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- Manti, Maria
(author)
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Developmental origins of polycystic ovary syndrome : role of early adverse life events on adult health
- 2020
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Doctoral thesis (other academic/artistic)abstract
- The research focus of this thesis is polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, associated with reproductive, cardio-metabolic, and mental health complications. Despite the high prevalence, little is known about the etiology of the syndrome. The scope of the current thesis was to investigate aspects of the developmental origins of the syndrome, with focus on the impact of adverse environmental factors during pregnancy on PCOS-associated features in the offspring. To reach these aims we employed three mouse model of PCOS and data from a Swedish national register-based cohort study. The thesis is divided into two parts. Part 1 investigates the effects of maternal androgen excess and maternal obesity on the mental health of adult male and female offspring. Study I demonstrated that maternal androgen exposure increases anxiety-like behavior in the first generation of female mouse offspring, but not male offspring, while maternal obesity affects male offspring behavior, but not female offspring. This sexually dimorphic response to the two prominent environmental stimuli was further supported by sex-specific changes in gene expression within the amygdala and hypothalamus. Study II provided evidence that daughters of women with PCOS are at increased risk to be diagnosed with anxiety disorders, but not the sons, using a Swedish national register-based cohort study. It further showed that maternal androgen exposure can lead to transgenerational transmission of anxiety-like behavior in the third generation of female mice, but not the male offspring, without major impact of maternal obesity. Finally, the male germline (first generation of male offspring with no change in behavior) did also transgenerationally transmit an anxiety-like behavior to the third generation of male offspring. Part 2 investigates the effects of an adverse maternal and/or postnatal environment on the cardiovascular and metabolic health of females, using mouse models of PCOS. Study III revealed that maternal androgen excess leads to cardiac hypertrophy in adult female offspring, accompanied by gene expression changes in the left ventricle, without the presence of metabolic dysfunction. It was further shown that this adverse cardiac phenotype is the result of an early cardiac reprogramming. In addition, cardiovascular assessment of a mouse model of PCOS with continuous exposure to androgens from prepuberty to adulthood, demonstrated cardiac hypertrophy and increased vasocontractile responses, while simultaneous administration of the antiandrogen flutamide could only partially prevent the observed phenotype. Finally, in study IV, developmental, reproductive and metabolic complications were revealed in a transgenic mouse model of PCOS that overexpresses ovarian nerve growth factor. Ovarian excess of nerve growth factor led to developmental defects in the female fetus, including growth restriction, reduction of germ cell number and delayed primary oocyte maturation. In addition, the adult transgenic female mice displayed disrupted estrous cyclicity and ovarian expression changes of steroidogenic genes and epigenetic markers. Lastly, these mice developed metabolic complications, as shown by impaired glucose metabolism, aberrant adipose tissue function, and liver steatosis.
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| 2. |
- Manti, Maria, et al.
(author)
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Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspring.
- 2020
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In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 116:3, s. 619-632
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Journal article (peer-reviewed)abstract
- Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is suggested to increase the risk for cardiovascular disease. How PCOS may lead to adverse cardiac outcomes is unclear and here we hypothesized that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity in mice induce adverse metabolic and cardiac programming in female offspring that resemble the reproductive features of the syndrome.The maternal obese PCOS phenotype was induced in mice by chronic high-fat-high-sucrose consumption together with prenatal DHT exposure. The prenatally androgenized (PNA) female offspring displayed cardiac hypertrophy during adulthood, an outcome that was not accompanied by aberrant metabolic profile. The expression of key genes involved in cardiac hypertrophy was up-regulated in the PNA offspring, with limited or no impact of maternal obesity. Furthermore, the activity of NADPH oxidase, a major source of reactive oxygen species in the cardiovascular system, was down-regulated in the PNA offspring heart. We next explored for early transcriptional changes in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an up-regulation of transcription factors involved in cardiac hypertrophic remodelling and of the calcium-handling gene, Slc8a2. Finally, to determine the specific role of androgens in cardiovascular function, female mice were continuously exposed to DHT from pre-puberty to adulthood, with or without the antiandrogen flutamide. Continuous exposure to DHT led to adverse left ventricular remodelling, and increased vasocontractile responses, while treatment with flutamide partly alleviated these effects.Taken together, our results indicate that intrauterine androgen exposure programmes long-lasting heart remodelling in female mouse offspring that is linked to left ventricular hypertrophy and highlight the potential risk of developing cardiac dysfunction in daughters of mothers with PCOS.
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| 3. |
- Manti, Maria, et al.
(author)
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Skeletal Muscle Immunometabolism in Women With Polycystic Ovary Syndrome : A Meta-Analysis
- 2020
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In: Frontiers in Physiology. - : Frontiers Media S.A.. - 1664-042X. ; 11
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Research review (peer-reviewed)abstract
- Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting up to 15% of women at reproductive age. The main features of PCOS are hyperandrogenism and irregular menstrual cycles together with metabolic dysfunctions including hyperinsulinemia and insulin resistance and a 4-fold increased risk of developing type 2 diabetes. Despite the high prevalence the pathophysiology of the syndrome is unclear. Insulin resistance in women with PCOS likely affect the skeletal muscle and recently it was demonstrated that changes in DNA methylation affects the gene expression in skeletal muscle that in part can explain their metabolic abnormalities. The objective of this work was to combine gene expression array data from different datasets to improve statistical power and thereby identify novel biomarkers that can be further explored. In this narrative review, we performed a meta-analysis of skeletal muscle arrays available from Gene Expression Omnibus and from publications. The eligibility criteria were published articles in English, and baseline (no treatment) skeletal muscle samples from women with PCOS and controls. The R package Metafor was used for integration of the datasets. One hundred and fourteen unique transcripts were differentially expressed in skeletal muscle from women with PCOS vs. controls (q < 0.05), 87% of these transcripts have not been previously identified as altered in PCOS muscle. ING2, CDKAL1, and AKTIP had the largest differential increase in expression, and TSHZ2, FKBP2, and OCEL1 had the largest decrease in expression. Two genes, IRX3 and CDKAL1 were consistently upregulated (q < 0.05) in the individual analyses and meta-analysis. Based on the meta-analysis, we identified several dysregulated immunometabolic pathways as a part of the molecular mechanisms of insulin resistance in the skeletal muscle of women with PCOS. The transcriptomic data need to be verified by functional analyses as well as proteomics to advance our understanding of PCOS specific insulin resistance in skeletal muscle.
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| 4. |
- Risal, Sanjiv, et al.
(author)
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Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome
- 2019
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In: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 25:12, s. 1894-1904
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Journal article (peer-reviewed)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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| 5. |
- Risal, Sanjiv, et al.
(author)
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Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome
- 2023
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In: Cell Reports Medicine. - : Cell Press. - 2666-3791. ; 4:5
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Journal article (peer-reviewed)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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| 6. |
- Stener-Victorin, Elisabet, et al.
(author)
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Origins and Impact of Psychological Traits in Polycystic Ovary Syndrome
- 2019
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In: Medical sciences. - : MDPI. - 2076-3271. ; 7:8
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Research review (peer-reviewed)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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| 7. |
- Strauss, Leena, et al.
(author)
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Consistent and effective method to define the mouse estrous cycle stage by deep learning based model.
- 2024
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In: Journal of Endocrinology. - 0022-0795 .- 1479-6805. ; 261:3
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Journal article (peer-reviewed)abstract
- The mouse estrous cycle is divided into four stages: proestrus (P), estrus (E), metestrus (M) and diestrus (D). The estrous cycle affects reproductive hormone levels in a wide variety of tissues. Therefore, to obtain reliable results from female mice, it is important to know the estrous cycle stage during sampling. The stage can be analyzed from a vaginal smear under a microscope. However, it is time-consuming, and the results vary between evaluators. Here, we present an accurate and reproducible method for staging the mouse estrous cycle in digital whole slide images (WSIs) of vaginal smears. We developed a model using a deep convolutional neural network (CNN) in a cloud-based platform, Aiforia Create. The CNN was trained by supervised pixel-level multiclass semantic segmentation of image features from 171 hematoxylin-stained samples. The model was validated by comparing the results obtained by CNN with those of four independent researchers. The validation data included three separate studies comprising altogether 148 slides. The total agreement attested by the Fleiss kappa value between the validators and the CNN was excellent (0.75), and when D, E and P were analyzed separately, the kappa values were 0.89, 0.79 and 0.74, respectively. The M stage is short and not well defined by the researchers. Thus, identification of the M stage by the CNN was challenging due to the lack of proper ground truth, and the kappa value was 0.26. We conclude that our model is reliable and effective for classifying the estrous cycle stages in female mice.
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