Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood

Abstract

More than 7 million individuals have been conceived by Assisted Reproductive Technologies (ART) and there is clear evidence that ART is associated with a range of adverse early life outcomes, including rare imprinting disorders. The periconception period and early embryogenesis are associated with widespread epigenetic remodeling, which can be influenced by ART, with effects on the developmental trajectory in utero, and potentially on health throughout life. Here we profile genome-wide DNA methylation in blood collected in the newborn period and in adulthood (age 22–35 years) from a unique longitudinal cohort of ART-conceived individuals, previously shown to have no differences in health outcomes in early adulthood compared with non-ART-conceived individuals. We show evidence for specific ART-associated variation in methylation around birth, most of which occurred independently of embryo culturing. Importantly, ART-associated epigenetic variation at birth largely resolves by adulthood with no direct evidence that it impacts on development and health.

Integrated multi-omics reveal epigenomic disturbance of assisted reproductive technologies in human offspring

“…Our study was mainly focused on the effects of different fertilization methods and freeze-thawing and only involved newborns, lacking postnatal follow-up data on the enrolled populations. However, it is worth noting that the two stable DMRs ( CHRNE- and PRSS16 - associated) persisting in adults reported previously [65] were both observed in our final neonatal DMRs identified. It suggested that a larger multicenter randomized controlled trial (RCT) along with detection of the epigenetic profiles of offspring in later life would be helpful for elucidation of continued epigenetic changes, their association with the long-term health risks, and exploration of the specific epigenetic impacts of other factors in ART treatment, such as the duration of embryo culture or the composition of culture system.…”

“…Recently, Boris Novakovic, et al. reported ART-related changes in DNA methylation of blood from ART and non-ART-conceived individuals in the CHART cohort by using the EPIC array [65] . However, there were only 18 DMRs identified in their neonates’ group, which might stem in part from the limited number and special genomic locations of selected CpGs.…”

Long-Term Phenotypic and Proteomic Changes Following Vitrified Embryo Transfer in the Rabbit Model

“…Nevertheless, extreme stressors, such as ART conditions, can force developing embryos to carry out a strong reshaping of their developmental trajectories to guarantee their short-term survival [ 3 , 4 , 5 ]. However, this reprogramming in embryonic cells that subsequently forms tissues and organ systems may influence an individual’s susceptibility to alterations in growth, development and health [ 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Controversially, ART has been linked in humans with adverse obstetric and perinatal outcomes, birth defects, cancers, growth disorders, obesity and chronic ageing-related diseases [ 10 ].…”

Long-Term Effects Following Fresh/Vitrified Embryo Transfer Are Transmitted by Paternal Germline in a Large Size Rabbit Cohort

“…Moreover, we found a comparable growth performance between FT and VT animals from both the Pc and Mc generations, suggesting that disturbing optimal embryo development through its recovery, in vitro handling, and mechanical manipulation during its transfer to a new foster mother was the principal trigger of transmissible effects, rather than embryo cryopreservation per se. Mounting evidence suggests that ARTs incur short- and long-term developmental deviations in the offspring, which are thought to be mediated by epigenetic mechanisms [ 1 , 2 , 3 , 13 , 14 , 15 , 17 , 23 , 27 ]. Recently, we demonstrated that both mandatory ARTs involved in a vitrified embryo transfer procedure (i.e., embryo transfer and embryo cryopreservation) incurred cumulative developmental effects, reducing the growth performance as in vitro manipulation increased [ 12 ].…”

“…The concept of developmental programming suggests that the early life environment influences offspring characteristics in later life, but growing evidence also suggests that these effects may also be manifested in further generations without further suboptimal exposure [ 16 , 17 , 18 , 19 , 20 ]. Our recent study demonstrated that the transfer of cryopreserved embryos incurs transgenerationally inheritable effects over the offspring growth performance, adult body weight, phenotype of vital organs, and their molecular physiology and metabolism [ 20 ].…”