Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes

Abstract

Polycystic ovary syndrome (PCOS) is the most common ovulatory defect in women. Although most PCOS patients are obese, a subset of PCOS women are lean but show similar risks for adverse fertility outcomes. A lean PCOS mouse model was created using prenatal androgen administration. This developmentally programmed mouse model was used for this study. Our objective was to investigate if mitochondrial structure and functions were compromised in oocytes obtained from lean PCOS mouse. The lean PCOS mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were isolated and were used to investigate inner mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance and electron microscopy. Our results demonstrate that lean PCOS mice have similar weight to that of the controls but exhibit glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of their oocytes show impaired inner mitochondrial membrane function, elevated reactive oxygen species (ROS) and increased RNA transcript abundance. Electron microscopy of the oocytes showed impaired mitochondrial ultrastructure. In conclusion, the lean PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial ultrastructure and function.

Comprehensive molecular features of polycystic ovary syndrome revealed by transcriptome analysis of oocytes and cumulus cells

“…Mitochondria are essential for oocyte development potential and oocyte rejuvenation 67 , and mitochondrial dysfunction in oocytes is found in women with PCOS 68,69 . Mitochondrial functions may be prematurely activated at GV stage oocytes of PCOS 70 , and the oocytes may have impaired mitochondrial ultrastructure and functions, including compromised inner mitochondrial membrane potential and electron transport chain 71 , consistent with our results. Crosstalk between oocytes and CCs also can be perturbed by alteration of the ovarian microenvironment, including oxidative stress caused by mitochondrial respiratory dysfunction, which leads to enhanced ROS production 72 .…”

Molecular Features of Polycystic Ovary Syndrome Revealed by Transcriptome Analysis of Oocytes and Cumulus Cells

“…The mitochondria are essential for oocyte development potential and oocyte rejuvenation (Labarta et al, 2019), and mitochondrial dysfunction in oocytes is found in women with PCOS (Ou et al, 2012;Zhang et al, 2019). Mitochondrial functions may be prematurely activated at GVstage oocytes of PCOS (Qi et al, 2020), and the oocytes exhibit impaired mitochondrial ultrastructure and functions, including compromised inner mitochondrial membrane potential and electron transport chain (Chappell et al, 2020), consistent with our results. The crosstalk between oocytes and CCs can also be perturbed by the alteration of the ovarian microenvironment, including oxidative stress caused by mitochondrial respiratory dysfunction, which leads to enhanced ROS production (May-Panloup et al, 2016).…”

Embryos from polycystic ovary syndrome patients with hyperandrogenemia reach morula stage faster than controls

“…Strikingly, our present study demonstrated very similar morphokinetic development results, despite controlling for BMI. In addition, prior animal work has shown impaired mitochondrial function in oocytes of a PCOS mouse model that also controlled for weight (45). These studies taken together highlight the complex and interwoven nature of metabolic dysfunction and obesity coinciding with HA.…”