Normal embryogenesis can not proceed without the machinery
of epigenetic regulation.
Epigenetics
• A mitotically and/or meiotically heritable changes in gene
expression that occur owing to modifications of the helical
structure without changes in the DNA sequence.
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Epigenetics
Four main types of epigenetic inheritance;
• DNA methylation
• Chromatin remodelling (Histone modification)
• Genomic imprinting
• Long-range control by chromatin structure
These mechanisms are interdependent and may be synergistic.
Epigenetic modifications in gene silencing
• A series of epigenetic
modifications transforms
transcriptionally active regions
of DNA into inactive compact
chromatin.
• Transcriptionally active chromatin
is associated with acetylated
histones, whereas inactive
chromatin has methylated DNA
and de-acetylated histones.
EPIGENETIC REPROGRAMMING
Epigenetic Reprogramming
• DNA methylation patterning and chromatin modifications are
required for normal tissue development during early development
stages.
• While cell-specific methylation patterns are relatively stable in
somatic cells, DNA methylation is subject to dynamic variations in
preimplantation embryos.
• Embryo is most vulnerable to environmental factors during
embryogenesis since the DNA synthetic rate is high.
• The proper or improper handling of these highly sensitive
periods may have significant short-term and long-term effects on
the individual and his/her progeny.
Epigenetic Reprogramming
• In normal developmental or disease situations, some cells
undergo ‘major epigenetic reprogramming’.
• The epigenome is particularly susceptible to dysregulation
during gestation, neonatal development, puberty and old age.
Epigenetic Reprogramming
The physiology and later the pathophysiology of epigenetic
reprogramming dynamics may be studied in four distinct phases:
-Fertilisation
-Early embryo development
-Gametogenesis
-Lifelong reprogramming
Dynamic reprogramming of the epigenome
during development
The first phase of methylation reprogramming occurs between
fertilisation and formation of the blastocyst.
Methylation levels in imprinted and nonimprinted
genes during early embryogenesis and gametogenesis
Nafee TM. BJOG 2008;115:158–168
Dynamic reprogramming of the epigenome
during development
Primordial germ cells undergo
demethylation as they migrate along the
genital ridge, both genomewide and
within imprinted loci and following this
erasure, CpG methylation of imprinted
genes is reestablished during
gametogenesis through de novo
methylation, in both eggs.
Abnormal expression of imprinted genes
• Abnormal expression of imprinted genes, through genetic or
epigenetic alterations, can lead to a number of diseases.
• These diseases are all characterized by a non-mendelian
inheritance and a parent-of-origin effect.
– Neuron-developmental: BWS, PWS and AS
– Metabolic disorders: transient neonatal diabetes mellitus
– Psychiatric/behavioral disorders: autism, schizophrenia,
and bipolar disorder
– Cancer: retinoblastoma
DEFECTIVE IMPRINTING IN ART
Various environmental factors, such as gamete in vitro
manipulation, or exposure to specific compounds during
pregnancy may lead to changes in the imprinting patterns of
genes and affect gametogenesis and embryonic development.
DEFECTIVE IMPRINTING IN ART
• New technical steps have been recently added to the IVF/ICSI
procedures, like testicular/ovarian tissue cryopreservation and
oocyte in vitro maturation as well as preimplantation genetic
diagnosis.
• It is presently not known whether these may expose the
gametes or early embryos to risks of imprinting defects.
• Recent studies have suggested that a number of specific
imprinting disorders might be more frequent in children
conceived by ART than naturally.
Selected human disorders linked to an imprinting
defect reported after ART
ARIANE PAOLONI-GIACOBINO PEDIATRIC RESEARCH 2007;61, No. 5, Pt 2,
In Vitro culture
Protein supplements
Media composition
Embryo environment
Glucose, energy substrates
Amino acids
Growth factors
Steroid hormones
Cytokines
Metabolic regulators
In vivo environment
Diet
Body composition
Potential short-term responses
“developmental plasticity”
Epigenetic modifications
Altered intracellular signalling
Metabolic stress
Apoptosis
Cell proliferation disturbed
Tom P. Fleming, BIOLOGY OF REPRODUCTION 71, 1046–1054 (2004)
• Evidence now indicates that singletons born after ART are at
increased risk of premature birth, very low birth weight, and
perinatal mortality, compared with singletons born to fertile
women.
• They are also at increased risk for sex chromosome
abnormalities, attributable in part to parental chromosomal
abnormalities.
Presented at the ART Workshop: Evaluation of Genetic and Epigenetic Risks Associated with
Reproductive Technologies and Infertility, January 14–15, 2005, Toronto, Ontario, Canada.
• Evidence is suggestive but not sufficient to conclude that
there is an increased risk for rare genetic syndromes involving
loss of imprinting, such as Beckwith-Wiedemann syndrome
and Angelman syndrome.
PREGNANCY OUTCOME
ARTs were linked to an increased risk of;
• Intrauterine growth restriction (OR: 1.59)
• Premature birth
• < 33 weeks of gestation: OR:2.99
• < 37 weeks of gestation: OR, 1.93
• Low birth weight (1,500 g: OR:3.78)
• In utero death (OR:2.40)
• Angelman syndrome and Beckwith-Wiedemann syndrome
Jackson RA, Obstet Gynecol 2004, Halliday J, Am J Hum Genet 2004,
Wennerholm , 2000, Anthony 2002, Hansen 2005, Klemetti 2005, Ka¨lle´n
2005, Schieve 200 4; Jackson 2004, Helmerhorst 2004
PREGNANCY OUTCOME
Poikkeus et al 2007
N.Turhan
OBSTETRİCS VE NEONATAL OUTCOME
Poikkeus et al 2007
N.Turhan
LIFELONG EPIGENETIC REPROGRAMMING:
AGEING, DIET AND ENVIRONMENTAL
TOXINS
Lifelong epigenetic reprogramming:
ageing, diet and environmental toxins
DNA methylation patterns change with age;
1. Global DNA hypomethylation
2. Gene-specific hypermethylation of some CpG islands
Richardson B. Ageing Res Rev 2003;2:245-61.
Waterland RA, Jirtle RL. Nutrition 2004;20:63–8.
Lifelong epigenetic reprogramming: ageing,
diet and environmental toxins
DNA hypomethylation
Genomic instability
Overexpression of proto-oncogenes
27
Lifelong epigenetic reprogramming:
ageing, diet and environmental toxins
Gene silencing due to hypermethylation  with age.
Silencing of genes impair control of cell cycle, apoptosis,
detoxification and cholesterol metabolism.
28
Lifelong epigenetic reprogramming:
ageing, diet and environmental toxins
Dietary and other lifestyle exposures
Epigenetic-mediated changes in gene expression
Change cell function and
health throughout the life course
29
NUTRITION
NUTRITION
Folate, B12, Se, phytochemicals (genistein,polyphenolics)
food contaminants (As)
DNA methylation
31
Folic acid
DIET
DHF
DNMT
DNA methylation
Choline
Diet
32
POTENTIAL IMPLICATIONS OF EPIGENETIC
MODULATION IN OBSTETRICS
Nutrient-gen interactions in early pregnancy
Periconceptional and early pregnancy nutrient-gene interactions;
–
–
–
–
The quality of gamates and fertilization capacity
Embryogenesis and fetal growth
The trophoblast invasion of decidua and spiral arteries
Angiogenesis, vasculogenesis and vascular function
Nutrient-gen interactions in early pregnancy
• Folate, present in follicular fluid and seminal plasma, may
influence the quality of oocytes and sperm.
• This is supported by the significantly increased sperm count
after folic acid and zincsulphate intervention.
Wong WY. Fertil Steril 2002
O’Leary VB. Am J Med Genet 2002
Nutrient-gen interactions in early pregnancy
Folate deficiency and mild hyperhomocysteinemia detrimentally
affect the precise control of embryonic cellular processes such
as migration, differentiation, proliferation, apoptosis and
intracellular signaling.
Loscalzo J. Circulation 2001
Nutrient-gen interactions in early pregnancy
• A diminished embryonic folate status, due to MTHFR and
MTHFR polymorphism’s and interactions with exogenous and
endogenous determinants are risk factors for neural tube and
congenital heart defects.
• Folate deficiency and hyperhomocysteinemia are related to
carotid artery wall thickness and cardiovascular diseases in
later life.
Nutrient-gen interactions in early pregnancy
• The disbalanced folate, homocysteine and NO-status may
disturb embryonic vasculogenesis.
• Nutrient shortages will affect trophoblast function and invasion
and may contribute to spontaneous abortion, preeclampsia
and fetal growth restriction.
Steegers-Theunissen RPM. Br J Obstet Gynaecol, 2000, Leung DH. Am J Obstet Gynecol
2001, Makedos G. Arch Gynecol Obstet 2007, Cotter AM.Am J Obstet Gynecol 2001
Nutrient-gen interactions in early pregnancy
• Apoptosis increases in trophoblastic cells cultured in folate-free
medium.
• Increased apoptosis demonstrated in the placentas from the
pregnancies complicated by preeclampsia.
• Women who develop severe preeclampsia have higher plasma
homocysteine levels in early pregnancy than women who
remain normotensive throughout pregnancy.
Nutrient-gen interactions in early pregnancy
DEFECTIVE IMPRINTING
• Imprinted genes acting on fetoplacental growth;
– Paternally expressed
IGF2, MEST/PEG1, PEG3, INS1, INS2, and MEST
– Maternally expressed;
IGF2R, H19, and GRB10
• These genes are thought to play a role in matching the
placental nutrient supply to fetal nutrient demands.
Nutrient-gen interactions in early pregnancy
DEFECTIVE IMPRINTING
• Fetal growth;
– Maternally imprinted genes enhance
– Paternally imprinted genes diminish or suppress
• Placental growth;
– Paternally expressed genes enhance
– Maternally expressed genes reduce
• Imprinting depends on differential methylation.
• Early malnutrition may alter the methylation pattern, with
consequences for placental function and embryo development.
ARIANE PAOLONI-GIACOBINO PEDIATRIC RESEARCH 2007;61, No. 5, Pt 2,
Nutrient-gen interactions in early pregnancy
High-protein diets in sheep during the periconceptional
period have been associated with reduced developmental
viability and increased fetal and birth weights.
McEvoy TG. Anim Reprod Sci 1997
McEvoy TG. Theriogenology 2001
Nutrient-gen interactions in early pregnancy
• A low-protein diet fed to rats during the preimplantation
period before return to control diet for the remainder of
gestation is associated with several changes in postnatal
phenotype even though offspring were fed a normal diet;
– low birth weight
– subsequent overcompensatory adolescent growth
– onset of adult hypertension
– alterations in relative organ sizing in a gender-specific
manner
Kwong WY. Development 2000
Nutrient-gen interactions in early pregnancy
• Humans ingest approximately 50 mmol of methyl groups per
day of which 60% are derived from choline.
• Excess or deficiency of endogenous or exogenous choline,
methionine, folic acid, vitamin B12, vitamin B6, and zinc may
alter the methyl supply.
• Such a change is expected to affect DNA methylation.
• Genomic DNA methylation status was found to correlate
directly with folate status and inversely with homocysteine levels.
Low concentrations of dietary and
circulating folate
• Neural tube defect
• Preterm delivery
• Low infant birthweight
• Fetal growth retardation
• Premature rupture of membranes
• Defective maternal erythropoiesis
Scholl TO. Am J Clin Nutr 2000;71(5 Suppl):1295S–1303S. Tamura T. Am J Clin Nutr 2006;83:993–
1016. Heil SG. Mol Genet Metab 2001;73:164–72. Shaw GM. Public Health Rep 2004;119:170–3.
Knudtson EJ.Am J Obstet Gynecol 2004;191:537–41.
Low concentrations of dietary and
circulating folate
• Defective growth of the uterus and mammary gland and growth
of the placenta, placental infarctions
• The subsequently elevated maternal homocysteine
concentrations, a metabolic consequence of folate deficiency,
has been associated both with increased recurrent miscarriage,
placental abruption, and pre-eclampsia.
Scholl TO. Am J Clin Nutr 2000;71(5 Suppl):1295S–1303S. Tamura T. Am J Clin Nutr 2006;83:993–
1016. Heil SG. Mol Genet Metab 2001;73:164–72. Shaw GM. Public Health Rep 2004;119:170–3.
Knudtson EJ.Am J Obstet Gynecol 2004;191:537–41.
Folate supplementation during pregnancy
• Supplementing a mother’s nutritionally adequate diet with
extra folic acid, vitamin B12, choline, and betaine can
permanently affect the offspring’s DNA methylation at
epigenetically susceptible loci.
• Population-based supplementation with folic acid, intended to
reduce the incidence of neural tube defects, may have
unintended influences on the establishment of epigenetic gene
regulatory mechanisms during human embryonic development.
Waterland RA, Jirtle RL Mol Cell Biol 2003;23:5293–300.
Finnell RH et al. J Nutr 2002;132(8 Suppl): 2457S–2461S.
Friso S, Choi SW. Curr Drug Metab 2005;6:37–46.
CONCLUSION
Conclusion
• Epigenetic modifications may persist transgenerationally
despite the lack of continued exposure to environmental
influences in future generations.
• Aberrant epigenetic gene regulation has been proposed as a
mechanism for several diseases, including carcinogenesis,
imprinting disorders, Alzheimer’s disease, schizophrenia,
asthma, and autism.
Conclusion
• Obstetricians are undoubtedly responsible for providing care
to women and their fetuses during some of the most dynamic
windows for epigenetic reprogramming.
• Reproductive life planning and periconception advice
• Women
• Men
• Approaches to life style in fertility clinics
• Preconception interview
• Planning
• Advice
• Information
• Resources
Conclusion
Fertility fitness;
• Lessons on diet
• Periconception medicine;
– Life style factors before conception for natural and induced
pregnancies.
Conclusion
Conclusion
• The impact of environmental and nutritional factors on the
dynamic state of the epigenome and their potential roles in
epigenetic dysregulation in determining maternal, fetal and
long-term outcomes should be taken into consideration.
• Obstetricians are undoubtedly responsible for providing care
to women and their fetuses during some of the most dynamic
windows for epigenetic reprogramming.
IVF TEK GEBELİKLERİ
• Helsinki University Central Hospital
• 7 yıllık kohort çalışma (1997–2003)
• Tek doğumla sonuçlanan Taze TET, ÇET ve spontan tek
gebeliklerin obstetrik ve neonatal sonuçları
karşılaştırılmış
Poikkeus P. Hum Reprod 2007
N.Turhan
TET SONRASI OBSTETRİK VE
NEONATAL SONUÇLAR
Poikkeus et al 2007
N.Turhan
TET SONRASI OBSTETRİK VE
NEONATAL SONUÇLAR
TET gebeliklerinde yaş, parite ve sosyoekonomik duruma
göre sonuçlar düzenlendiğinde kontrol grubuna göre;
– C/S riski
OR=1.54
– Preterm doğum
OR=2.85
– Düşük doğum ağırlığı
OR=2.01
Poikkeus et al 2007
N.Turhan
TET SONRASI OBSTETRİK VE
NEONATAL SONUÇLAR
Tekil IVF gebeliklerinde transfer edilen embryo sayısından çok kişiye ait
faktörler ve infertilite ile ilgili mekanizmalar neonatal sonuçları etkiler.
Poikkeus et al 2007
N.Turhan
İVF TEK GEBELİKLERİ
Acaba tranfer edilen embryo sayısının etkisi var mı?
• İkiz veya daha fazla çoğul gebelikle başlayan IVF/ICSI
tekil gebeliklerinde prematür doğum oranı yüksek
Dickey et al 2004
• Erken USG de birden fazla FKA olan IVF/ICSI tekil
gebeliklerinde düşük doğum ağırlığı oranı yüksek
Schieve et al 2002
N.Turhan
TET SONRASI OBSTETRİK VE
NEONATAL SONUÇLAR
1998 -2003 TET gebelikleri prospektif olarak toplanmış
251 TET sonrası tekil gebelik sonuçları 59 535 spontan
tekil gebelik sonuçları ile karşılaştırılmış
D. De. Neubourg et al. Hum Reprod 2006
N.Turhan
TET SONRASI OBSTETRİK VE
NEONATAL SONUÇLAR
De Neubourge 2006
N.Turhan
TET SONRASI OBSTETRİK VE
NEONATAL SONUÇLAR
De Neubourge 2006
N.Turhan
TET SONRASI OBSTETRİK VE
NEONATAL SONUÇLAR
TET yapılan iyi prognozlu hastalarda gebelik şansı
daha düşük olsa da gebelik sonuçları spontan tekil
gebeliklerden farklı değildir.
De Neubourge 2006
N.Turhan
Genomic imprinting
Genomic imprinting in mammals describes the
situation where there is nonequivalence in expression
of alleles at certain gene loci, dependent on the parent
of origin.
Reik W, Walter J.Genet Dev 1998;8:154–64.
Tilghman SM. Cell 1999;96:185–93.
Genomic imprinting
The expression of either the paternally or maternally
inherited allele is consistently repressed, resulting in
monoallelic expression of a particular gene.
The same pattern of monoallelic expression is faithfully
transmitted to daughter cells following cell division.
Genomic imprinting
PWS and AS are both due to
deletion of 15q11-13, but manifest
differently depending on whether the
allele was inherited from the mother
or the father.
Failure to inherit the paternal
region gives PWS.
Failure to inherit the maternal
region gives AS.
FETAL ORIGINS HYPOTHESIS OF
ADULT DISEASE
Fetal origins hypothesis of adult disease
Barker hypothesis;
The observation that individual subjects who were small or
disproportionately large at birth had higher occurrence of adult;
– obesity
– coronary artery disease
– hypertension
– type II diabetes at middle age
Ravelli GP. N Engl J Med 1976;295:349–53, Muskiet FA. Reprod Toxicol 2005;20:403–
10, Curhan GC. Circulation 1996;94:3246–50, Barker DJ. Br J Obstet Gynaecol
1992;99:275–6, Barker DJ. J Am Coll Nutr 2004;23(6 Suppl):588S–595S.
Fetal origins hypothesis of adult disease
• Experimental data in animals and recent human
observations have suggested that early-life exposures can
result in alterations to a range of systems, including the
hypothalamic–pituitary–adrenal axis, blood pressure and
insulin sensitivity.
Michael J.Davies and Robert J. Norman TRENDS in Endocrinology & Metabolism Vol.13 No.9 2002
Fetal origins hypothesis of adult diseases
The presence of PCO is associated positively with birth weight
and insulin sensitivity, whereas an underlying insulin resistance
appears to be associated with indicators of impaired fetal growth.
Studies have consistently related low birth weight with insulin
resistance.
Cresswell, J.L. Lancet 1997;350:1131–1135
Michelmore, K. Clin. Endocrinol. (Oxf.) 2001;55:439–446
Phillips, D.I. Clin. Exp. Pharmacol. Physiol 2001:28;967–970
Fetal origins hypothesis of adult diseases
Of babies weighing >3.9 kg born to mothers weighing >58.1 kg in
pregnancy, 44% had PCO.
The heavy babies were also larger as adults, with an average BMI >25
kg m2.
Cresswell JL. Lancet. 1997 Oct 18;350(9085):1131-5.
Fetal origins hypothesis of adult diseases
Obese, hirsute women with PCO with higher ovarian androgens have
higher birthweight and maternal obesity.
Thin women with PCO have altered hypothalamic control of LH release
resulting from prolonged gestation.
Cresswell JL. Lancet. 1997 Oct 18;350(9085):1131-5.
Fetal origins hypothesis of adult diseases
Experimental administration of testosterone to pregnant rhesus monkeys
results in virilization of external genitalia, masculinization of behavior,
delayed menarche, increased insulin secretion and enlarged and
polyfollicular ovaries.
Abbott, D.H. In Polycystic Ovary Syndrome (Chang, R.J. et al., eds), pp. 119–133,
Periconceptional Environment
Fetal growth is most vulnerable to maternal dietary deficiencies
of nutrients (e.g. protein and micronutrients) during the peri-
implantation period and the period of rapid placental development.
Maloney CA, Rees WD.Reproduction 2005;130:401–1, Waterland RA, Jirtle RL Nutrition
2004;20:63–8, Gluckman PD, Hanson MA. Horm Res 2006;65(Suppl 3):5–14.
Smoking & Female Infertility
• Current tobacco smoking by women decreases
ovarian function and is manifested by increased
basal levels of follicle stimulating hormone.
• Such women produce fewer oocytes during ART and
have lower pregnancy rates.
Neal MS. Hum Reprod 2005;20:2531–5.
Smoking & Male Infertility
• Current smoking by the male partner also
decreases pregnancy rates through direct
effects on sperm and by exposing the woman
partner to side-stream smoke.
Maternal Smoking during pregnancy
Inverse association between maternal smoking during pregnancy
and total sperm count (p = 0.002). Men exposed to more than 19
cigarettes daily during pregnancy had ;
– 9% lower semen volume (p = 0.04)
– 38% lower total sperm count (p = 0.11)
– 17% lower sperm concentration (p = 0.47) compared with
unexposed men.
• The odds ratio for oligospermia was 2.16 among exposed men
compared with the unexposed.
• No associations were found for sperm motility or morphology.
Ramlau-Hansen CH. Am J Epidemiol. 2007 165(12):1372-9.
Parental periconceptional smoking and
male: female ratio of newborn infants
• The offspring sex ratio (male to female) was lower
when either one or both of the parents smoked more
than 20 cigarettes per day compared with couples in
which neither of the parents smoked.
• The lowest sex ratio among children whose mothers
and fathers both smoked more than 20 cigarettes per
day (p<0.0001).
• Parental periconceptional smoking might be a
contributing factor to a lower male to female sex ratio
of offspring.
• Fukuda M, Fukuda K, Shimizu T, Andersen CY, Byskov
AG.
Oxidative Stress and Male Infertility
Tremellen K. Hum Reprod Update 2008, pp. 1-16
Oxidative Stress and Male infertility
Men’s age and infertility
As men’s age increases, the time required for
a couple to conceive lengthens, even after
controlling for the woman’s age and other risk
factors for reduced fertility.
Hassan MAM. Fertil Steril 2003
the odds ratio for infertility was 1.20 for overweight men [BMI 25–29.9) and 1.36 for obese
men (BMI 30–34.9) relative to men with low-normal BMI (20.0–22.4).
When BMI was divided into eight categories, there was a trend of increased infertility with
increased male BMI.
Linear regression revealed a significant (P , .05) and negative relationship between
BMI and the total number of normal-motile sperm cells.
The number of normal-motile sperm cells per BMI group was as follows: normal,
18.66106; overweight, 3.66106; and obese, 0.7 6 106.
• a steadily increasing rate of infertility for BMIs above 24
• Even among women who subsequently became pregnant,
increasing BMI was correlated with longer times to
conception and pregnancy (3). Once pregnancy is achieved
in a woman with a high BMI, there is a substantially
increased risk of miscarriage and of pregnancy
complications.
• The chances of congenital abnormalities, pregnancy
induced hypertension, diabetes mellitus, preterm labor,
surgically assisted delivery, shoulder dystocia, stillbirth and
neonatal death, and postpartum complications are all
substantially increased (4).
data from Wang et al. on several thousand women undergoing IVF indicated
a very substantial increase in failed IVF once the BMI reached 30.
Obesity & early and recurrent
miscarriage
There is a high incidence of early and recurrent
miscarriages in overweight women compared
with controls.
Wang JX. Obes Res 2002;10:551–4.
Lashen H. Hum Reprod 2004;19:1644–6.
Factors associated with premature delivery
Effects of obesity on assisted
reproductive technology outcomes
• The first cycles of ovum donation and stratified the
recipients by BMI
• The eggs obtained from healthy donors with a BMI
range of 22.3 3.5 kg/m2.
• A significantly decreased implantation rate as the
BMI increased and an ongoing pregnancy rate that
was significantly decreased with the raised BMI.
Bellver J. Fertil Steril. 2007;88:446-51.
Effects of obesity on assisted reproductive
technology outcomes
• The other studies on the use of the donor egg model
did not support the observation that increased BMI
has a negative impact on implantation rates.
Wattanakumtornkul S. Fertil Steril 2003;80:336–40.
Styne-Gross A. Fertil Steril 2005;83:1629–34.
Nonobese users had a reduction (OR ¼ 0.54) in risk of SGA (<5th percentile); there was no
effect among obese women. There was no effect of multivitamin use on risk of preterm
births (34–<37 weeks) or SGA(5th–<10th percentiles).
Conclusion
• Reproductive life planning and periconception advice
• Women
• Men
• Approaches to life style in fertility clinics
•
•
•
•
•
Preconception interview
Planning
Advice
Information
Resources
Conclusion
Fertility fitness;
• Lessons on diet
• Periconception medicine;
– Life style factors before conception for natural and induced
pregnancies.
Histone modification
Methylation
Acetylation
111
Histone modification
Change the chromatin structure
Influence DNA accessibility to factors regulating
replication, repair and transcription
Genes repressed or active
112
Fetal programming
Both increased and decreased expression of IGF2 alter
placental size and efficiency.
Imprinting, in this case, depends on differential methylation.
Early malnutrition may alter the methylation pattern, with
consequences for placental function and embryo development.
Fetal origins hypothesis of adult diseases
The severity and duration of nausea and vomiting;
• Negatively correlated with birth weight
• Reduced risk of miscarriage in women identified to be at risk
• Reduced risk of miscarriage in teenage pregnancy.
Zhou, Q. et al. () Birth 1999:26; 108–114
Furneaux, E.C. Obstet. Gynecol. Surv. 2001:56;775–782
Fetal origins hypothesis of adult diseases
Elevated mean serum insulin (± SD) after oral glucose tolerance test
by age in low-birthweight children (triangles) compared to normal
birthweight children (circles).
Ibanez L. 1998 J. Clin. Endocrinol. Metab.
Nutrient-gen interactions in early pregnancy
Maternal diet may have a lifelong effect on gene
expression with the potential to cause susceptibility for
chronic diseases in adulthood.
Nutrient-gen interactions in early pregnancy
• Folate, present in follicular fluid and seminal plasma, may
influence the quality of oocytes and sperm.
• This is supported by the significantly increased sperm count
after folic acid and zincsulphate intervention.
• The associations between polymorphism’s in MTHFR and MTHFR
genes and the increasing likelihood of meiotic nondisjunctions,
such as in Down syndrome, support this hypothesis.
Wong WY. Fertil Steril 2002
O’Leary VB. Am J Med Genet 2002
Fetal origins hypothesis of adult diseases
Birth weights >4 kg were associated with relative risks of 1.5–
1.7 for breast cancer compared with normal birth weights of
2.5–2.9 kg.
Trichopoulos, D. Lancet 1990:335;939–940
Nutrient-gen interactions in early pregnancy
• Angiogenesis, vasculogenesis and vascular function are
dependent on the genetic constition of the embryo, derived
from both parents, and the maternal genetically controlled
nutritional environment.
• The disbalanced folate, homocysteine and NO-status may
disturb embryonic vasculogenesis, through which the delivery
and clearence of these and other nutrients is compromised.
• Nutrient shortages will affect trophoblast function and invasion
and may contribute to spontaneous abortion, preeclampsia
and fetal growth restriction.
Steegers-Theunissen RPM. Br J Obstet Gynaecol, 2000, Leung DH. Am J Obstet Gynecol
2001, Makedos G. Arch Gynecol Obstet 2007, Cotter AM.Am J Obstet Gynecol 2001
Fetal programming
• Intrauterine epigenetic reprogramming of the GH/IGF axis may
influence postnatal growth and insulin resistance, serving as the
link between fetal growth and adult onset disease.
• IUGR is likely to involve GH/IGF axis with distinct changes in the
growth factors and their interaction with corresponding
receptors.
Periconceptional Environment
The chance of having a live birth from ART therapy is influenced
by the health habits and the infertility diagnoses of the couple.
IVF TEK GEBELİKLERİ
• Helsinki University Central Hospital
• 7 yıllık kohort çalışma (1997–2003)
• Tek doğumla sonuçlanan Taze TET, ÇET ve spontan tek
gebeliklerin obstetrik ve neonatal sonuçları
karşılaştırılmış
Poikkeus P. Hum Reprod 2007
N.Turhan
Low concentrations of dietary and circulating folate
•
•
•
•
•
•
Neural tube defect
Preterm delivery
Low infant birthweight
Fetal growth retardation
Defective maternal erythropoiesis
Defective growth of the uterus and mammary gland and growth
of the placenta, placental infarctions
• Premature rupture of membranes
• The subsequently elevated maternal homocysteine
concentrations, a metabolic consequence of folate deficiency,
has been associated both with increased recurrent miscarriage,
placental abruption, and pre-eclampsia.
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2006;83:993–1016. Heil SG. Mol Genet Metab 2001;73:164–72. Shaw GM. Public Health Rep
2004;119:170–3. Knudtson EJ.Am J Obstet Gynecol 2004;191:537–41.