Epigenetics and assisted reproductive technology: a call for investigation

Abstract

A surprising set of recent observations suggests a link between assisted reproductive technology (ART) and epigenetic errors--that is, errors involving information other than DNA sequence that is heritable during cell division. An apparent association with ART was found in registries of children with Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma. Here, we review the epidemiology and molecular biology behind these studies and those of relevant model systems, and we highlight the need for investigation of two major questions: (1) large-scale case-control studies of ART outcomes, including long-term assessment of the incidence of birth defects and cancer, and (2) investigation of the relationship between epigenetic errors in both offspring and parents, the specific methods of ART used, and the underlying infertility diagnoses. In addition, the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes.

Figure 1

Dynamic reprogramming of the epigenome during development. Epigenetic marks, including DNA methylation and genomic imprinting, are reprogrammed during normal gametogenesis. Primordial germ cells undergo epigenetic erasure as they migrate along the genital ridge, and epigenetic marks are reestablished during gametogenesis, differentially in sperm (blue) and egg (pink). For example, after fertilization, there is active demethylation of the paternal pronucleus, and then a second wave of passive demethylation of the zygote genome. Imprinted genes (dotted line) are protected from this erasure. During development, tissue-specific epigenetic patterns emerge. The drawing is stylized, as details are unknown.