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If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

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.

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.

Background/objectivesMaternal obesity together with androgen excess in mice negatively affects placental function and maternal and fetal liver function as demonstrated by increased triglyceride content with dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage. To identify changes in molecular pathways that might promote diseases in adulthood, we performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess.MethodsAfter ten weeks on a control diet (CD) or high fat/high sugar-diet, dams were mated with males fed the CD. Between gestational day (GD) 16.5 and GD 18.5, mice were injected with vehicle or dihydrotestosterone (DHT) and sacrificed at GD 18.5 prior to dissection of the placentas and fetal livers. Four pools of female placentas and fetal livers were subjected to a global proteomic analysis. Total and phosphorylated proteins were filtered by ANOVA q < 0.05, and this was followed by two-way ANOVA to determine the effect of maternal obesity and/or androgen exposure.ResultsIn placenta, phosphorylated ATP-citrate synthase was decreased due to maternal obesity, and phosphorylated catechol-O-methyltransferase (COMT) was differentially expressed due to the interaction between maternal diet and DHT exposure. In fetal liver, five total proteins and 48 proteins phosphorylated in one or more sites, were differentially expressed due to maternal obesity or androgen excess. In fetal liver, phosphorylated COMT expression was higher in fetus exposed to maternal obesity.ConclusionThese results suggest a common regulatory mechanism of catecholamine metabolism in the placenta and the fetal liver as demonstrated by higher phosphorylated COMT expression in the placenta and fetal liver from animals exposed to diet-induced maternal obesity and lower expression of phosphorylated COMT in animals exposed to maternal androgen excess.

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 off spring, while maternal obesity affects male offspring behavior, but not female off spring. 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.

Monocytes and lymphocytes play a key role in physiologic wound healing and might be involved in the impaired mechanisms observed in diabetes. Skin wound macrophages are represented by tissue resident macrophages and infiltrating peripheral blood recruited monocytes which play a leading role during the inflammatory phase of wound repair. The impaired transition of diabetic wound macrophages from pro-inflammatory M1 phenotypes to anti-inflammatory pro-regenerative M2 phenotypes might represent a key issue for impaired diabetic wound healing. This review will focus on the role of immune system cells in normal skin and diabetic wound repair. Furthermore, it will give an insight into therapy able to immuno-modulate wound healing processes toward to a regenerative anti-inflammatory fashion. Different approaches, such as cell therapy, exosome, and dermal substitute able to promote the M1 to M2 switch and able to positively influence healing processes in chronic wounds will be discussed.

Daughters of women with polycystic ovary syndrome (PCOS) are more likely to be diagnosed with PCOS, including reproductive and metabolic dysfunctions. Our recent research has demonstrated that dihydrotestosterone (DHT) exposure during late pregnancy results in transgenerational transmission of PCOS susceptibility to female offspring. But it remains unclear whether the transmission of the PCOS-like phenotypes is induced by in utero environment or via germ cell reprogramming, and whether treatment by exercise or androgen receptor blocker, flutamide, can prevent disease transmission. To model PCOS condition, donor mice were implanted with a continuous releasing DHT or vehicle pellet at 4 weeks of age. A subset of DHT exposed F0 donors had either free access to running wheels or were implanted with a slow-releasing flutamide pellet. Mice were exposed with or without treatment for either 6 weeks before IVF or 10 weeks prior to phenotypic testing. Here we present the phenotype of the F0 donors and the result of IVF to generate first (F1) and second (F2) generation offspring. Donors weigh more already after 2 weeks of DHT exposure and had more fat mass with larger adipocyte size, impaired glucose tolerance, and heavier kidney after 10 weeks of androgenization, which was reversed by both flutamide and exercise intervention. Moreover, DHT exposure increased circulating androgens and donors were completely acyclic. Simultaneous treatment with flutamide reversed the elevated androstenedione, testosterone, and restored estrus cyclicity, indicating that androgen receptor blocker can reverse hyperandrogenemia and reproductive dysfunction, whereas exercise failed to improve these phenotypes. After 6 weeks of exposure or treatment, donor oocytes were superovulated for IVF. Fewer oocytes per donor were found in androgenized + flutamide lineage, but no significant difference was observed in oocyte to two-cell embryo conversion rate after fertilization among all groups. Although the number of live offspring at weaning was similar among all groups, a trend of more F1 male than female offspring was found in both androgenized and androgenized + exercise lineage. Similar results were obtained in the F1 females when generating F2 offspring by IVF, which androgenized + flutamide lineage showed fewer oocytes per donor upon superovulation and more F2 male than female offspring was obtained in androgenized lineage at weaning. We here show that the androgenized donors develop clear PCOS-like phenotypes and give rise to more male than female F1 and F2 offspring. While blocking androgen receptor reverses both metabolic and reproductive disturbance in the donor, it also shows a negative impact on the donor and F1 female oocyte maturation process, although number of offspring via IVF is not affected. Excercise, however, only reverses the metabolic phenotypes in the F0 donor mice with no impact on IVF outcome.

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder of unclear etiology in women and is characterized by androgen excess, insulin resistance, and mood disorders. The gut microbiome is known to influence conditions closely related with PCOS, and several recent studies have observed changes in the stool microbiome of women with PCOS. The mechanism by which the gut microbiome interacts with PCOS is still unknown.We used a mouse model to investigate if diet-induced maternal obesity and maternal DHT exposure, mimicking the lean and obese PCOS women, cause lasting changes in the gut microbiome of offspring. Fecal microbiome profiles were assessed using Illumina paired-end sequencing of 16S rRNA gene V4 amplicons.We found sex-specific effects of maternal and offspring diet, and maternal DHT exposure on fecal bacterial richness and taxonomic composition. Female offspring exposed to maternal obesity and DHT displayed reproductive dysfunction and anxietylike behavior. Fecal microbiota transplantation from DHT and diet-induced obesity exposed female offspring to wild-type mice did not transfer reproductive dysfunction and did not cause the expected increase in anxietylike behavior in recipients.Maternal obesity and androgen exposure affect the gut microbiome of offspring, but the disrupted estrous cycles and anxietylike behavior are likely not microbiome-mediated.

Chronic limb-threatening ischemia (CLTI), the most advanced form of peripheral arterial disease (PAD), is the comorbidity primarily responsible for major lower-limb amputations, particularly for diabetic patients. Autologous cell therapy has been the focus of efforts over the past 20 years to create non-interventional therapeutic options for no-option CLTI to improve limb perfusion and wound healing. Among the different available techniques, peripheral blood mononuclear cells (PBMNC) appear to be the most promising autologous cell therapy due to physio-pathological considerations and clinical evidence, which will be discussed in this review. A meta-analysis of six clinical studies, including 256 diabetic patients treated with naive, fresh PBMNC produced via a selective filtration point-of-care device, was conducted. PBMNC was associated with a mean yearly amputation rate of 15.7%, a mean healing rate of 62%, and a time to healing of 208.6 ± 136.5 days. Moreover, an increase in TcPO2 and a reduction in pain were observed. All-cause mortality, with a mean rate of 22.2% and a yearly mortality rate of 18.8%, was reported. No serious adverse events were reported. Finally, some practical and financial considerations are provided, which point to the therapy’s recommendation as the first line of treatment for this particular and crucial patient group.

Nerve growth factor is a member of the neurotrophin family and within the ovary, it plays an important role in sympathetic innervation and in the development and maintenance of folliculogenesis. Despite its critical role, excessive levels of ovarian NGF may lead to ovarian pathology and to the development of features of polycystic ovary syndrome (PCOS), which is the most common endocrine disorder among women of reproductive age. Here, using a transgenic mouse model overexpressing NGF selectively in the ovary (17NF mice), we studied how ovarian sympathetic hyperactivity affects embryonic development and reproductive and metabolic function in adulthood. Firstly, we showed that ovarian NGF excess caused growth restriction in the developing female fetuses, which was driven by defects in the placenta function. Moreover, the 17NF fetuses experienced a reduction of germ cell number along with delayed gonocyte and primary oocyte maturation. The adult 17NF mice displayed irregular cyclicity and aberrant ovarian expression of steroidogenic genes and epigenetic markers. The ovarian sympathetic hyperactivity also led to increased systemic sympathetic outflow, indicated by increased circulating dopamine levels, and to metabolic dysfunction in adulthood. The 17NF mice had increased adiposity, impaired glucose metabolism and decreased energy expenditure. The subcutaneous and parametrial fat depots displayed impaired function due to ovarian NGF excess, wherein the subcutaneous fat increased mass by enhanced preadipocyte differentiation and enlarged adipocyte size, while the parametrial fat had smaller adipocyte size and a modest increase in stimulated lipolysis. These defects also led to hepatic steatosis. Overall, our findings indicate that ovarian sympathetic hyperactivity has deleterious effects on whole-body homeostasis and leads to impaired embryonic development and to reproductive and metabolic defects in adult life.