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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 (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), adiponectin receptor 1 and 2 (ADIPOR1 and ADIPOR2), AMH and androgen receptor (AR) 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 LEPR, 2 of LEP, 1 of ADIPOR2 and 2 of AR. Boys showed differences in 5 CpG sites of LEP, 3 of AMH and 9 of AR. Maternal metformin treatment prevented some of these changes in LEP, ADIPOR2 and partially in AR in girls, and in LEP and AMH 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.

SUBMITTER: Echiburu B

PROVIDER: S-EPMC7595597 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:An ability to switch between primarily oxidizing fat in the fasted state to carbohydrate in the fed state, termed metabolic flexibility, is associated with insulin sensitivity. Metabolic flexibility has been explored previously in women with polycystic ovary syndrome (PCOS), yet the independent or synergistic contributions of androgen excess and/or insulin resistance is not yet known. Therefore, the purpose of this article was to characterize metabolic flexibility in women with PCOS compared to women of normal BMI, obesity, or type 2 diabetes (T2DM). Methods:Eighty-six weight-stable women; thirty with either PCOS (n?=?30), or fifty-six with obesity (n?=?12), T2DM (n?=?27), or normal BMI (n?=?17) underwent a hyperinsulinemic euglycemic clamp and indirect calorimetry to measure insulin sensitivity and substrate oxidation via indirect calorimetry, respectively. Results:All analyses were adjusted for differences in age, ethnicity, and BMI between groups. Women with PCOS were less metabolically flexible compared to healthy women with obesity (p?<?0.0001), normal BMI (p?<?0.0001), but after controlling for glucose disposal rate, were similar to women with T2DM (p?=?0.99). When dividing women with PCOS above and below the mean cutoff for insulin resistance, the insulin resistant women with PCOS had lower rates of non-oxidative glucose metabolism (p?=?0.0001), higher levels of percent free testosterone (p?=?0.04), a higher free androgen index (p?=?0.006), more visceral adipose tissue (p?=?0.02), and were less metabolically flexible (p?=?0.007). Conclusions:Women with T2DM were as metabolically inflexible as women with PCOS. When stratifying women with PCOS into those who are metabolically flexible and inflexible, the women who are inflexible display greater amounts of visceral fat and androgen excess. The inability to alter substrate use given the physiological stimulus may lead to subsequent increases in adiposity in women with PCOS thereby further worsening the insulin resistance. Trial registration number:Clinical Trials.gov, NCT01482286. Registered 30 November 2011.

Project description:BackgroundMetformin is widely used in pregnancy to treat gestational diabetes mellitus and polycystic ovary syndrome (PCOS). Association between PCOS and developmental delay in offspring, and larger head circumference of metformin-exposed newborns has been reported. The objective of this study was to explore whether metformin exposure in utero had any effect on offspring cognitive function.MethodThe current study is a follow-up of two randomized, placebo-controlled studies which were conducted at 11 public hospitals in Norway In the baseline studies (conducted in 2000-2003, and 2005-2009), participants were randomized to metformin 1700 and 2000 mg/d or placebo from first trimester to delivery. There was no intervention in the current study. We invited parents of 292 children to give permission for their children to participate; 93 children were included (mean age 7.7 years). The follow-up study was conducted in 2014-2016. The Wechsler Preschool and Primary Scale of Intelligence version III and the Wechsler Intelligence Scale for Children version IV were applied for cognitive assessment. Androstenedione and testosterone were measured in maternal blood samples at four time-points in pregnancy.ResultsWe found no difference in mean, full scale IQ in metformin (100.0 (SD 13.2)) vs. placebo-exposed (100.9 (SD 10.1)) children. There was an association between metformin exposure in utero and borderline intellectual function of children (full scale IQ between 70 and 85). Free testosterone index in gestational week 19, and androstenedione in gestational week 36 correlated positively to full scale IQ.ConclusionsWe found no evidence of long-term effect of metformin on average child cognitive function. The increase of borderline intellectual functioning in metformin-exposed children must be interpreted with caution due to small sample size.Trial registrationThe baseline study was registered on 12 September 2005 at the US National Institute of Health (ClinicalTrials.gov) # NCT00159536.

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

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