Placental Imprinting Variation Associated with Assisted Reproductive Technologies and Subfertility

Infertility affects one in six couples in developed nations, resulting in an increasing use of assisted reproductive technologies (ART). Both ART and subfertility appear to be linked to lower birth weight outcomes, setting infants up for poor long-term health. Prenatal growth is, in part, regulated via epigenetically controlled imprinted genes in the placenta. Although differences in DNA methylation between ART and control infants have been found, it remains unclear whether these differences are due to the ART procedures or to the underlying parental subfertility and how these methylation differences affect imprinted gene expression. In this study, we examined the expression of 108 imprinted genes in placental tissues from infants born to subfertile parents (n = 79), matched naturally conceived controls (n = 158), and infants conceived using <i>in vitro</i> fertilization (IVF, n = 18). Forty-five genes were identified as having significantly different expression between the subfertile infants and controls, whereas no significant differences were identified between the IVF and control groups. The expression of four genes—<i>IGF2, NAPIL5, PAX8-AS1</i>, and <i>TUBGCP5</i>—was significantly downregulated in the IVF compared to the subfertile group. Three of the 45 genes significantly dysregulated between subfertile and control placentae—<i>GRB10, NDN</i>, and <i>CD44</i> —were found to have a significant positive correlation between expression and birth weight. Methylation levels for these three genes and four others—<i>MKRN3, WRB, DHCR24</i>, and <i>CYR61</i>—were significantly correlated with expression. Our findings indicate that epigenetic differences in placentas resulting from IVF pregnancies may be related to the underlying subfertility in parents utilizing IVF rather than the IVF procedure itself.