Epigenetic Risks of Medically Assisted Reproduction

Abstract

Since the birth of Louise Joy Brown, the first baby conceived via in vitro fertilization, more than 9 million children have been born worldwide using assisted reproductive technologies (ART). In vivo fertilization takes place in the maternal oviduct, where the unique physiological conditions guarantee the healthy development of the embryo. During early embryogenesis, a major wave of epigenetic reprogramming takes place that is crucial for the correct development of the embryo. Epigenetic reprogramming is susceptible to environmental changes and non-physiological conditions such as those applied during in vitro culture, including shift in pH and temperature, oxygen tension, controlled ovarian stimulation, intracytoplasmic sperm injection, as well as preimplantation embryo manipulations for genetic testing. In the last decade, concerns were raised of a possible link between ART and increased incidence of imprinting disorders, as well as epigenetic alterations in the germ cells of infertile parents that are transmitted to the offspring following ART. The aim of this review was to present evidence from the literature regarding epigenetic errors linked to assisted reproduction treatments and their consequences on the conceived children. Furthermore, we provide an overview of disease risk associated with epigenetic or imprinting alterations in children born via ART.

Keywords: assisted reproductive technology; epigenetics; human in vitro fertilization; imprinting disorders.

Figure 1

Scheme illustrating in vitro and in vivo fertilization. Controlled ovarian stimulation (COS) is used to promote follicle growth, maturation, and ovulation. ART adopts either IVF or ICSI for fertilization. Following fertilization, the preimplantation embryo is cultured in incubators, where suboptimal culture conditions such as pH, oxygen, temperature, and osmolality may affect its further development. Finally, the in vitro-produced embryo is transferred to the uterus at the cleavage or blastocyst stage. On the other hand, in vivo the female and male gametes interact together and the sperm fertilizes the oocyte in the infundibulum. Next, the developing embryo moves towards the uterus interacting with the female reproductive system in a physiologic and optimal environment.

Figure 2

The human blastocyst. The structure comprises two differentiated cell types and a central cavity filled with fluid (blastocoel cavity). The inner cell mass (ICM) becomes the fetus and the trophectoderm (TE) cells later develop into the placenta.

Figure 3

Epigenetic reprogramming during the early stage of embryo development. Post-fertilization, the paternal genome undergoes active demethylation, whereas the maternal genome is passively demethylated. The scheme illustrates the stage of development at which different ART techniques are employed.

Figure 4

Paternal and maternal lifestyle prior to conception may affect sperm and oocyte epigenetic changes, offspring epigenetics, and phenotypic abnormalities, including increased risk of cardiovascular and metabolic disease in later life.