1. |
- Asp, Joline, et al.
(författare)
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Alcohol exposure prior to pregnancy-does hazardous consumption affect placenta- and inflammatory-mediated pregnancy outcomes? A Swedish population-based cohort study.
- 2022
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Ingår i: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 101:12, s. 1386-1394
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol consumption during pregnancy is related to severe birth complications such as low birthweight, preterm birth and birth defects. During the last decade, the Alcohol Use Disorders Identification Test (AUDIT) has been used as a screening tool in Swedish maternal healthcare units to identify hazardous, pre-pregnancy alcohol use. However, evaluation of the screening with AUDIT, as well as adverse maternal or neonatal outcomes, has not been assessed at a national level.This was a population-based cohort study of 530458 births from 2013 to 2018 using demographic, reproductive and maternal health data from the Swedish Pregnancy Register. Self-reported alcohol consumption in the year before pregnancy, measured as AUDIT scores, was categorized into moderate (6-13 points) and high-risk (14-40 points) consumption, with low-risk (0-5 points) consumption as the reference group. Associations with pregnancy- and birth outcomes were explored with logistic regressions using generalized estimating equation models, adjusting for maternal and socioeconomic characteristics. Estimates are presented as adjusted odds ratios (aORs) with 95% confidence intervals (CIs).High-risk and moderate pre-pregnancy alcohol consumption was associated with preeclampsia, preterm birth and birth of an infant small for gestational age (SGA), but these associations were nonsignificant after adjustments. Prior moderate-risk (aOR 1.29, 95% CI 1.17-1.42) and high-risk consumption (aOR 1.62, 95% CI 1.17-2.25) increased the likelihood of intrapartum and neonatal infections.Apart from identifying hazardous alcohol consumption prior to pregnancy and the offer of counseling, screening with the AUDIT in early pregnancy indicates a high risk of inflammatory-/placenta-mediated pregnancy and birth outcomes. For most outcomes, AUDIT was not an independent contributor when adjusting for confounding factors. Hazardous alcohol use prior to pregnancy was independently linked to intrapartum and neonatal infections; conditions associated with morbidity and long-term sequalae. These associations may be explained by alcohol-induced changes in the maternal or fetal immune system in early pregnancy or persistent alcohol intake during pregnancy, or may depend on unidentified confounding factors.
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2. |
- Aswad, Amr, et al.
(författare)
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Evolutionary history of endogenous Human Herpesvirus 6 reflects human migration out of Africa
- 2021
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Ingår i: Molecular biology and evolution. - : Oxford University Press. - 0737-4038 .- 1537-1719. ; 38:1, s. 96-107
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Tidskriftsartikel (refereegranskat)abstract
- Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result about 70 million people harbour the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if i) these integrations are ancient, ii) if they still occur, and iii) whether circulating virus strains differ from integrated ones. Here we used next generation sequencing and mining of public human genome datasets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly-related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or "reactivation" of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa.
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3. |
- Axfors, Cathrine, et al.
(författare)
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Cohort profile : the Biology, Affect, Stress, Imaging and Cognition (BASIC) study on perinatal depression in a population-based Swedish cohort
- 2019
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: With the population-based, prospective Biology, Affect, Stress, Imaging and Cognition (BASIC) cohort, we aim to investigate the biopsychosocial aetiological processes involved in perinatal depression (PND) and to pinpoint its predictors in order to improve early detection.PARTICIPANTS: From September 2009 to November 2018, the BASIC study at Uppsala University Hospital, Sweden, has enrolled 5492 women, in 6478 pregnancies, of which 46.3% first-time pregnancies and with an average age of 31.5 years. After inclusion around gestational week 16-18, participants are followed-up with data collection points around gestational week 32, at childbirth, as well as three times postpartum: after 6 weeks, 6 months and 1 year. At the last follow-up, 70.8% still remain in the cohort.FINDINGS TO DATE: In addition to internet-based surveys with self-report instruments, participants contribute with biological samples, for example, blood samples (maternal and from umbilical cord), biopsies (umbilical cord and placenta) and microbiota samples. A nested case-control subsample also takes part in cognitive and emotional tests, heart rate variability tests and bioimpedance tests. Subprojects have identified various correlates of PND of psychological and obstetric origin in addition to factors of the hypothalamic-pituitary-adrenal axis and immune system.FUTURE PLANS: In parallel with the completion of data collection (final follow-up November 2019), BASIC study data are currently analysed in multiple subprojects. Since 2012, we are conducting an ongoing follow-up study on the participants and their children up to 6 years of age (U-BIRTH). Researchers interested in collaboration may contact Professor Alkistis Skalkidou (corresponding author) with their request to be considered by the BASIC study steering committee.
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4. |
- Berlin, Henrik, et al.
(författare)
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Effects and cost-effectiveness of postoperative oral analgesics for additional postoperative pain relief in children and adolescents undergoing dental treatment: Health technology assessment including a systematic review
- 2019
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 14:12
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Forskningsöversikt (refereegranskat)abstract
- Background There is an uncertainty regarding how to optimally prevent and/or reduce pain after dental treatment on children and adolescents. Aim To conduct a systematic review (SR) and health technology assessment (HTA) of oral analgesics administered after dental treatment to prevent postoperative pain in children and adolescents aged 3-19 years. Design A PICO-protocol was constructed and registered in PROSPERO (CRD42017075589). Searches were conducted in PubMed, Cochrane, Scopus, Cinahl, and EMBASE, November 2018. The researchers (reading in pairs) assessed identified studies independently, according to the defined inclusion and exclusion criteria, following the PRISMA-statement. Results 3,963 scientific papers were identified, whereof 216 read in full text. None met the inclusion criteria, leading to an empty SR. Ethical issues were identified related to the recognized knowledge gap in terms of challenges to conduct studies that are well-designed from methodological as well as ethical perspectives. Conclusions There is no scientific support for the use or rejection of oral analgesics administered after dental treatment in order to prevent or reduce postoperative pain in children and adolescents. Thus, no guidelines can be formulated on this issue based solely on scientific evidence. Well-designed studies on how to prevent pain from developing after dental treatment in children and adolescents is urgently needed.
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5. |
- Bhalla, Nayanika, et al.
(författare)
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Spatial transcriptomics of human placentas reveal distinct RNA patterns associated with morphology and preeclampsia
- 2023
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Ingår i: Placenta. - : Elsevier BV. - 0143-4004 .- 1532-3102. ; 139, s. 213-216
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Tidskriftsartikel (refereegranskat)abstract
- Spatial transcriptomics (ST) maps RNA level patterns within a tissue. This technology has not been previously applied to human placental tissue. We demonstrate analysis of human placental samples with ST. Unsupervised clustering revealed that distinct RNA patterns were found corresponding to different morphological structures. Additionally, when focusing upon terminal villi and hemoglobin associated structures, RNA levels differed between placentas from full term healthy pregnancies and those complicated by preeclampsia. The results from this study can provide a benchmark for future ST studies in placenta.
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6. |
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7. |
- Callbo, Paliz Nordlof, et al.
(författare)
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Novel Associations Between Mid-Pregnancy Cardiovascular Biomarkers and Preeclampsia: An Explorative Nested Case-Control Study
- 2024
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Ingår i: REPRODUCTIVE SCIENCES. - 1933-7191 .- 1933-7205. ; 31, s. 1391-1400
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Tidskriftsartikel (refereegranskat)abstract
- Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (similar to 18 weeks' gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.
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8. |
- Castro, Rita Amiel, et al.
(författare)
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Pregnancy-related hormones and COMT genotype : Associations with maternal working memory
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 132
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Tidskriftsartikel (refereegranskat)abstract
- Women experience different degrees of subjective cognitive changes during pregnancy. The exact mechanism underlying these changes is unknown, although endocrine alterations and genetics may be contributing factors. We investigated whether multiple pregnancy-related hormones were associated with working memory function assessed with the Digit Span Test (DST) in late pregnancy. Moreover, we examined whether the catechol-Omethyltransferase (COMT) genotype, previously related to working memory, was an effect modifier in this association. In this population-based panel study, we recorded psychiatric history, medication use, socio-demographic characteristics, and psychological well-being, gathered blood and saliva samples, and administered the DST at gestational weeks 35-39 (N = 216). We conducted multivariate linear regressions with DST as outcome, with different hormones and COMT genotype, adjusting for covariates including maternal age, BMI, education, depressive symptoms, and parity. We repeated these analyses excluding women with elevated depressive symptoms. Higher DST total scores were associated with increased free estradiol concentrations (B = 0.01, p = 0.03; B = 0.01, p = 0.02) in all participants and in participants without depressive symptoms, respectively, whereas DST forward was positively associated with free estradiol only in women without depressive symptoms (B = 0.01, p = 0.04). Lower total testosterone concentrations (B = -0.03, p = 0.01) enhanced DST backward performance in non-depressed women. Maternal higher education was significantly associated with the DST subscales in all participants. No significant differences emerged when considering the COMT genotype. Our results suggest differential associations of free estradiol and total testosterone levels with working memory function in late pregnancy.
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9. |
- Cederlöf, Elin Täufer, et al.
(författare)
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Biomarkers associated with cardiovascular disease in women with spontaneous preterm birth : A case-control study.
- 2024
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - 0001-6349 .- 1600-0412.
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Women with spontaneous preterm birth have an increased risk of cardiovascular disease later in life. Studies suggest potential pathophysiological mechanisms in common, but whether these could be identified by measurement of soluble circulating protein biomarkers in women with spontaneous preterm birth is unknown. The aim of this study was to determine if protein biomarkers associated with cardiovascular disease distinguish women with spontaneous preterm birth from healthy controls, both at pregnancy and at follow up.MATERIAL AND METHODS: Study participants were identified in the population-based Uppsala biobank of pregnant women in Sweden, where plasma samples were collected in mid-pregnancy. In a first screening phase, we identified participants who subsequently experienced spontaneous preterm birth (<37 weeks) in the index pregnancy (N = 13) and controls (N = 6). In these samples, differences in protein expression were examined by comparative mass spectrometry. In a second validation phase, we invited 100 cases with previous spontaneous preterm birth in the index pregnancy and 100 controls (matched for age, body mass index, and year of delivery) from the same source population, to a follow-up visit 4-15 years after pregnancy. At follow up, we collected plasma samples and data on cardiovascular risk factors. We measured concentrations of selected biomarkers identified in the screening phase, as well as lipid profiles in samples both from pregnancy (biobank) and follow up.CLINICALTRIALS: gov registration NCT05693285.RESULTS: In the screening phase, fibrinogen, cadherin-5, complement C5, factor XII, plasma kallikrein, apolipoprotein M, and vitamin D-binding protein differed significantly at pregnancy. In the validation phase, 65 women agreed to participate (35 cases and 30 controls), with a median follow-up time of 11.8 years since pregnancy. The concentration of fibrinogen (p = 0.02) and triglycerides (p = 0.03) were slightly higher in cases compared with matched controls at follow up.CONCLUSIONS: Compared with women without preterm birth, those with spontaneous preterm birth had slightly higher concentrations of fibrinogen, both at mid-pregnancy and a decade after pregnancy. Additionally, we found slightly higher concentration of triglycerides at follow up in women with previous spontaneous preterm birth. The relevance of this finding is uncertain but might indicate potential pathophysiological mechanisms in common between spontaneous preterm birth and cardiovascular disease.
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10. |
- de Goffau, Marcus C., et al.
(författare)
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Human placenta has no microbiome but can contain potential pathogens
- 2019
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 572:7769, s. 329-334
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Tidskriftsartikel (refereegranskat)abstract
- We sought to determine whether pre-eclampsia, spontaneous preterm birth or the delivery of infants who are small for gestational age were associated with the presence of bacterial DNA in the human placenta. Here we show that there was no evidence for the presence of bacteria in the large majority of placental samples, from both complicated and uncomplicated pregnancies. Almost all signals were related either to the acquisition of bacteria during labour and delivery, or to contamination of laboratory reagents with bacterial DNA. The exception was Streptococcus agalactiae (group B Streptococcus), for which non-contaminant signals were detected in approximately 5% of samples collected before the onset of labour. We conclude that bacterial infection of the placenta is not a common cause of adverse pregnancy outcome and that the human placenta does not have a microbiome, but it does represent a potential site of perinatal acquisition of S. agalactiae, a major cause of neonatal sepsis.
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11. |
- Döring, Nora, et al.
(författare)
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Labour market position of young people and premature mortality in adult life : A 26-year follow-up of 569 528 Swedish 18 year-olds
- 2021
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Ingår i: The Lancet Regional Health. - : Elsevier BV. - 2666-7762. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Throughout the industrialized world, demand for low skilled labour is falling. The length of schooling is increasing in response, but so is the proportion of individuals not finishing upper secondary school. The objective of this study was to evaluate the associations between labour market positions at age 18 and all-cause and suicide- and accident-specific mortality in later adulthood.Methods: Labour market positions at age 18 were categorized for all Swedes born 1972-77 (n=630 959) into four main groups: employed, successful students, students not about to qualify (SNAQs), and individuals not in employment, education or training (NEETs). Cox proportional hazard models were fitted to assess allcause, suicide and accident mortality up to 2016 (ages 39-44), adjusting for high school grades, parental and own prior psychiatric diagnoses, and childhood socioeconomic status.Findings: SNAQs had substantially increased all-cause (men: HR=2.10; 95% CI 1.92-2.28, women: HR=1.64; 95% CI: 1.44-1.86), suicide (men: HR=2.16; CI: 1.86-2.51, women: HR=2.10; 95% CI 1.64-2.69), and accident specific (men: HR=2.08; 95% CI 1.77-2.44, women: 1.87; 95% CI 1.33;2.62) mortality risks compared to successful students. The risks were similar for NEETs. There was no increased risk among full-time employed compared to successful students.Interpretation: Expanding the educational system may be a natural response to falling demand for low skilled labour but not by far one that corrects the major societal challenge of it. Unless educational systems adequately respond to this challenge, only more inequality is to be expected ahead.
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12. |
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13. |
- Edvinsson, Åsa, 1982-, et al.
(författare)
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Placental glucocorticoid receptors are not affected by maternal depression or SSRI treatment.
- 2020
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 125:1, s. 30-36
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prenatal depression is common, with an estimate that up to one in five pregnant women suffers from depressive symptoms. Maternal depression is associated with poor pregnancy outcomes such as preterm birth and low birth-weight. Such outcomes possibly affect offspring development. Previous studies suggest placental RNA levels of the glucocorticoid receptor are altered by maternal depression or anxiety; this stress may affect the placenta of male and female foetuses differently. However, it is unknown if the protein levels and activity of this receptor are additionally affected in women with depressive symptoms or being pharmacologically treated for depression.Methods: In this study, we investigated whether the glucocorticoid receptor (NR3C1) in the placenta is affected by maternal depression and/or selective serotonin reuptake inhibitor (SSRIs) treatment. Placentas from 45 women with singleton, term pregnancies were analysed by Western blot to determine glucocorticoid receptor levels, and by DNA-binding capacity to measure glucocorticoid receptor activation.Results: There were no differences in levels of the glucocorticoid receptor or activity between groups (control, depressive symptoms, and SSRI treatment; n = 45). Similarly, there was no difference in placental glucocorticoid receptor levels or activity dependent upon foetal sex.Conclusion: Maternal depression and SSRI treatment do not affect the glucocorticoid receptors in the placenta.
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14. |
- Edvinsson, Åsa, 1982-, et al.
(författare)
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The effect of antenatal depression and antidepressant treatment on placental tissue : a protein-validated gene expression study.
- 2019
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Ingår i: BMC Pregnancy and Childbirth. - : Springer Science and Business Media LLC. - 1471-2393 .- 1471-2393. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Antenatal depression affects 10-20% of pregnant women. Around 2-4% of European pregnant women use antidepressant treatment, most commonly selective serotonin reuptake inhibitors (SSRIs). Poor pregnancy outcomes, such as preterm birth and low birth weight, have been described in women with antenatal depression and in pregnant women on SSRI treatment. However, the effects of antenatal depression and antidepressant treatment on the placenta are largely unknown. The aim of this work was to compare placental gene and protein expression in healthy women, women with untreated antenatal depression and women on antidepressant treatment during pregnancy.METHODS: Placental samples from 47 controls, 25 depressed and 45 SSRI-treated women were analysed by means of qPCR using custom-designed TaqMan low-density arrays (TLDAs) for 44 genes previously known to be involved in the pathophysiology of depression, and expressed in the placenta. Moreover, placental protein expression was determined by means of immunohistochemistry in 37 healthy controls, 13 women with untreated depression and 21 women on antidepressant treatment. Statistical comparisons between groups were performed by one-way ANOVA or the Kruskal-Wallis test.RESULTS: Nominally significant findings were noted for HTR1A and NPY2R, where women with untreated depression displayed higher gene expression than healthy controls (p < 0.05), whereas women on antidepressant treatment had similar expression as healthy controls. The protein expression analyses revealed higher expression of HTR1A in placentas from women on antidepressant treatment, than in placentas from healthy controls (p < 0.05).CONCLUSION: The differentially expressed HTR1A, both at the gene and the protein level that was revealed in this study, suggests the involvement of HTR1A in the effect of antenatal depression on biological mechanisms in the placenta. More research is needed to elucidate the role of depression and antidepressant treatment on the placenta, and, further, the effect on the fetus.
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15. |
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16. |
- Gaccioli, Francesca, et al.
(författare)
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Fetal inheritance of chromosomally integrated human herpesvirus 6 predisposes the mother to pre-eclampsia
- 2020
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Ingår i: Nature Microbiology. - : Springer Nature. - 2058-5276. ; 5:7, s. 901-908
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Tidskriftsartikel (refereegranskat)abstract
- Pre-eclampsia (typically characterized by new-onset hypertension and proteinuria in the second half of pregnancy) represents a major determinant of the global burden of disease1,2. Its pathophysiology involves placental dysfunction, but the mechanism is unclear. Viral infection can cause organ dysfunction, but its role in placentally related disorders of human pregnancy is unknown3. We addressed this using RNA sequencing metagenomics4-6 of placental samples from normal and complicated pregnancies. Here, we show that human herpesvirus 6 (HHV-6, A or B) RNA was detected in 6.1% of cases of pre-eclampsia and 2.2% of other pregnancies. Fetal genotyping demonstrated that 70% of samples with HHV-6 RNA in the placenta exhibited inherited, chromosomally integrated HHV-6 (iciHHV-6). We genotyped 467 pre-eclampsia cases and 3,854 controls and found an excess of iciHHV-6 in the cases (odds ratio of 2.8, 95% confidence intervals of 1.4-5.6, P = 0.008). We validated this finding by comparing iciHHV-6 in a further 740 cases with controls from large-scale population studies (odds ratio of 2.5, 95% confidence intervals of 1.4-4.4, P = 0.0013). We conclude that iciHHV-6 results in the transcription of viral RNA in the human placenta and predisposes the mother to pre-eclampsia.
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17. |
- Gaccioli, Francesca, et al.
(författare)
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Placental Streptococcus agalactiae DNA is associated with neonatal unit admission and foetal pro-inflammatory cytokines in term infants
- 2023
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Ingår i: Nature Microbiology. - : Springer Nature. - 2058-5276. ; 8:12, s. 2338-2348
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus agalactiae (Group B Streptococcus; GBS) is a common cause of sepsis in neonates. Previous work detected GBS DNA in the placenta in ~5% of women before the onset of labour, but the clinical significance of this finding is unknown. Here we re-analysed this dataset as a case control study of neonatal unit (NNU) admission. Of 436 infants born at term (≥37 weeks of gestation), 7/30 with placental GBS and 34/406 without placental GBS were admitted to the NNU (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.3-7.8). We then performed a validation study using non-overlapping subjects from the same cohort. This included a further 239 cases of term NNU admission and 686 term controls: 16/36 with placental GBS and 223/889 without GBS were admitted to the NNU (OR 2.4, 95% CI 1.2-4.6). Of the 36 infants with placental GBS, 10 were admitted to the NNU with evidence of probable but culture-negative sepsis (OR 4.8, 95% CI 2.2-10.3), 2 were admitted with proven GBS sepsis (OR 66.6, 95% CI 7.3-963.7), 6 were admitted and had chorioamnionitis (inflammation of the foetal membranes) (OR 5.3, 95% CI 2.0-13.4), and 5 were admitted and had funisitis (inflammation of the umbilical cord) (OR 6.7, 95% CI 12.5-17.7). Foetal cytokine storm (two or more pro-inflammatory cytokines >10 times median control levels in umbilical cord blood) was present in 36% of infants with placental GBS DNA and 4% of cases where the placenta was negative (OR 14.2, 95% CI 3.6-60.8). Overall, ~1 in 200 term births had GBS detected in the placenta, which was associated with infant NNU admission and morbidity.
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18. |
- Henriksson, Hanna E., et al.
(författare)
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Blood plasma metabolic profiling of pregnant women with antenatal depressive symptoms
- 2019
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Antenatal depression affects similar to 9-19% of pregnant women and can exert persistent adverse effects on both mother and child. There is a need for a deeper understanding of antenatal depression mechanisms and the development of tools for reliable diagnosis and early identification of women at high risk. As the use of untargeted blood metabolomics in the investigation of psychiatric and neurological diseases has increased substantially, the main objective of this study was to investigate whether untargeted gas chromatography-mass spectrometry (GC-MS) plasma metabolomics in 45 women in late pregnancy, residing in Uppsala, Sweden, could indicate metabolic differences between women with and without depressive symptoms. Furthermore, seasonal differences in the metabolic profiles were explored. When comparing the profiles of cases with controls, independently of season, no differences were observed. However, seasonal differences were observed in the metabolic profiles of control samples, suggesting a favorable cardiometabolic profile in the summer vs. winter, as indicated by lower glucose and sugar acid concentrations and lactate to pyruvate ratio, and higher abundance of arginine and phosphate. Similar differences were identified between cases and controls among summer pregnancies, indicating an association between a stressed metabolism and depressive symptoms. No depression-specific differences were apparent among depressed and non-depressed women, in the winter pregnancies; this could be attributed to an already stressed metabolism due to the winter living conditions. Our results provide new insights into the pathophysiology of antenatal depression, and warrant further investigation of the use of metabolomics in antenatal depression in larger cohorts.
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19. |
- Jansson, Nina, 1976, et al.
(författare)
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Activation of Placental mTOR Signaling and Amino Acid Transporters in Obese Women Giving Birth to Large Babies.
- 2013
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 98:1, s. 105-13
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Tidskriftsartikel (refereegranskat)abstract
- Context: Babies of obese women are often large at birth, which is associated with perinatal complications and metabolic syndrome later in life. The mechanisms linking maternal obesity to fetal overgrowth are largely unknown. Objective: We tested the hypothesis that placental insulin/IGF-I and mammalian target of rapamycin (mTOR) signaling is activated and amino acid transporter activity is increased in large babies of obese women. Design and Setting: Pregnant women were recruited prospectively for collection of placental tissue at a university hospital and academic biomedical center. Patients or Other Participants: Twenty-three Swedish pregnant women with first trimester body mass index ranging from 18.5 to 44.9 kg/m(2) and with uncomplicated pregnancies participated in the study. Interventions: There were no interventions. Main Outcome Measures: We determined the phosphorylation of key signaling molecules (including Akt, IRS-1, S6K1, 4EBP-1, RPS6, and AMPK) in the placental insulin/IGF-I, AMPK, and mTOR signaling pathways. The activity and protein expression of the amino acid transporter systems A and L were measured in syncytiotrophoblast microvillous plasma membranes. Results: Birth weights (range, 3025-4235 g) were positively correlated to maternal body mass index (P < 0.05). The activity of placental insulin/IGF-I and mTOR signaling was positively correlated (P < 0.001), whereas AMPK phosphorylation was inversely (P < 0.05) correlated to birth weight. Microvillous plasma membrane system A, but not system L, activity and protein expression of the system A isoform SNAT2 were positively correlated to birth weight (P < 0.001). Conclusions: Up-regulation of specific placental amino acid transporter isoforms may contribute to fetal overgrowth in maternal obesity. This effect may be mediated by activation of insulin/IGF-I and mTOR signaling pathways, which are positive regulators of placental amino acid transporters.
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20. |
- Junus, Katja, 1982-, et al.
(författare)
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Elevated mid-pregnancy plasma levels of angiotensin-converting enzyme 2 in women prior to the development of preeclampsia.
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Preeclampsia and cardiovascular disease (CVD) share multiple features and risk factors. Circulating angiotensin-converting enzyme 2 (ACE2) is increased in CVD and mediates SARS-CoV-2 entry into host cells, causing COVID-19 infection. The role of ACE2 in preeclampsia pathophysiology is unknown. We hypothesized that circulating ACE2 is increased in mid-pregnancy in women later developing preeclampsia. We included 296 women later developing preeclampsia (cases) and 333 women with a continuous healthy pregnancy (controls). Circulating ACE2 was measured with an immunoassay based on proximity extension assay technology, with levels being expressed as relative quantification on a log2 scale. Median (interquartile range) ACE2 levels were higher in cases than in controls; 3.84 (3.50-4.24) vs. 3.72 (3.45-4.04), p=0.002. Adjusted logistic regression models showed a 60% increased risk for later development of preeclampsia with one unit elevation of ACE2 (adjusted odds ratio (aOR) 1.60, 95% confidence intervals (CI) 1.17-2.18). Preterm preeclampsia (diagnosis before 37 gestational weeks, n=97) seemed to have a stronger ACE2 association than term preeclampsia, n=199 (aORs, 95% Cis 2.14, 1.15-3.96 and 1.52, 1.04-2.23, respectively). Circulating ACE2 is increased at mid-pregnancy in women later developing preeclampsia, particularly preterm preeclampsia. Thus, our finding indicates a partly shared pathophysiological pathway between preeclampsia and CVD.
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21. |
- Kunovac Kallak, Theodora, 1985-, et al.
(författare)
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Differential gene expression in two consecutive pregnancies between same sex siblings and implications on maternal constraint
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate how placental gene expression differs in two consecutive pregnancies in same sex siblings, and its possible association with the "maternal constraint" hypothesis. Material was gathered from the BASIC study (Biological, Affect, Stress, Imaging, and Cognition in Pregnancy and the Puerperium), a population based prospective study that was started in 2009 in Uppsala. Over 900 specimens of placenta biopsies were collected and out of these 10 women gave birth twice, to the same sex child, and were included in this study. The total RNA was isolated and prepared from frozen villous tissue from the placenta and further analyzed by use of Ion AmpliSeq Human Transcriptome Gene Expression kit. A total of 234 genes differed significantly between the first and second pregnancy placentas, when adjusting for delivery mode, maternal BMI and gestational age. Of special interest was the down-regulated group of genes in the second pregnancy. Exemplified by Pentraxin 3, SRY-Box Transcription Factor 9, and Serum Amyloid A1, which all were associated with biological processes involved in the immune system and inflammation. Further, protein-protein interaction analysis visualized them as hub genes interacting with several of the other differentially expressed genes. How these altered gene expressions affect maternal constraint during pregnancy needs further validation in lager study cohorts and also future validation in functional assays.
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22. |
- Kunovac Kallak, Theodora, 1985-, et al.
(författare)
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DNA methylation in cord blood in association with prenatal depressive symptoms
- 2021
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Ingår i: Clinical Epigenetics. - : BioMed Central (BMC). - 1868-7083 .- 1868-7075. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prenatal symptoms of depression (PND) and anxiety affect up to every third pregnancy. Children of mothers with mental health problems are at higher risk of developmental problems, possibly through epigenetic mechanisms together with other factors such as genetic and environmental. We investigated DNA methylation in cord blood in relation to PND, taking into consideration a history of depression, co-morbidity with anxiety and selective serotonin reuptake inhibitors (SSRI) use, and stratified by sex of the child. Mothers (N = 373) prospectively filled out web-based questionnaires regarding mood symptoms and SSRI use throughout pregnancy. Cord blood was collected at birth and DNA methylation was measured using Illumina MethylationEPIC array at 850 000 CpG sites throughout the genome. Differentially methylated regions were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p-values < 0.05 were considered significant.Results: No differential DNA methylation was associated with PND alone; however, differential DNA methylation was observed in children exposed to comorbid PND with anxiety symptoms compared with healthy controls in ABCF1 (log twofold change - 0.2), but not after stratification by sex of the child. DNA methylation in children exposed to PND without SSRI treatment and healthy controls both differed in comparison with SSRI exposed children at several sites and regions, among which hypomethylation was observed in CpGs in the promoter region of CRBN (log2 fold change - 0.57), involved in brain development, and hypermethylation in MDFIC (log2 fold change 0.45), associated with the glucocorticoid stress response.Conclusion: Although it is not possible to assess if these methylation differences are due to SSRI treatment itself or to more severe depression, our findings add on to existing knowledge that there might be different biological consequences for the child depending on whether maternal PND was treated with SSRIs or not.
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23. |
- Kunovac Kallak, Theodora, 1985-, et al.
(författare)
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Maternal prenatal depressive symptoms and toddler behavior : an umbilical cord blood epigenome-wide association study
- 2022
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Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Children of mothers with prenatal depressive symptoms (PND) have a higher risk of behavioral problems; fetal programming through DNA methylation is a possible underlying mechanism. This study investigated DNA methylation in cord blood to identify possible "at birth" signatures that may indicate susceptibility to behavioral problems at 18 months of age. Cord blood was collected from 256 children of mothers who had self-reported on symptoms of depression during pregnancy and the behavior of their child at 18 months of age. Whole genome DNA methylation was assessed using Illumina MethylationEPIC assay. The mother and child pairs were categorized into four groups, based on both self-reported depressive symptoms, PND or Healthy control (HC), and scores from the Child Behavior checklist (high or low for internalizing, externalizing, and total scores). Adjustments were made for batch effects, cell-type, and clinical covariates. Differentially methylated sites were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p values < 0.05 were considered significant. The analysis was also stratified by sex of the child. Among boys, we observed higher and correlated DNA methylation of one CpG-site in the promoter region of TPP1 in the HC group, with high externalizing scores compared to HC with low externalizing scores. Boys in the PND group showed lower DNA methylation in NUDT15 among those with high, compared to low, internalizing scores; the DNA methylation levels of CpGs in this gene were positively correlated with the CBCL scores. Hence, the differentially methylated CpG sites could be of interest for resilience, regardless of maternal mental health during pregnancy. The findings are in a relatively healthy study cohort, thus limiting the possibility of detecting strong effects associated with behavioral difficulties. This is the first investigation of cord blood DNA methylation signs of fetal programming of PND on child behavior at 18 months of age and thus calls for independent replications.
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24. |
- Kunovac Kallak, Theodora, 1985-, et al.
(författare)
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Study protocol : The cross-sectional Uppsala weight gain in pregnancy study (VIGA study)
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : UPSALA MED SOC. - 0300-9734 .- 2000-1967. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: More than two in five Swedish women are overweight or obese when becoming pregnant. Maternal overweight or obesity and excessive pregnancy weight gain are associated with several adverse pregnancy outcomes. The underlying mechanisms that link maternal adiposity, diet, exercise, pregnancy weight gain with pregnancy outcome are incompletely understood. Methods: We describe the design for a cross-sectional study of pregnant women at Uppsala University Hospital, Sweden. All participants delivered by elective cesarean section before the onset of labor. At inclusion, participants answered two questionnaires concerning their dietary and exercise habits. Fasting maternal blood samples (buffy coat, plasma, serum) were collected. During the cesarean section, biopsies of maternal subcutaneous and visceral adipose tissues were obtained. Placental tissue was collected after delivery. All biological samples were processed as soon as possible, frozen on dry ice, and stored at -70 degrees C. Pregnancy outcomes and supplementary maternal characteristics were collected from medical records. Results: In total, 143 women were included in the study. Of these women, 33.6% were primiparous, 46.2% had a pre-pregnancy body mass index (BMI) over 25 kg/m(2), and 11.2% of the offspring were born large for gestational age (LGA). Complete collection, that is both questionnaires and all types of biological samples, was obtained from 81.1% of the participants. Conclusions: This study is expected to provide a resource for exploration of the associations between maternal weight, diet, exercise, pregnancy weight gain, and pregnancy outcome. Results from this study will be published in peer-reviewed, international scientific journals. This study was approved by the Regional Ethics Review Board in Uppsala (approval no 2014/353) and with an amendment by the Swedish Ethical Review Authority (approval no 2020-05844).
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25. |
- Lager, Susanne, et al.
(författare)
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Abnormal placental CD8+ T cell infiltration is a feature of fetal growth restriction and pre-eclampsia.
- 2020
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Ingår i: Journal of Physiology. - 0022-3751 .- 1469-7793. ; 598:23, s. 5555-5571
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Tidskriftsartikel (refereegranskat)abstract
- KEY POINTS: Placental pathological abnormalities are more frequently observed in complicated pregnancies than in healthy pregnancies Infiltration of CD8+ T-cells into the placental villous tissue occurred in both fetal growth restriction and pre-eclampsia, whereas CD79α+ B-cell infiltration was only apparent with reduced fetal growth. Vascularisation, fibrin depositions, macrophage and neutrophil infiltration in the placenta did not differ between healthy and complicated pregnancies.ABSTRACT: Fetal growth restriction (FGR) and pre-eclampsia are severe, adverse pregnancy outcomes. Alterations in placental histology are frequently reported in these pregnancy complications and are often based upon scoring by pathologists. However, many alterations are also observed in placenta from uncomplicated pregnancies. Moreover, knowledge of disease state may bias assessment. We sought to perform an objective comparison of placental microscopic appearance in normal and complicated pregnancies. Placental villous tissue (n = 823) and edge biopsies (n = 488) from 871 individual, singleton pregnancies were collected after delivery. Cases of small-for-gestational-age (SGA) or pre-eclampsia were matched with healthy controls. A subset of the SGA cases displayed signs of FGR. Cases of pre-term delivery were also included. Tissue sections were stained with H&E or antibodies for CD8, CD14, CD31, CD79α, elastase. Images were scored by two experienced pathologists for pathological features or analysed by image analysis and stereology. Analyses were performed blind to case-control status and gestational age. Volume fraction of T-cells increased in placentas from pregnancies complicated by pre-eclampsia (adjusted odds ratio (aOR) 1.46, 95% CI 1.12-1.90) and FGR (aOR 1.64, 95% CI 1.11-2.43), whereas B-cells only increased in FGR (aOR 1.65, 95% CI 1.05-2.60). Pathological abnormalities in villous tissue were reported in 21.4% (88/411) of complicated pregnancies and 14.3% (52/363) of controls (OR 1.62, 95% CI 1.12-2.37). There were no differences in the fractions of endothelial cells, fibrin deposition, macrophages, and neutrophils when comparing normal and complicated pregnancies. In conclusion, FGR and pre-eclampsia are associated with T-cell infiltration of the placenta and placental pathological abnormalities. This article is protected by copyright. All rights reserved.
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26. |
- Lager, Susanne, et al.
(författare)
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Alcohol consumption habits and associations with anxiety or depressive symptoms postpartum in women with high socioeconomic status in Sweden.
- 2022
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Ingår i: Archives of Women's Mental Health. - : Springer Nature. - 1434-1816 .- 1435-1102.
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Tidskriftsartikel (refereegranskat)abstract
- Postpar tum depression and anxiety are common among new mothers. It is well-established that in the general population alcohol use is associated with depression and anxiety. Linking alcohol consumption to symptoms of postpartum depression (PPDS) or postpartum anxiety (PPAS) is presently less established. This study aims to determine if alcohol consumption pre-pregnancy, 6 weeks postpartum, 6 months postpartum, or changes in alcohol consumption are associated with PPDS or PPAS. Longitudinal data on 3849 women from a Swedish perinatal cohort were analyzed using logistic regression analyses for associations between alcohol consumption and symptoms of anxiety or depression, as assessed with the Edinburgh Postnatal Depression Scale. There was no association between pre-pregnancy drinking habits and PPDS (p = 0.588, n = 2479) or PPAS (p = 0.942; n = 2449) at 6 weeks postpartum. Similarly, no associations were observed between concurrent drinking habits at 6 weeks postpartum and PPAS (p = 0.070, n = 3626), 6 months postpartum and PPDS (0.647, n = 3461) or PPAS (p = 0.700, n = 3431). However, there was an association between drinking habits at 6 weeks postpartum and concurrent PPDS (p = 0.047, n = 3659). In conclusion, robust associations were not found between postpartum alcohol consumption and mood symptoms. This lack of association between poor mental health and risk behaviors in new mothers could be interpreted as a result of long-term policy work and high participation in Swedish maternity care. Future studies need to address these research questions in more diverse socio-cultural contexts.
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27. |
- Lager, Susanne, 1978
(författare)
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Cytokines and lipids in pregnancy – effects on developmental programming and placental nutrient transfer
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Metabolic disturbances, in particular those associated with nutritional challenges, that take place during development, both in utero and early postnatal life, have long-lasting health consequences on an individual. The most pronounced evidence of these challenges is a deviation in birth weight. This is a process recognized as developmental programming of adult health and disease. The etiologies of metabolic health disorders such as insulin resistance and obesity are complex; and developmental programming may be a factor contributing to the increased worldwide prevalence. Women who are overweight or diabetic have a higher risk for delivering large infants, and such infants are themselves at an increased risk of developing metabolic disturbances. Fetal growth is intimately linked to placental nutrient transport capacity. We hypothesized that the altered nutritional, hormonal, and metabolic environment of overweight or diabetic women (hyperlipidemia, pro-inflammatory status) modifies placental nutrient transport and contributes to altering the adult phenotype of these children. The aim of this thesis was to investigate the importance of maternal interleukin-6 during development for offspring adiposity and insulin sensitivity at an adult age in mice, examine the effects of cytokines and lipids on human placental nutrient transport functions and to describe mechanisms underlying these changes. The main findings of this thesis were: Interleukin-6 deficient mice weighed more and had a more pronounced adiposity which developed at a younger age if born of interleukin-6 deficient dams compared to dams with a heterozygote interleukin-6 genotype. At an older age (6 to 7 months of age) both groups had enlarged adipocytes and reduced insulin sensitivity. Wild-type mice fostered by interleukin-6 deficient dams also weighed more, had an augmented adiposity and larger adipocytes, and higher systemic leptin levels at an adult age compared to wild-type mice fostered by wild-type dams. Milk from interleukin-6 deficient dams contained twofold higher leptin concentrations compared to milk from wild-type dams. These observations suggest that lack of maternal interleukin-6 or, alternatively, factors modified by this cytokine have developmental programming effects that contribute to the development of adipose tissue and obesity. Using primary cell cultures of human trophoblast cells, we demonstrated the production site of placental lipoprotein lipase to be cytotrophoblast cells and syncytiotrophoblast. We also observed that elevated levels of free fatty acids and triglycerides reduce trophoblast lipoprotein lipase activity; while insulin, interleukin-6, and tumor necrosis factor-α had no regulatory effect on lipoprotein lipase. Interleukin-6 did however increase placental lipid accumulation. Free fatty acids changed the release of cytokines from trophoblast cells and stimulated amino acid uptake through the System A transporter. Using RNA interference techniques, we demonstrated that toll-like receptor 4 is required for fatty acids to stimulate placental amino acid uptake. In summary, we found that an altered maternal hormonal or metabolic environment can affect the developing fetus, causing long-term programming effects on adult phenotype. The effects of cytokines on placental lipid transport were moderate; however, there was a pronounced effect of fatty acids upon amino acid uptake. Therefore maternal circulating factors known to be altered in obesity may augment placental nutrient transport and contribute to an accelerated fetal growth.
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28. |
- Lager, Susanne, 1978, et al.
(författare)
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Effect of IL-6 and TNF-α on fatty acid uptake in cultured human primary trophoblast cells.
- 2011
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Ingår i: Placenta. - : Elsevier BV. - 1532-3102 .- 0143-4004. ; 32:2, s. 121-7
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Tidskriftsartikel (refereegranskat)abstract
- Maternal obesity and gestational diabetes (GDM) are conditions associated with fetal overgrowth and excessive fat accumulation in the fetus, implicating an increased placental nutrient transfer in these pregnancies. Obese and GDM mothers have altered metabolism and hormone levels, including elevation of maternal circulatory lipids and pro-inflammatory cytokines. We tested the hypothesis that interleukin (IL)-6 and tumor necrosis factor (TNF)-α stimulate placental fatty acid transport, as these pro-inflammatory cytokines have been shown to affect lipid metabolism in other tissues. In cultured primary human trophoblast cells IL-6, but not TNF-α, stimulated fatty acid accumulation, as measured by BODIPY fluorescence. The increased fatty acid accumulation could not be explained by an increased expression of key components in placental fatty acid transport, such as adipophilin, fatty acid transport protein (FATP)1, FATP4, or lipoprotein lipase. In a cohort of lean and overweight/obese pregnant women, increasing maternal third trimester IL-6 plasma concentrations correlated with decreasing placental lipoprotein lipase activity. However, as no effect on lipoprotein lipase activity was observed in cultured trophoblast cells after exposure to either IL-6 or TNF-α, the correlation between maternal circulatory IL-6 levels and placental lipoprotein lipase activity at term is unlikely to represent a cause-and-effect relationship. In conclusion, high levels of IL-6 stimulate trophoblast fatty acid accumulation, which could contribute to an excessive nutrient transfer in conditions associated with elevated maternal IL-6 such as obesity and gestational diabetes.
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29. |
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30. |
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31. |
- Lager, Susanne, 1978, et al.
(författare)
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Oleic acid stimulates system A amino acid transport in primary human trophoblast cells mediated by toll-like receptor 4
- 2013
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Ingår i: Journal of Lipid Research. - 0022-2275. ; 54:3, s. 725-733
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Tidskriftsartikel (refereegranskat)abstract
- Obese women have an increased risk to deliver large babies. However, the mechanisms underlying fetal overgrowth in these pregnancies are not well understood. Obese pregnant women typically have elevated circulating lipid levels. We tested the hypothesis that fatty acids stimulate placental amino acid transport, mediated via toll-like receptor 4 (TLR4) and mammalian target of rapamycin (mTOR) signaling pathways. Circulating NEFA levels and placental TLR4 expression were assessed in women with varying prepregnancy body mass index (BMI). The effects of oleic acid on system A and system L amino acid transport, and on the activation of the mTOR (4EBP1, S6K1, rpS6), TLR4 (IĸBɑ, JNK, p38 MAPK), and STAT3 signaling pathways were determined in cultured primary human trophoblast cells. Maternal circulating NEFAs (n = 33), but not placental TLR4 mRNA expression (n = 16), correlated positively with BMI (P < 0.05). Oleic acid increased trophoblast JNK and STAT3 phosphorylation (P < 0.05), whereas mTOR activity was unaffected. Furthermore, oleic acid doubled trophoblast system A activity (P < 0.05), without affecting system L activity. siRNA-mediated silencing of TLR4 expression prevented the stimulatory effect of oleic acid on system A activity. Our data suggest that maternal fatty acids can increase placental nutrient transport via TLR4, thereby potentially affecting fetal growth.
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32. |
- Lager, Susanne, 1978, et al.
(författare)
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Perinatal lack of maternal IL-6 promotes increased adiposity during adulthood in mice.
- 2011
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 152:4, s. 1336-46
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Tidskriftsartikel (refereegranskat)abstract
- The perinatal environment appears important in establishing metabolic phenotypes in adulthood. Mice deficient in IL-6 (IL-6(-/-)) tend to develop mature-onset obesity, but it is unknown whether perinatal exposure to IL-6 produced by the dam influences the metabolism of adult offspring. To address this issue, we monitored IL-6(-/-) offspring of IL-6(-/-) or IL-6(+/-) dams, as well as wild-type (WT) mice. At adult age, IL-6(-/-) mice weighed significantly more and had more body fat than WT mice, regardless of maternal genotype, and had lower insulin sensitivity. This phenotype was more pronounced in IL-6(-/-) offspring of IL-6(-/-) dams, because they gained weight significantly faster than IL-6(-/-) offspring of IL-6(+/-) dams and had more body fat and higher serum leptin levels at an earlier age. The leptin content was 2-fold higher in milk from IL-6(-/-) than WT dams. However, cross-fostering IL-6(-/-) mice with WT dams did not alter body weight, body composition, or adipocyte size at adult age compared with IL-6(-/-) mice fostered by IL-6(-/-) dams. Conversely, WT mice fostered by IL-6(-/-) dams weighed significantly more than those fostered by WT dams and had more body fat, larger adipocytes, and altered hypothalamic gene expression. We conclude that body fat of adult mice can be increased by perinatal exposure to factors affected by lack of maternal IL-6.
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33. |
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34. |
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35. |
- Lindberger, Emelie, et al.
(författare)
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Early Mid-pregnancy Blood-Based Proteins as Possible Biomarkers of Increased Infant Birth Size in Sex-Stratified Analyses
- 2023
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Ingår i: Reproductive Sciences. - : Springer. - 1933-7191 .- 1933-7205. ; 30, s. 1165-1175
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to evaluate the associations of 92 maternal blood-based proteins with increased infant birth size. The study was performed at the Uppsala University Hospital, Sweden, and included 857 mother and child dyads. The mean age of the women was 30.3 years, and 53.2% were nulliparous. Blood samples were collected at mean 18 + 2 weeks' gestation, and the Olink cardiovascular II panel was used to measure 92 proteins, either known to be or suspected to be markers of cardiovascular and inflammatory disease in humans. Multiple linear regression models adjusted for maternal age, parity, pre-conception BMI, height, and smoking were performed to evaluate the association of each individual protein with infant birth size. We also performed sex-stratified analyses. Eight proteins (Matrix metalloproteinase-12 (MMP-12), Prostasin (PRSS8), Adrenomedullin (ADM), Pappalysin-1 (PAPP-A), Angiotensin-converting enzyme 2 (ACE2), Sortilin (SORT1), Lectin-like oxidized LDL receptor 1 (LOX-1), and Thrombomodulin (TM)) were associated with infant birth size after false discovery rate adjustment. In the analyses including only female infants, ten proteins (MMP-12, Growth/differentiation factor 2 (GDF-2), PRSS8, SORT1, ADM, Interleukin-1 receptor antagonist protein (IL-1ra), Leptin (LEP), ACE2, TM, and Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A)) were associated with infant birth size. Two proteins (PAPP-A and PRSS8) were associated with infant birth size among male infants. Our study suggests several proteins as potential biomarkers for increased birth weight, and our findings could act as a base for future research to identify new potential markers that could be added to improve screening for large infants.
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36. |
- Liu, Yunjun, et al.
(författare)
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A Redox-Mediated Modulation of Stem Bolting in Transgenic Nicotiana sylvestris Differentially Expressing the External Mitochondrial NADPH Dehydrogenase.
- 2009
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Ingår i: Plant Physiology. - : Oxford University Press (OUP). - 1532-2548. ; 150, s. 1248-1259
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Tidskriftsartikel (refereegranskat)abstract
- Cytosolic NADPH can be directly oxidized by a calcium-dependent NADPH dehydrogenase, NDB1, present in the plant mitochondrial electron transport chain. However, little is known regarding the impact of modified cytosolic NADPH reduction levels on growth and metabolism. Nicotiana sylvestris plants overexpressing potato NDB1 displayed early bolting whereas sense-suppression of the same gene led to delayed bolting, with consequential changes in flowering time. The phenotype was dependent on light irradiance, but not linked to any change in biomass accumulation. Whereas the leaf NADPH/NADP(+)-ratio was unaffected, the stem NADPH/NADP(+)-ratio was altered following the genetic modification and strongly correlated to the bolting phenotype. Metabolic profiling of the stem displayed that the NADP(H) change affected relatively few, albeit central, metabolites, including 2-oxoglutarate, glutamate, ascorbate, sugars and hexose phosphates. Consistent with the phenotype, the modified NDB1 level also affected expression of putative floral meristem identity genes of the SQUAMOSA and LEAFY types. Further evidence for involvement of the NADPH redox in stem development was seen in the distinct decrease in the stem apex NADPH/NADP(+)-ratio during bolting. Additionally, the potato NDB1 protein was specifically detected in mitochondria, and a survey of its abundance in major organs revealed that the highest levels are present in green stems. The results thus strongly suggest that NDB1 in the mitochondrial electron transport chain can, by modifying cell redox levels, specifically affect developmental processes.
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37. |
- Magnusson-Olsson, AnneLiese, et al.
(författare)
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Effect of maternal triglycerides and free fatty acids on placental LPL in cultured primary trophoblast cells and in a case of maternal LPL deficiency.
- 2007
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Ingår i: Am J Physiol Endocrinol Metab. ; 293:1
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Tidskriftsartikel (refereegranskat)abstract
- Maternal hypertriglyceridemia is a normal condition in late gestation and is an adaptation to ensure an adequate nutrient supply to the fetus. Placental lipoprotein lipase (LPL) is involved in the initial step in transplacental fatty acid transport as it hydrolyzes maternal triglycerides (TG) to release free fatty acids (FFA). We investigated LPL activity and protein (Western blot) and mRNA expression (real-time RT-PCR) in the placenta of an LPL-deficient mother with marked hypertriglyceridemia. The LPL activity was fourfold lower, LPL protein expression 50% lower, and mRNA expression threefold higher than that of normal, healthy placentas at term (n = 4-7). To further investigate the role of maternal lipids in placental LPL regulation, we isolated placental cytotrophoblasts from term placentas and studied LPL activity and protein and mRNA expression after incubation in Intralipid (as a source of TG) and oleic, linoleic, and a combination of oleic, linoleic, and arachidonic acids as well as insulin. Intralipid (40 and 400 mg/dl) decreased LPL activity by approximately 30% (n = 10-14, P < 0.05) and 400 microM linoleic and linoleic-oleic-arachidonic acid (n = 10) decreased LPL activity by 37 and 34%, respectively. No major changes were observed in LPL protein or mRNA expression. We found no effect of insulin on LPL activity or protein expression in the cultured trophoblasts. To conclude, the activity of placental LPL is reduced by high levels of maternal TG and/or FFA. This regulatory mechanism may serve to counteract an excessive delivery of FFA to the fetus in conditions where maternal TG levels are markedly increased.
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38. |
- Piltonen, Terhi T., et al.
(författare)
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Circulating antimüllerian hormone and steroid hormone levels remain high in pregnant women with polycystic ovary syndrome at term
- 2019
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 111:3, s. 588-596.e1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate plasma antimullerian hormone (AMH) concentration and its relation to steroid hormone levels in pregnant women with polycystic ovary syndrome (PCOS) and controls at term.Design: Case-control study.Setting: University-affiliated hospital.Patient(s): A total of 74 pregnant women at term: 25 women with PCOS (aged 31.6 ± 3.9 years [mean ± standard deviation], body mass index 24.0 ± 3.9 kg/m2, mean gestational length 279 ± 9 days) and 49 controls (aged 31.7 ± 3.3 years, body mass index 24.0 ± 3.3 kg/m2, mean gestational length 281 ± 9 days).Intervention(s): None.Main Outcome Measure(s): Plasma AMH and steroid hormone levels.Result(s): Antimullerian hormone, T, and androstenedione levels were higher in women with PCOS at term compared with controls, whereas estrogen and P levels were similar. The differences were pronounced in women carrying a female fetus. Testosterone and AMH levels correlated positively in both groups, but E2 levels only in women with PCOS.Conclusion(s): Pregnant women with PCOS present with elevated AMH and androgen levels even at term, suggesting a hormonal imbalance during PCOS pregnancy. Differences were detected especially in pregnancies with a female fetus, raising the question of whether female pregnancies are more susceptible to AMH and steroid hormone actions.
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39. |
- Ridell, Karin, et al.
(författare)
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Oral health-related quality-of-life in Swedish children before and after dental treatment under general anesthesia
- 2015
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Ingår i: Acta Odontologica Scandinavica. - : Taylor & Francis. - 0001-6357 .- 1502-3850. ; 73:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective. This study evaluated oral health-related quality-of-life (OHRQoL) in children and families before and after dental treatment under general anesthesia because of severe caries or molar-incisor hypomineralization (MIH). Materials and methods. A consecutive sample of the parents/caregivers of children (3–14 years) in need of treatment under general anesthesia participated in the study. The children were divided into two groups: 3–6 years and 7–14 years. The 49-item questionnaire that was administered before and after general anesthesia comprised the Child Oral Health Quality of Life-components of the Parental-Caregivers Perception Questionnaire (P-CPQ), the Family Impact Scale (FIS) and two global questions concerning oral health and general well-being. The P-CPQ domains were Oral symptoms, Functional limitations, Emotional well-being and Social well-being. The FIS items assessed impact on family life. Results. In both age groups, a significant decrease (p < 0.001) occurred in overall P-CPQ and the Oral symptoms, Functional limitations and Emotional limitations domains of the P-CPQ. Mean values for the Social well-being domain decreased significantly in the older (p < 0.05) but not the younger age group. Mean values for FIS decreased significantly in the younger (p < 0.001) and the older (p < 0.05) age groups. Conclusions. Dental treatment of severe caries or MIH, performed under general anesthesia, had an immediate effect on the oral health-related quality-of-life in the children in this study and a positive impact on the family situation.
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40. |
- Seblova, Dominika, et al.
(författare)
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Thirty-year trends in dementia : a nationwide population study of Swedish inpatient records
- 2018
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Ingår i: Clinical Epidemiology. - 1179-1349. ; 10, s. 1679-1693
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Tidskriftsartikel (refereegranskat)abstract
- Background: The continuous growth of the current dementia epidemic is contingent on the stability of age- and sex-specific trends over time. However, recent evidence suggests declining or stable trends. The aim of this study was to evaluate the real-world changes in the burden of dementia in older adults in Sweden from 1987 to 2016 by estimating age- and sex-specific incidence of dementia diagnosis in hospital inpatient records (dementia incidence). Differences in trends by sex, age, and educational levels were also examined. Methods: The entire Swedish population aged 65 years and older was followed up from 1987 to 2016. Age-, sex-, and education-stratified dementia incidence rates for every follow-up year were estimated using the National Patient Register. Hazard ratio of receiving a dementia diagnosis in the inpatient records per 1 calendar year increase was estimated with discrete time logistic models with a complementary log-log link. Results: After increase, especially in those >85 years of age, dementia incidence started to decrease in the last 5 years of the study period. After 2011, 1 calendar year increase was associated with lower hazard ratio of receiving a hospital diagnosis of dementia. The decrease had the highest magnitude in 70-74-year-olds (5.5%), followed by 75-79-year-olds (-4.5%) and 80-84-year-olds (-4.0%). The decrease was present in both sexes and at all educational levels up to 90 years of age. Age was associated with the level of dementia incidence, and the trends differed by age group. Educational gradient was observed. University-educated older adults had the lowest rates of dementia. However, the trend over time did not substantially differ by sex or educational level. Conclusion: Our results provide more evidence that dementia incidence may be declining. They also suggest that at least in hospitals, the number of new patients with dementia may decrease in the future.
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41. |
- Shao, Linus Ruijin, 1964, et al.
(författare)
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Down-Regulation of Cilia-Localized IL-6R{alpha} by 17{beta}-Estradiol in Mouse and Human Fallopian Tubes.
- 2009
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Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 297:1
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Tidskriftsartikel (refereegranskat)abstract
- The action of Interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6Ralpha and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6Ralpha is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17beta-estradiol (E2), but not progesterone (P4), causes a time-dependent decrease in IL-6Ralpha expression which is blocked by the estrogen receptor (ER) antagonist ICI 182,780. Exposure of different ER-selective agonists, PTT or DPN, demonstrated an ER subtype-specific regulation of IL-6Ralphaalpha in mouse fallopian tubes. In contrast to IL-6Ralpha, gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6Ralpha and gp130 in IL-6 knockout mice was found to be normal; however, E2 treatment increased IL-6Ralpha, but not gp130, in IL-6 knockout mice compared to wild-type mice. Furthermore, expression levels of IL-6Ralpha, but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings unveil a potential role for cilia-specific IL-6Ralpha in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6Ralpha in the fallopian tube. Key words: estrogen, IL-6R, cilia, fallopian tube.
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42. |
- Sundström, Johan, Professor, 1971-, et al.
(författare)
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Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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43. |
- Tarvainen, Ilari, et al.
(författare)
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Identification of phthalate mixture exposure targets in the human and mouse ovary in vitro
- 2023
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Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 119
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Tidskriftsartikel (refereegranskat)abstract
- Chemical health risk assessment is based on single chemicals, but humans and wildlife are exposed to extensive mixtures of industrial substances and pharmaceuticals. Such exposures are life-long and correlate with multiple morbidities, including infertility. How combinatorial effects of chemicals should be handled in hazard charac-terization and risk assessment are open questions. Further, test systems are missing for several relevant health outcomes including reproductive health and fertility in women. Here, our aim was to screen multiple ovarian cell models for phthalate induced effects to identify biomarkers of exposure. We used an epidemiological cohort study to define different phthalate mixtures for in vitro testing. The mixtures were then tested in five cell models representing ovarian granulosa or stromal cells, namely COV434, KGN, primary human granulosa cells, primary mouse granulosa cells, and primary human ovarian stromal cells. Exposures at epidemiologically relevant levels did not markedly elicit cytotoxicity or affect steroidogenesis in short 24-hour exposure. However, significant effects on gene expression were identified by RNA-sequencing. Altogether, the exposures changed the expression of 124 genes on the average (9-479 genes per exposure) in human cell models, without obvious concentration or mixture-dependent effects on gene numbers. The mixtures stimulated distinct changes in different cell models. Despite differences, our analyses suggest commonalities in responses towards phthalates, which forms a starting point for follow-up studies on identification and validation of candidate biomarkers that could be developed to novel assays for regulatory testing or even into clinical tests.
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44. |
- Thorgeirsdottir, Lilja, et al.
(författare)
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Study protocol: establishment of a multicentre pre-eclampsia database and biobank in Sweden: GO PROVE and UP MOST, a prospective cohort study
- 2021
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 11:11
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction Pre-eclampsia, a multisystem disorder in pregnancy, is one of the most common causes of maternal morbidity and mortality worldwide. However, we lack methods for objective assessment of organ function in pre-eclampsia and predictors of organ impairment during and after pre-eclampsia. The women’s and their partners’ experiences of pre-eclampsia have not been studied in detail. To phenotype different subtypes of the disorder is of importance for prediction, prevention, surveillance, treatment and follow-up of pre-eclampsia.The aim of this study is to set up a multicentre database and biobank for pre-eclampsia in order to contribute to a safer and more individualised treatment and care.Methods and analysis This is a multicentre cohort study. Prospectively recruited pregnant women ≥18 years, diagnosed with pre-eclampsia presenting at Sahlgrenska University Hospital, Uppsala University Hospital and at Södra Älvsborgs Hospital, Sweden, as well as normotensive controls are eligible for participation. At inclusion and at 1-year follow-up, the participants donate biosamples that are stored in a biobank and they are also asked to participate in various organ-specific evaluations. In addition, questionnaires and interviews regarding the women’s and partner’s experiences are distributed at follow-up.Ethics and dissemination By creating a database and biobank, we will provide the means to explore the disorder in a broader sense and allow clinical and laboratory discoveries that can be translated to clinical trials aiming at improved care of women with pre-eclampsia. Further, to evaluate experiences and the psychological impact of being affected by pre-eclampsia can improve the care of pregnant women and their partners. In case of incidental pathological findings during examinations performed, they will be handled in accordance with clinical routine. Data are stored in a secure online database. Biobank samples are identified through the women’s personal identification number and pseudonymised after identification in the biobank before analysis.This study was approved by the regional ethical review board in Gothenburg on 28 December 2018 (approval number 955-18) and by the Swedish Ethical Review Authority on 27 February 2019 (approval number 2019-00309).
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45. |
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46. |
- Visser, Nadja, et al.
(författare)
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Epidemiologically relevant phthalates affect human endometrial cells in vitro through cell specific gene expression changes related to the cytoskeleton and mitochondria
- 2024
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Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 128
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Tidskriftsartikel (refereegranskat)abstract
- Phthalates are endocrine disrupting chemicals (EDCs) found in common consumer products such as soft plastics and cosmetics. Although the knowledge regarding the adverse effects of phthalates on female fertility are accumulating, information on the hormone sensitive endometrium is still scarce. Here, we studied the effects of phthalates on endometrial cell proliferation and gene expression. Human endometrial primary epithelial and stromal cells were isolated from healthy fertile-aged women (n=3), and were compared to endometrial cell lines T-HESC and Ishikawa. Three different epidemiologically relevant phthalate mixtures were used, defined by urine samples in the Midlife Women Health Study (MWHS) cohort. Mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was used as a single phthalate control. Cells were harvested for proliferation testing and transcriptomic analyses after 24 h exposure. Even though all cell models responded differently to the phthalate exposures, many overlapping differentially expressed genes (DEGs, FDR<0.1), related to cell adhesion, cytoskeleton and mitochondria were found in all cell types. The qPCR analysis confirmed that MEHHP significantly affected cell adhesion gene vinculin (VCL) and NADH:ubiquinone oxidoreductase subunit B7 (NDUFB7), important for oxidative phosphorylation. Benchmark dose modelling showed that MEHHP had significant concentrationdependent effects on cytoskeleton gene actin-beta (ACTB). In conclusion, short 24 h phthalate exposures significantly altered gene expression cell-specifically in human endometrial cells, with six shared DEGs. The mixture effects were similar to those of MEHHP, suggesting MEHHP could be the main driver in the mixture. Impact of phthalate exposures on endometrial functions including receptivity should be addressed.
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47. |
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48. |
- Zhang, Yuehui, et al.
(författare)
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Hyperandrogenism and insulin resistance-induced fetal loss : evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome
- 2019
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Ingår i: Journal of Physiology. - : WILEY. - 0022-3751 .- 1469-7793. ; 597:15, s. 3927-3950
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Tidskriftsartikel (refereegranskat)abstract
- Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown. Herein, pregnant rats chronically treated with 5 alpha-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients. Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta. Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin. Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats. Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy. Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5 alpha-dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin-treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute important contributors to fetal loss in DHT+insulin-treated pregnant rats. Many of the molecular pathways leading to placental abnormalities and fetal loss in DHT+insulin treatment were also seen in pregnant rats treated with DHT alone, whereas pregnant rats treated with insulin alone often exerted distinct effects on placental gene expression compared to insulin treatment in combination with DHT. We also found that treatment with the antioxidant N-acetylcysteine (NAC) improved fetal survival in DHT+insulin-treated pregnant rats, an effect related to changes in Keap1/Nrf2 and nuclear factor-kappa B signalling. However, NAC administration resulted in fetal loss in normal pregnant rats, most likely due to PCOS-like endocrine abnormality induced by the treatment. Our results suggest that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondria-ROS-SOD1/Nrf2 changes in the placenta. Our findings also suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.
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49. |
- Zhang, Yuehui, et al.
(författare)
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Hyperandrogenism and insulin resistance-induced fetal loss: evidence for placental mitochondrial abnormalities and elevated ROS production in pregnant rats that mimic the clinical features of PCOS. : PCOS-induced fetal loss is linked to placental defects
- 2019
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Ingår i: The Journal of physiology. - 1469-7793. ; 597:15, s. 3927-3950
-
Tidskriftsartikel (refereegranskat)abstract
- Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown. Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients. Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed SOD1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS), and impaired formation of the placenta. Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin. Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats. Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5α-dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin-treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed SOD1 and Keap1/Nrf2 antioxidant responses constitute important contributors to fetal loss in DHT+insulin-treated pregnant rats. Many of the molecular pathways leading to placental abnormalities and fetal loss in DHT+insulin treatment were also seen in pregnant rats treated with DHT alone, whereas pregnant rats treated with insulin alone often exerted distinct effects on placental gene expression compared to insulin treatment in combination with DHT. We also found that treatment with the antioxidant N-acetylcysteine (NAC) improved fetal survival in DHT+insulin-treated pregnant rats, an effect related to changes in Keap1/Nrf2 and NFκB signaling. However, NAC administration resulted in fetal loss in normal pregnant rats, most likely due to PCOS-like endocrine abnormality induced by the treatment. Our results suggest that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondrial-ROS-SOD1/Nrf2 changes in the placenta. Our findings also suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy. This article is protected by copyright. All rights reserved.
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50. |
- Zhang, Yuehui, et al.
(författare)
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Hyperandrogenism and insulin resistance modulate gravid uterine and placental ferroptosis in PCOS-like rats. : Uterine and placental ferroptosis in pregnant PCOS-like rats
- 2020
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Ingår i: The Journal of endocrinology. - 1479-6805. ; 246:3, s. 247-63
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces hyperandrogenism and insulin resistance (HAIR) and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, and increased Dpp4 mRNA expression. In contrast, in placentas co-exposed to DHT and INS we found decreased Dpp4 mRNA expression and increased Cisd1 mRNA expression. Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.
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