DNA methylation in promoter regions of genes involved in the reproductive and metabolic function of children born to women with PCOS

Abstract

Clinical and experimental evidences indicate that epigenetic modifications induced by the prenatal environment are related to metabolic and reproductive derangements in polycystic ovary syndrome (PCOS). Alterations in the leptin and adiponectin systems, androgen signalling and antimüllerian hormone (AMH) levels have been observed in PCOS women and in their offspring. Using a targeted Next-Generation Sequencing (NGS), we studied DNA methylation in promoter regions of the leptin (<i>LEP</i>), leptin receptor (<i>LEPR</i>), adiponectin (<i>ADIPOQ</i>), adiponectin receptor 1 and 2 (<i>ADIPOR1</i> and <i>ADIPOR2</i>), <i>AMH</i> and androgen receptor (<i>AR</i>) genes in 24 sons and daughters of women with PCOS (12 treated with metformin during pregnancy) and 24 children born to non-PCOS women during early infancy (2-3 months of age). Genomic DNA was extracted from whole blood, bisulphite converted and sequenced by NGS. Girls showed differences between groups in 1 CpG site of <i>LEPR</i>, 2 of <i>LEP</i>, 1 of <i>ADIPOR2</i> and 2 of <i>AR</i>. Boys showed differences in 5 CpG sites of <i>LEP</i>, 3 of <i>AMH</i> and 9 of <i>AR</i>. Maternal metformin treatment prevented some of these changes in <i>LEP</i>, <i>ADIPOR2</i> and partially in <i>AR</i> in girls, and in <i>LEP</i> and <i>AMH</i> in boys. Maternal BMI at early pregnancy was inversely correlated with the methylation levels of the ChrX-67544981 site in the whole group of girls (r = -0.530, p = 0.008) and with the global Z-score in all boys (r = -0.539, p = 0.007). These data indicate that the intrauterine PCOS environment predisposes the offspring to acquire certain sex-dependent DNA methylation patterns in the promoter regions of metabolic and reproductive genes.