Are there subtle genome-wide epigenetic alterations in normal offspring conceived by assisted reproductive technologies?

Abstract

Objective To review recent data regarding subtle, but widespread epigenetic alterations in phenotypically normal offspring conceived of ART compared to offspring conceived in vivo. Design A PubMed computer search was performed to identify relevant articles. Setting Research institution. Intervention(s) None. Result(s) Studies in animals indicate that in vitro culture may be associated with widespread alterations in imprinted genes, compared to in vivo-conceived offspring. Recently, studies in humans have likewise demonstrated widespread changes in DNA methylation, including genes linked to adipocyte development, insulin signaling, and obesity in offspring conceived by ART, compared to in vivo-conceived children. Changes in multiple imprinted genes following ART were also noted in additional studies, which suggested that the diagnosis of infertility may explain the differences between in vivo-conceived and ART offspring. Conclusion(s) These data suggest that ART is associated with widespread epigenetic modifications in phenotypically normal children, and that these modifications may increase risk of adverse cardiometabolic outcomes. Further research is needed to elucidate the possible relationship between ART, genome-wide alterations in imprinted genes, and their potential relevance to subtle cardiometabolic consequences reported in ART offspring.

A Molecular Perspective on Procedures and Outcomes with Assisted Reproductive Technologies

“…In total, the studies comparing DNA methylation between children conceived in vitro and children conceived in vivo point to subtle differences at many genes. In agreement with data derived from experiments in the mouse, extraembryonic tis- Modified from data in Batcheller et al (2011).…”

“…Such comparisons have been performed in multiple laboratories, initially targeting small numbers of imprinted genes (reviewed by Batcheller et al 2011; systematic review and meta-analysis by Lazaraviciute et al 2014;Nelissen et al 2014;Whitelaw et al 2014;Melamed et al 2015), under the assumption that imprinted genes might be more susceptible to effects of epigenetic disruption (Table 2), and in a modest numbers of patients.…”

Differences in infant feeding practices by mode of conception in a United States cohort

“…ART procedures are associated with epigenetic modifications of genes related to growth and metabolism(28,29) as well as not achieving catch-up body weight in infancy. (12) Perhaps feeding practices are altered to compensate for the unique health and growth of infants conceived with these technologies.…”

In Vitro Fertilization Affects Growth and Glucose Metabolism in a Sex-Specific Manner in an Outbred Mouse Model1

“…In addition, there is also a small but significant increase in imprinting disorders, including Angelman and Beckwith-Wiedemann syndromes [10]. While some studies of children conceived by ART showed no clear metabolic abnormalities [11,12], others have shown statistically significant differences in fat deposition, increased blood pressure, and increased fasting glucose [13][14][15].…”