Sayeras Haag, Rosa Cristina

Universitat Autònoma de Barcelona. Facultat de Biociències

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Do Assisted Reproductive Technologies Implicate  Epigenetic Risks?  Rosa Cristina Sayeras Haag, Biomedical Sciences, UAB  Mentor:  Dra. Francesca Vidal,  Department of Cell Biology, Phisiology and Immunology, UAB Introduction Recent estimations suggest that 1 in 10 people of reproductive age are infertile. There is a high percentage of couples requesting the use of Assisted Reproductive Technology (ART).   Although some risks due to the use of this technology have been described, ART are considered safe. However, there is some controversy about ART contribution to increased epigenetic risk in offspring.  After commenting the genetic imprinting cycle and their relation with ART, epigenetic risks due to this technology will be revised.              Genetic imprinting Imprinted genes has either a paternal or maternal expression (figure 1). Errors in the imprinting marks can be responsible for human diseases such as Angelman Syndrome (AS) or Beckwith-Widemann Syndrome (BWS).   Genomic imprinting requires sex-specific marks in the genome which imply a resetting of these marks in every generation. The imprinting cycle (figure 2) consists in three phases: ART and imprinting  The use of ART necessarily involves the acquisition and sometimes manipulation of gametes, zygotes or embryos during the time when imprinting takes place. The most discussed procedures used in ART as possible inductors of imprinting errors are:   ART and human disease  Since 2002 several studies have been published describing an increased risk of AS and BWS after the use of ART, and especially after the use of IVF and ICSI.    Angelman Syndrome Neurodevelopmental disorder   (1 in 16.000 births)  In a general population 5% of AS cases are due to imprinting errors  The 35’3% of ART-associated AS have aberrant imprinting.   Beckwith-Widemann Syndrome Overgrowth disorder with  (1 in 13.700 births)  In a general population 50-60% of BWS cases are due to imprinting errors  The 58’7% of ART-associated BWS  have aberrant imprinting Glossary  ART: all treatments or procedures used for the purpose of achieving a pregnancy. ART includes, but it is not limited to, handling of human gametes or of embryos, in vitro fertilization, embryo transfer and gametes or embryo cryopreservation. ART does not include assisted insemination.  Infertility: a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.  Epigenetics: gene expression regulation based on changes in the chromatin structure that is not dependent on the DNA sequence and is inheritable.   Imprinted genes: genes that have a monoallelic expression due to an epigenetic regulation. Conclusions  Considering the overlap between the majority of epigenetic reprogramming events during the gametogenesis or the embryonic development and the timing of ART, it is possible that suboptimal conditions in ART may induce imprinting errors.  But, is there a real risk? Yes, there are risks There is an increased number of ART-associated imprinting disorders caused by aberrant imprinting No, there are no risks The recent cohort studies have failed to confirm the association between ART and imprinting disorders MORE STUDIES ARE NEEDED Selected Bibliography  Eroglu A et al. Role of ART in imprinting disorders. Semin Reprod Med 2012;30:92-104. Laprise SL. Implications of epigenetics and genomic imprinting in assisted reproductive technologies. Mol Reprod Dev. 2009 Nov;76(11):1006-18 Lucifero D et al. Potential significance of genomic imprinting defects for reproduction and assisted reproductive technology. Hum Reprod Update. 2004 Jan-Feb;10(1):3-18 Marchesi DE et al. Embryo manipulation and imprinting. Semin Reprod Med. 2012 Aug;30(4):323-34. Figure 1. Non-imprinted genes are expressed from either both alleles (gene A) or none of them (gene B). Imprinted genes have a monoallelic expression, therefore they allow only the paternal allele (gene C) or the maternal allele (gene D) expression.   Adapted from: Eroglu et al. Semin Reprod Med. 2012;30:92-104    Figure 2. Methylation dynamics during germ cells development, fertilization and early embryo development. Methylation dynamics of paternal and maternal imprinted genes are shown by the dark blue and dark red lines respectively. Light blue and light red show the methylation dynamics of  paternal and maternal non-imprinted genes respectively.  The phases during development when ART procedures may induce imprinting errors are: SOPS =suboptimal sperm, SO = superovulation, IVM =in vitro maturation of oocytes, IVF = in vitro fertilization, ICSI =intracytoplasmic sperm injection, EC = embryo culture.    Adapted from: Lucifero et al. Hum Reprod Update. 2004;10:3-18    Non imprinted Genes         Expressed Gene        Non-Expressed Gene Imprinted Genes     Paternal Expressed Gene    Maternal Expressed Gene    C                                               D    C                                               D    A                                               B    A                                               B Superovulation: premature release of oocytes In vitro maturation of oocytes: abnormal environment for the gametes maturation  The use of suboptimal sperm: immature imprinting marks In vitro fertilization: abnormal environment   ICSI: stress due to the procedure Embryo culture: abnormal environment when general demethylation occurs Erasure: takes place in the primordial germ cells (PGCs).  Establishment: takes place during the germ cells development. Imprinting marks are acquired earlier in the development in male gametes than in females. Maintenance: during the early embryo development there is a general demethylation of the genome that does not affect imprinted genes.       Erasure                                                                      Establishment                                                                                                                    Maintenance             SOPS                                   SO                                    ICSI                         EC                                                        IVM                                               IVF                                                                                                     Germ cell development                                              Fertilization                                                 Early embryo development Methylation  Time 

Do assisted reproductive technologies implicate epigenetic risks?

http://ddd.uab.cat/pub/tfg/2013/112860/TFG_rosacristinasayerashaag.pdf

Do assisted reproductive technologies implicate epigenetic risks?

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