Epigenetic Effects of Assisted Reproductive Technologies

Assisted reproductive technologies (ART) encompass procedures such as ovarian stimulation, in vitro fertilisation, intracytoplasmic sperm injection and embryo cryopreservation. These interventions coincide with critical windows of epigenetic reprogramming during gametogenesis and early embryonic development. Accumulating evidence indicates that ovarian hormone treatments, culture conditions and mechanical manipulations can perturb DNA methylation patterns, histone modifications and the establishment of parent-of-origin imprints. Such epigenetic disturbances have been linked to altered placental morphology, dysregulated nutrient transport and long-term changes in growth trajectories, metabolic regulation and neurodevelopment. Although many imprinting perturbations appear transient, some loci retain aberrant marks that may predispose offspring to rare imprinting disorders or subtle phenotypic alterations. Understanding these effects is essential for optimising protocols that safeguard the epigenome and ensure the wellbeing of ART-conceived individuals.

Research from Nature Portfolio

Genome-wide analyses of human placental tissue have revealed that ART-associated methylation changes concentrate in pathways governing hormonal signalling, insulin secretion, vascular development and neuronal differentiation. In particular, reductions in the expression of TRIM28 and NOTCH3 implicate impaired angiogenesis and growth, while decreased methylation stability at imprinted domains points to a weakened imprint maintenance machinery. Comparative evaluation of fresh versus frozen embryo transfer established that growth-related methylation alterations coincide more strongly with fresh transfers, whereas some compensatory changes emerge following cryopreservation. Longitudinal profiling of blood methylation demonstrates that ART-linked DNA methylation differences are most pronounced at birth but largely normalise by early adulthood. These findings suggest that although ART can introduce epigenetic variation during the periconceptional period, most of these alterations resolve over time without apparent adverse health outcomes in mature offspring.

Epigenetic Effects of Assisted Reproductive Technologies publication trend

The graph below shows the total number of articles in epigenetic effects of assisted reproductive technologies across all publications each year (not limited to Nature Index journals).

Technical terms

DNA methylation: Addition of a methyl group to cytosine bases, a key epigenetic mark that modulates gene expression.

Genomic imprinting: Parent-of-origin-specific gene expression regulated by epigenetic marks established during gametogenesis.

5-methylcytosine (5mC): The methylated form of cytosine, associated with transcriptional repression.

5-hydroxymethylcytosine (5hmC): An oxidised derivative of 5mC involved in active DNA demethylation pathways.

Imprinting control region: A DNA segment bearing differential methylation that governs monoallelic expression of imprinted clusters.

References

1. High estrogen during ovarian stimulation induced loss of maternal imprinted methylation that is essential for placental development via overexpression of TET2 in mouse oocytes. Cell Communication and Signaling (2024).
2. Genome-wide DNA methylation and gene expression in human placentas derived from assisted reproductive technology. Communications Medicine (2024).
3. Long-Term Effects of ART on the Health of the Offspring. International Journal of Molecular Sciences (2023).
4. Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes. Reproductive Biology and Endocrinology (2024).
5. Capturing sex-specific and hypofertility-linked effects of assisted reproductive technologies on the cord blood DNA methylome. Clinical Epigenetics (2023).
6. Association of four imprinting disorders and ART. Clinical Epigenetics (2019).
7. Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood. Nature Communications (2019).