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

Echiburú, Bárbara; Milagro, Fermı́n I.; Crisosto, Nicolás; Pérez-Bravo, Francisco; Flores, Cristián; Arpón, Ana; Salas-Pérez, Francisca; Recabarren, Sergio E; Sir-Petermann, Teresa; Maliqueo, Manuel

doi:10.1080/15592294.2020.1754674

Cited by 24 publications

(10 citation statements)

References 92 publications

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“…It was universally acknowledged that higher AMH concentrations were in accordance with increased serum androgen [ 34 ]. It could be a possible mechanism in PCOS pathogenesis that AMH methylation or altered steroid receptor balance in the fetal ovary (granulosa cells) due to rising androgens results inhibition of follicle growth [ 35 ]. Reduced P450 aromatase and augmented androgen-producing enzyme activity were found in the placental tissue of women with PCOS, which impaired the placental protective function of the fetus from maternal hyperandrogenism and allowed the passage of testosterone through the placenta [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Elevated Anti-Müllerian Hormone Levels in Newborns of Women with Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis Based on Observational Studies

Zhou

Wen

et al. 2021

Reprod. Sci.

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We performed this updated systematic review and meta-analysis to evaluate anti-Müllerian hormone levels (AMH) in newborns of mothers with polycystic ovary syndrome (PCOS) compared with healthy controls. A search of the literature was conducted in the PubMed, MEDLINE, EMBASE, Cochrane Library, CBM, CNKI, WANFANG, and VIP for articles to assess AMH levels in offspring of PCOS and non-PCOS mothers irrespective of language. These databases were searched from their inception to December 7, 2020. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS) scoring system. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were adopted to calculate the overall estimates with random-effects models. A total of 6 studies with 846 participants were included. The pooled analysis found an increased AMH level in the umbilical cord blood in newborns of PCOS mothers (SMD =0.62, 95% CI [0.28, 0.95]). Subgroup analyses revealed an elevation of AMH concentrations in female neonates, neonates born to American and Asian PCOS mothers. In addition, higher AMH levels were also found in studies diagnosed by the National Institute of Health (NIH) criteria, maternal clinical/biochemical hyperandrogenism, or maternal body mass index (BMI) >30 kg/m2. Meta-regression analysis suggested that diagnostic criterion contributed mostly to the high heterogeneity. We demonstrated that AMH levels in neonates born to PCOS mothers were essentially higher, which indicates that AMH may act as an enigmatic role in the pathogenesis of PCOS which inhibits folliculogenesis in the fetal stage.

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Section: Discussionmentioning

confidence: 99%

Elevated Anti-Müllerian Hormone Levels in Newborns of Women with Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis Based on Observational Studies

Zhou

Wen

et al. 2021

Reprod. Sci.

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“…Evidence from human studies supports the contention that the in utero environment can influence the genesis of PCOS and related comorbidities. Women diagnosed with PCOS can give rise to children that exhibit sex-dependent DNA methylation patterns in regulatory regions of various metabolic and reproductive genes (including adiponectin, AMH and the androgen receptor) associated with this condition [136,137]. In such studies, however, it is difficult to disentangle the effects of maternal genotype.…”

Section: Prenatal Diet Epigenetics and Pcosmentioning

confidence: 99%

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence

Steegers‐Theunissen

Wiegel

Jansen

et al. 2020

IJMS

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Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS.

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“…Recent research has shown that CpG hypomethylation regarding GHRHR , AKR1C3 , RETN , and MAMLD1 and hypermethylation regarding TNF , which can indirectly contribute to androgen excess, were consistent with increased and decreased levels of the corresponding gene transcripts, respectively ( Sagvekar et al, 2019 ). In addition, research has shown that the children of women with PCOS show a sex-specific pattern of DNA methylation in the promoter regions of genes associated with the reproductive and metabolic features of PCOS at early infancy ( Echiburú et al, 2020 ). However, the specific effects of the DNA methylation on the associated gene expression and downstream metabolism remain unknown.…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptomic and Epigenetic Study of PCOS: Impact of Map3k1 and Map1lc3a Promoter Methylation on Autophagy

Qin

Zhao

et al. 2021

Front. Genet.

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Polycystic ovary syndrome (PCOS) is a prevalent heterogeneous endocrine and metabolic disorder in women of reproductive age. Epigenetic mechanisms contribute to the development of PCOS. Nevertheless, the role of DNA methylation in the development of PCOS remains unclear. To investigate the molecular mechanisms underlying the hyperandrogenic phenotype of PCOS, dihydrotestosterone (DHT)-induced prenatally androgenized (PNA) mice were used to mimic this phenotype. Ovarian samples from PNA and control mice were subjected to methyl-CpG-binding domain (MBD)-seq and RNA-seq, and validation was conducted using methylation-specific polymerase chain reaction (MSP) and quantitative real-time PCR (RT-qPCR). Immunohistochemical analysis (using anti-LC3II antibody) and transmission electron microscopy were conducted using ovarian tissue sections (which included granulosa cells) from PNA and control mice. There were 857 genes with differentially methylated promoter regions and 3,317 differentially expressed genes (DEGs) in the PNA mice compared to the control mice. Downregulation of Dnmt1 (which encodes DNA methyltransferase 1), accompanied by global hypomethylation, was observed in the PNA mice compared to the control mice. The promoter regions of Map3k1 (which encodes MEKK1) and Map1lc3a (which encodes LC3II) were hypomethylated, accompanied by upregulation of Map3k1 and Map1lc3a mRNA expression. The autophagy profiling results showed that LC3II protein expression and autophagosomes were significantly increased in the granulosa cells of PNA mice. Additionally, the mRNA expression of genes related to the mitogen-activated protein kinase (MAPK)/p53 pathway (Mapk14, Mapkapk3, and Trp53) and the autophagy-related gene Becn1 were significantly increased. DHT could change the DNA methylation and transcription level of Map3k1 and lead to an activation of autophagy in granulosa cells. These observations indicated that the change in autophagy may be driven by MAPK/p53 pathway activation, which may have been caused by DHT-induced transcriptional, and the methylation level changed of the key upstream gene Map3k1. Our study provides a novel genetic basis and new insights regarding the pathogenesis of PCOS.

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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

Cited by 24 publications

References 92 publications

Elevated Anti-Müllerian Hormone Levels in Newborns of Women with Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis Based on Observational Studies

Elevated Anti-Müllerian Hormone Levels in Newborns of Women with Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis Based on Observational Studies

Polycystic Ovary Syndrome: A Brain Disorder Characterized by Eating Problems Originating during Puberty and Adolescence

Integrated Transcriptomic and Epigenetic Study of PCOS: Impact of Map3k1 and Map1lc3a Promoter Methylation on Autophagy

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