| 1. |
- Ascani, Angelo, et al.
(författare)
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The role of B cells in immune cell activation in polycystic ovary syndrome.
- 2023
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Ingår i: eLife. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here, we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knockout mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS.
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| 2. |
- Lu, Haojiang
(författare)
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Polycystic ovary syndrome and maternal obesity : does it programme transgenerational dysfunction?
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As one of the most prevalent syndromes among reproductive-aged women, polycystic ovary syndrome (PCOS) manifests with endocrine, reproductive and metabolic disturbances. However, the etiology of PCOS is yet to be fully understood. Here in this thesis, we set out to understand whether and how PCOS can be transmitted to the future generations. More importantly, we wanted to address if the transmission of PCOS-related reproductive and metabolic phenotypes achieves a transgenerational pattern. With the help of Swedish national register-based studies and Chilean case-control studies, we obtained unique databases to investigate the disease inheritance in daughters and sons of women with and without PCOS. The use of two different PCOS mouse models further allowed us to study the transgenerational inheritance of PCOS. Study I of this thesis focused on female offspring of women with PCOS or PCOS- like mouse models. We demonstrated a five-fold increased risk of daughters of women with PCOS to be diagnosed with the syndrome. In mice exposed to androgens during late pregnancy with or without diet-induced obesity, we showed a transgenerational inheritance of irregular estrous cycles, pregnancy complications and metabolic disturbances, including increased adiposity and liver steatosis, in female offspring. We also identified preserved common gene signatures between mouse oocytes derived from all generations and serum and adipose tissue of women and daughters of women with PCOS, indicating a role of oocyte epigenetics in mediating this transgenerational transmission. It is not only the female offspring that are affected by the hyperandrogenic in utero environment. Study II revealed an increased likelihood of obesity diagnosis in sons of women with PCOS. This was further supported by mouse transgenerational studies, where great grandsons also suffer from reproductive and metabolic disturbances attributed to maternal androgen exposure, although maternal obesity elicited a wider range of alterations in phenotypes and sperm small non- coding RNAs. Study III set out to understand the molecular changes upon gestational androgen exposure. Impaired placenta development with decreased trophoblast lineage formation capacity was confirmed both in pregnant mice and human trophoblast organoids, thus identifying a potential underlying cause for PCOS-associated pregnancy complications. The findings of Study I and II led to the aim of Study IV, to identify the role of germ cells in mediating PCOS inheritance without the impact of the maternal intrauterine environment. Here a transgenerational inheritance of metabolic alterations, including increased adiposity and liver steatosis in both female and male lineages were observed. Importantly, we showed that donor exercise effectively rescued the abnormal metabolic phenotypes across the generations. Although the identification of the epigenetic mechanism underlying this inheritance is ongoing, our phenotypic data provided evidence supporting the role of germ cells in mediating PCOS transmission.
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| 3. |
- Risal, Sanjiv, et al.
(författare)
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Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome
- 2019
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Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 25:12, s. 1894-1904
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Tidskriftsartikel (refereegranskat)abstract
- How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.
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| 4. |
- Risal, Sanjiv, et al.
(författare)
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Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome
- 2023
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Ingår i: Cell Reports Medicine. - : Cell Press. - 2666-3791. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1–F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline.
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| 5. |
- Stener-Victorin, Elisabet, et al.
(författare)
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Origins and Impact of Psychological Traits in Polycystic Ovary Syndrome
- 2019
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Ingår i: Medical sciences. - : MDPI. - 2076-3271. ; 7:8
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Forskningsöversikt (refereegranskat)abstract
- Women with polycystic ovary syndrome (PCOS) exhibit compromised psychiatric health. Independent of obesity, women with PCOS are more susceptible to have anxiety and depression diagnoses and other neuropsychiatric disorders. During pregnancy women with PCOS display high circulating androgen levels that may cause prenatal androgen exposure affecting the growing fetus and increasing the risk of mood disorders in offspring. Increasing evidence supports a non-genetic, maternal contribution to the development of PCOS and anxiety disorders in the next generation. Prenatal androgenized rodent models reflecting the anxiety-like phenotype of PCOS in the offspring, found evidence for the altered placenta and androgen receptor function in the amygdala, together with changes in the expression of genes associated with emotional regulation and steroid receptors in the amygdala and hippocampus. These findings defined a previously unknown mechanism that may be critical in understanding how maternal androgen excess can increase the risk of developing anxiety disorders in daughters and partly in sons of PCOS mothers. Maternal obesity is another common feature of PCOS causing an unfavorable intrauterine environment which may contribute to psychiatric problems in the offspring. Whether environmental factors such as prenatal androgen exposure and obesity increase the offspring’s susceptibility to develop psychiatric ill-health will be discussed.
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| 6. |
- Stener-Victorin, Elisabet, et al.
(författare)
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Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
- 2024
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Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.
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