User:Mavericks0718/sandbox
Environment
[edit]The study of epigenetic changes in PCOS in utero or after birth has become an emerging area of research. While extensive research is not currently available, some studies are looking into the connection between abnormal DNA methylation changes in various tissues and the development of PCOS[1]. Environmental exposure to endocrine disruptors such as phthalates could alter DNA methylation patterns, particularly in the ovaries, granulosa cells, and adipose tissue[1].
One study observed early embryonic development of mice subjected to di--(2-ethylhexyl) phthalate (DEHP) and the results showed abnormal methylation patterns in the Stra8 gene involved in meiosis initiation[2]. The gene for transcription factor Lhx8, involved in early follicular changes, was also impacted by DEHP when the neonatal mouse ovaries were analyzed. Together, these results showed DEHP induced epigenetic changes via DNA methylation to interfere with folliculogenesis, symptomatic of PCOS. Although DNA methylation in human embryonic development is not fully characterized, the animal model studies on epigenetic changes provide information to suggest that PCOS may have fetal origins[2].
Androgen excess is a central feature in the PCOS phenotype, and exposure in utero has shown PCOS-like features in adulthood. A study from 2014 induced DNA hypomethylation in the ovarian tissue of zebrafish exposed to androgens early in development[3]. Glucose homeostasis alterations were also observed. Furthermore, these effects were carried into the next generation, suggesting that epigenetic changes caused by excess androgens in the fetus could be transgenerational.
Stem Cell Models
[edit]Human embryonic stem cells (hESCs) derived from the inner cell mass of blastocyst-stage embryos of women with PCOS have shown abnormal lipid metabolism, consistent with the pathophysiology of the disease[4]. When the hESCs are differentiated into adipocytes, gene expression data from these fat cells reveal a downregulation or a decrease in genes linked to glucose, lipid, and steroid metabolism[5]. Despite the significant findings provided by hESC research to understand the earliest stages of PCOS development, there are limitations in studying human embryos due to legal prohibitions and ethical concerns.
Recent studies have successfully developed in vitro PCOS disease models through induced pluripotent stem cell technology (iPSC). Similar to hESCs, iPSC cells can be derived from patients and can differentiate into various cell types. Using adult somatic cells, iPSCs can reprogram the cells into a pluripotent state, which can then be specified to replicate PCOS-like traits. Furthermore, 3D “organoid” models of female reproductive tissue, such as the uterus and ovaries, produced from iPSCs, present a powerful way to stimulate the development of reproductive disorders such as PCOS in vitro[4].
Although not widely utilized, some researchers have explored the use of this biotechnology to model PCOS. One study that characterized the link between obesity and PCOS reprogrammed PCOS-derived urine epithelial cells into adipocytes and found that iPSC lines had greater glucose consumption along with lower insulin response compared to controls[6]. These are results consistent with symptoms of the disease. Studies on iPSCs have also contributed significantly to understanding the behavior of ovarian granulosa cells, which maintain follicular development and secrete steroid hormones[7]. The transcriptome data from the PCOS-derived iPSCs indicate dysfunctions in folliculogenesis and disruptions in the oocyte microenvironment.
Current growing data shows a strong association between mitochondrial malfunction and PCOS. iPSCs from PCOS patients have provided some evidence of impairments in glycolytic and mitochondrial functions[4]. Interestingly, these cells exhibited a higher number of copies of mitochondrial DNA compared to the control. This may support the idea that mitochondrial biosynthesis is elevated in these patients as a compensatory response to the aberrations seen in the metabolic processes[4].
iPSC models have great advantages over the ethical concerns in hESC research. One challenge to using this technology is controlling or assessing the intra-human variability, especially with a multifaceted disease such as PCOS. Nonetheless, these stem cell models are a valuable approach to gaining more insights into the disease.
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- ^ a b Liu, Yan-Nan; Qin, Yi; Wu, Bin; Peng, Hui; Li, Ming; Luo, Hai; Liu, Lin- Lin (2022-08). "DNA methylation in polycystic ovary syndrome: Emerging evidence and challenges". Reproductive Toxicology. 111: 11–19. doi:10.1016/j.reprotox.2022.04.010. ISSN 0890-6238.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Zhang, Teng; Li, Lan; Qin, Xun‐Si; Zhou, Yang; Zhang, Xi‐Feng; Wang, Lin‐Qing; De Felici, Massimo; Chen, Hong; Qin, Guo‐Qing; Shen, Wei (2014-01-24). "Di‐(2‐ethylhexyl) phthalate and bisphenol A exposure impairs mouse primordial follicle assembly in vitro". Environmental and Molecular Mutagenesis. 55 (4): 343–353. doi:10.1002/em.21847. ISSN 0893-6692.
- ^ Xu, Ning; Chua, Angela K.; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O. (2014-08-01). "Early Embryonic Androgen Exposure Induces Transgenerational Epigenetic and Metabolic Changes". Molecular Endocrinology. 28 (8): 1329–1336. doi:10.1210/me.2014-1042. ISSN 0888-8809. PMC 5414805. PMID 24992182.
- ^ a b c d Khatun, Masuma; Lundin, Karolina; Naillat, Florence; Loog, Liisa; Saarela, Ulla; Tuuri, Timo; Salumets, Andres; Piltonen, Terhi T.; Tapanainen, Juha S. (2024-01-01). "Induced Pluripotent Stem Cells as a Possible Approach for Exploring the Pathophysiology of Polycystic Ovary Syndrome (PCOS)". Stem Cell Reviews and Reports. 20 (1): 67–87. doi:10.1007/s12015-023-10627-w. ISSN 2629-3277. PMC 10799779. PMID 37768523.
- ^ Li, Peng-fen; and Sun, Ying-pu (2012-01-01). "Establishment of polycystic ovary syndrome-derived human embryonic stem cell lines". Gynecological Endocrinology. 28 (1): 25–28. doi:10.3109/09513590.2011.588748. ISSN 0951-3590. PMID 21780950.
{{cite journal}}:|first2=missing|last2=(help);|first3=missing|last3=(help);|first4=missing|last4=(help);|first5=missing|last5=(help);|first6=missing|last6=(help)CS1 maint: multiple names: authors list (link) - ^ Yang, Sheng; Ding, Shufang; Jiang, Xianglong; Sun, Bolan; Xu, Qianhua (2016-06). "Establishment and adipocyte differentiation of polycystic ovary syndrome‐derived induced pluripotent stem cells". Cell Proliferation. 49 (3): 352–361. doi:10.1111/cpr.12258. ISSN 0960-7722.
{{cite journal}}: Check date values in:|date=(help) - ^ Jozkowiak, Malgorzata; Piotrowska-Kempisty, Hanna; Kobylarek, Dominik; Gorska, Natalia; Mozdziak, Paul; Kempisty, Bartosz; Rachon, Dominik; Spaczynski, Robert Z. (2022-12-31). "Endocrine Disrupting Chemicals in Polycystic Ovary Syndrome: The Relevant Role of the Theca and Granulosa Cells in the Pathogenesis of the Ovarian Dysfunction". Cells. 12 (1): 174. doi:10.3390/cells12010174. ISSN 2073-4409. PMC 9818374. PMID 36611967.
{{cite journal}}: CS1 maint: unflagged free DOI (link)