Family Beginnings logo

 
  HOME
  OUR MISSION
  PROGRM ACCREDITATION
  SERVICES
  THE TEAM
  PATIENT EDUCATION
  IVF PACKET
  POOLED IVF w/ PGS
  MINI-IVF
  NEED AN EGG DONOR?
 BECOME AN EGG DONOR
 EMBRYO ADOPT. PKT
 GESTATIONAL SURROGACY
 PGD/PGS
 PGS ECONOMICS
 EGG FREEZING
 COUNSELING PACKET
 FET PACKET
  LONG DISTANCE IVF
 MALE FERT. TESTING
 OFFICE HYSTEROSCOPY
  NEW PATIENT PACKET
  LINKS
  EMAIL THE DOCTOR
  CONTACT US
  OUR NEW OFFICE
  OUR NEW IVF LAB
 
  Patient Portal
 
  Translate website
 

   

   

ART, Epigenetics, & Genetic Imprinting Diseases

Most mutations involve changes in DNA. The chromosomes are made up of DNA wrapped in special proteins called histones. Epigenetic mechanisms involve DNA and histone modification where gene changes are heritable and do not involve DNA sequence changes (1). Genes may be activated or repressed based on methyation status. Methlyation involves the placement of a methyl group, -CH3, on the DNA or protein which alters its function. Genomic imprinting refers to a unique mode of gene expression where the fetal growth and development are directed by the allele derived from the paternal or maternal chromosomes. Parent of origin expression is preserved through epigenetic modification. In a very real sense we inherit certain traits from our mother or father. More data suggests that these mechanisms are crucial for embryonic growth and survival. Some epigenetic diseases have been reported to be increased in the offspring of IVF-ICSI patients. Some cells where micromanipulation has been used, such as cloning and human embryonic stem cells, have shown abnormal imprinting. Whether it is the procedure itself, the patients or cells of origin, or culture of gametes/embryos is not clear. It is prudent to keep these factors in mind when we consider these technologies. The benefit should out weigh the risk.

Epigenetic modification of the genome changes throughout life from the primordial germ cell to mature gamete through zygote and embryo. ART/micromanipulation may affect the process at the time of oocyte maturation, manipulation, and gamete and embryo culture. Three phases are recognized: erasure, establishment, and maintenance (2). Imprints are erased in the germline as the primordial germ cells migrate to the future gonad by day E11.5 (i.e. embryonic day 11.5) in the mouse. Global demethylation occurs by E13.5 followed by re-methylation from E15.5 in many sequences (except CpG islands). Establishment, that is methylation, occurs later. In the female, the oocytes in the meiotic dictyate stage of arrest are not methylated until after birth, when methylation occurs during oocyte growth. High levels of DNA methyltransferase 1 (Dnmt1) are in the nucleus. After the zygote is formed, there is rapid active de-methylation of the male pronucleus within 4 hours of fertilization. The maternal genome is slowly and passively de-methylated. Imprinted genes retain their gamete derived methylation allowing allele specific, monoallelic expression during embryo growth (3). Thus, in the early embryo some genes are expressed based on which parent they came from. As you can see, in IVF we stimulate egg production, fertilize naturally or with ICSI, and grow the embryos in culture at a time when many of these events are occurring. Is it possible that our manipulations may alter these events?

Several experiments illustrate the importance of epigenetics to development and ART. Dnmt1 knockout mice (i.e. genetically engineered not to have this enzyme and therefore can not methylate DNA) fail to develop, paternal disomy conceptuses (both gene alleles from the father) have poor embryonic growth and normal extraembryonic membranes, and maternal disomy conceptuses (both gene alleles from the mother) have poor extraembryonic membrane development (4). Beckwith-Wiedemann Syndrome is linked to a cluster of imprinted genes on 11p15.5, Prader-Willi syndrome, (15p11-13) and Angleman Syndrome (15p11-13) are also associated with imprinting defects, as is retinoblastoma. Several clinical studies reported and increased incidence of these conditions in patients undergoing ART (reviewed in 4). Gosden et al, (5) noted a significant increase in these rare conditions and suggested increased surveillance of outcomes and larger studies. For instance, Angelman Syndrome has an incidence of 1/300,000 in the general population and 1/30,000 in ICSI (6). While this is a 10-fold increase, it is clear that very large studies are needed to confirm the data. Most studies to date are of insufficient power to detect real changes, but certainly raise the question whether the ICSI procedure may alter the DNA methylation status of the mature oocyte and zygote leading to serious disorders in children conceived through ICSI. From the above, it is important that we keep these factors in mind when we make our decisions to use these technologies and base these decisions on the most complete data and recommendations available.

References:

1. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. 2004. Nature429:457-463.

2. Constancia M, Pickard B, Kelsey G, Reik W. Imprinting mechanisms. 1998. Genome Research. 8(9):881-900.

3. Kelly TLJ, Trasler JM. Reproductive epigenetics. 2004. Clin. Genet. 65:247-260.

4. Niemitz EL, Fineberg AP. Epigenetics and assisted reproductive technology: a call for investigation. 2004. Am. J. Hum. Genet. 74:599-609.

5. Gosden R, Trasler J, Lucifero D, Faddy M. Rare congenital disorders, imprinted genes, and assisted reproductive technology. 2003. Lancet. 361: 1975-77.

6. Kurinczuk J. from theory to reality- just what are the data telling us about ICSI offspring health and future fertility and should we be concerned? 2003. Hum. Repro. 18(5)925-931.
 

 

Copyright 2004-2016 Family Beginnings, PC - Indianapolis, Indiana
Phone:  317-865-0411 and 317-595-3665
Disclaimer