| 1. |
- Björvang, Richelle D., et al.
(författare)
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Mixtures of persistent organic pollutants are found in vital organs of late gestation human fetuses
- 2021
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 283
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Tidskriftsartikel (refereegranskat)abstract
- Persistent organic pollutants (POPs) are industrial chemicals with long half-lives. Early life exposure to POPs has been associated with adverse effects. Fetal exposure is typically estimated based on concentrations in maternal serum or placenta and little is known on the actual fetal exposure. We measured the concentrations of nine organochlorine pesticides (OCPs), ten polychlorinated biphenyl (PCB) congeners, and polybrominated diphenyl ether (PBDE) congeners by gas chromatography – tandem mass spectrometry in maternal serum, placenta, and fetal tissues (adipose tissue, liver, heart, lung and brain) in 20 pregnancies that ended in stillbirth (gestational weeks 36–41). The data were combined with our earlier data on perfluoroalkyl substances (PFASs) in the same cohort (Mamsen et al. 2019). HCB, p,p’-DDE, PCB 138 and PCB 153 were quantified in all samples of maternal serum, placenta and fetal tissues. All 22 POPs were detected in all fetal adipose tissue samples, even in cases where they could not be detected in maternal serum or placenta. Tissue:serum ratios were significantly higher in later gestations, male fetuses, and pregnancies with normal placental function. OCPs showed the highest tissue:serum ratios and PFAS the lowest. The highest chemical burden was found in adipose tissue and lowest in the brain. Overall, all studied human fetuses were intrinsically exposed to mixtures of POPs. Tissue:serum ratios were significantly modified by gestational age, fetal sex and placental function. Importantly, more chemicals were detected in fetal tissues compared to maternal serum and placenta, implying that these proxy samples may provide a misleading picture of actual fetal exposures.
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| 2. |
- Bongaerts, Eva, et al.
(författare)
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Ambient black carbon particles in human ovarian tissue and follicular fluid
- 2023
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 179
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Tidskriftsartikel (refereegranskat)abstract
- Evidence indicates a link between exposure to ambient air pollution and decreased female fertility. The ability of air pollution particles to reach human ovarian tissue and follicles containing the oocytes in various maturation stages has not been studied before. Particulate translocation might be an essential step in explaining reproductive toxicity and assessing associated risks. Here, we analysed the presence of ambient black carbon particles in (i) follicular fluid samples collected during ovum pick-up from 20 women who underwent assisted reproductive technology treatment and (ii) adult human ovarian tissue from 5 individuals. Follicular fluid and ovarian tissue samples were screened for the presence of black carbon particles from ambient air pollution using white light generation by carbonaceous particles under femtosecond pulsed laser illumination. We detected black carbon particles in all follicular fluid (n = 20) and ovarian tissue (n = 5) samples. Black carbon particles from ambient air pollution can reach the ovaries and follicular fluid, directly exposing the ovarian reserve and maturing oocytes. Considering the known link between air pollution and decreased fertility, the impact of such exposure on oocyte quality, ovarian ageing and fertility needs to be clarified urgently.
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| 3. |
- Gidlöf, Sebastian
(författare)
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Congenital adrenal hyperplasia, cyp21a2 deficiency : clinical and physiological aspects of pregnancy, screening and growth
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The subjects dealt with in this thesis are clinical aspects of congenital adrenal hyperplasia (CAH), such as neonatal screening, growth and the incidence of CAH during the last century in Sweden. In addition, we have used CAH as a model system to study possible prenatal effects of androgen exposure on growth and gestational length. Gestational age at birth correlated with CYP21A2 genotype in girls (P < 0.01), but not in boys with CAH (n = 109; 62 females, 47 males) (Paper I). The exact number of gestational days was known in 66 patients (37 females, 29 males). The pregnancy was longer for females with the most severe form, null genotype, 285.7 days, than for I172N, 273.9 days (P < 0.01) or V281L, 274.7 days (P < 0.05), indicating that higher androgen levels in severe forms could explain this effect. No differences between genotypes were seen in CAH males, possibly because testicular androgen production is high in normal male foetuses and adrenal androgens therefore may not have an additional effect. The cortisol deficiency is equal in CAH girls and boys, making this deficiency a less likely explanation. Birth weight standard deviation score (SDS) corrected for gestational age in children with CAH (n = 73; 43 females, 30 males) did not differ from that of the reference population (mean, CI 95%: 0.0, -0.3 to 0.3, and 0.2, −0.2 to 0.6, for boys and girls, respectively) (Paper II). Nor did the birth weight differ between CYP21A2 genotype groups (P > 0.05). In 29 46,XY females with complete androgen insensitivity syndrome (CAIS), the mean birth weight SDS was similar to that of reference boys (mean, CI 95%: 0.1, -0.2 to 0.4) and higher than the reference of females (mean, CI 95%: 0.4, 0.1 to 0.7, P = 0.02). Hence, these results indicate that gestational age at birth, but not prenatal growth, is affected by androgen exposure. In a retrospective, population-based cohort study we investigated the apparent incidence of CAH in Sweden between 1910 and 2011 (Paper III). We identified 606 patients with known CYP21A2 genotype in 490 cases (81%). The female:male ratio was 1.25:1 for the whole cohort, but close to 1 in patients detected in the screening. The number of diagnosed patients increased dramatically in the 1960s and 1970s. The proportion of salt-wasting (SW) CAH compared to milder forms increased in both sexes after the introduction of neonatal screening from 114/242 to 165/292 (P < 0.05). The milder forms were diagnosed more often in females. This means that both boys and girls with SW CAH were missed before screening and that screening for CAH does not only increase the number of detected boys with SW CAH as previously thought, but also of girls. The neonatal screening for CAH in Sweden was studied from the start in 1986 to 2011 (Paper IV). A total of 2 737 932 neonates (99.8% of all live births) had been screened. No cases with evident SW CAH had been missed, sensitivity 100%. The sensitivity was lower in the simple virilising form, 79%, and non-classical CAH, 32%. The positive predictive value was higher in full-term infants, 25.1%, than in pre-terms, 1.4% (P < 0.001). The recall rate was lower in full-terms, 0.03%, than in pre-term infants, 0.57% (P < 0.001). An analysis of all publications describing neonatal screening programmes since 1996 revealed that the screening sensitivity correlated negatively with the duration of follow-up (P = 0.034). In contrast to current reports, our study shows that neonatal screening is effective in identifying SW CAH. Growth in CAH was studied in a prospective, observational cohort study including all children born or diagnosed with CAH between 1989 and 1994, 80 patients (46 females, 34 males). Most children were treated with a glucocorticoid dose within the recommended 10–15 mg/m2 body surface area. Corrected final height correlated with CYP21A2 genotype (P = 0.012). An important finding was that the corrected final height SDS was lower in patients who had been treated with the addition of prednisolone, -1.1 ± 1.0, than in those who had been treated with cortisone acetate and/or hydrocortisone alone, -0.60 ± 1.0 (P < 0.05). Furthermore, body mass index at 18 years of age was higher in patients treated with prednisolone, 25.3 ± 4.7 kg/m2, compared to 23.4 ± 4.5 kg/m2 (P < 0.05). Hence, the results suggest that treatment with prednisolone should be avoided in growing subjects with CAH.
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| 4. |
- Hassan, Jasmin, et al.
(författare)
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Reference standards for follicular density in ovarian cortex from birth to sexual maturity
- 2023
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Ingår i: Reproductive BioMedicine Online. - : Elsevier. - 1472-6483 .- 1472-6491. ; 47:4
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Tidskriftsartikel (refereegranskat)abstract
- Research question: Are age-normalized reference values for human ovarian cortical follicular density adequate for tissue quality control in fertility preservation?Design: Published quantitative data on the number of follicles in samples without known ovarian pathology were converted into cortical densities to create reference values. Next, a sample cohort of 126 girls (age 1-24 years, mean +/- SD 11 +/- 6) with cancer, severe haematological disease or Turner syndrome were used to calculate Z-scores for cortical follicular density based on the reference values.Results: No difference was observed between Z-scores in samples from untreated patients (0.3 +/- 3.5, n = 30) and patients treated with (0.5 +/- 2.9, n = 48) and without (0.1 +/- 1.3, n = 6) alkylating chemotherapy. Z-scores were not correlated with increasing cumulative exposure to cytostatics. Nevertheless, Z-scores in young treated patients (0-2 years -2.1 +/- 3.1, n = 10, P = 0.04) were significantly lower than Z-scores in older treated patients (11-19 years, 2 +/- 1.9, n = 15). Samples from patients with Turner syndrome differed significantly from samples from untreated patients (-5.2 +/- 5.1, n = 24, P = 0.003), and a Z-score of -1.7 was identified as a cut-off showing good diagnostic value for identification of patients with Turner syndrome with reduced ovarian reserve. When this cut-off was applied to other patients, analysis showed that those with indications for reduced ovarian reserve (n = 15) were significantly younger (5.9 +/- 4.2 versus 10.7 +/- 5.9 years, P = 0.004) and, when untreated, more often had non-malignant haematologic diseases compared with those with normal ovarian reserve (n = 24, 100% versus 19%, P = 0.009).Conclusion: Z-scores allow the estimation of genetic- and treatment-related effects on follicular density in cortical tissue from young patients stored for fertility preservation. Understanding the quality of cryopreserved tissue facilitates its use during patient counselling. More research is needed regarding the cytostatic effects found in this study.
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| 5. |
- Schimpf, Ulrike, 1977-, et al.
(författare)
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Topical reinforcement of the cervical mucus barrier to sperm
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 14:673
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Tidskriftsartikel (refereegranskat)abstract
- Close to half of the world’s pregnancies are still unplanned, reflecting a clear unmet need in contraception. Ideally, a contraceptive would provide the high efficacy of hormonal treatments, without systemic side effects. Here, we studied topical reinforcement of the cervical mucus by chitosan mucoadhesive polymers as a form of female contraceptive. Chitosans larger than 7 kDa effectively cross-linked human ovulatory cervical mucus to prevent sperm penetration in vitro. We then demonstrated in vivo using the ewe as a model that vaginal gels containing chitosan could stop ram sperm at the entrance of the cervical canal and prevent them from reaching the uterus, whereas the same gels without chitosan did not substantially limit sperm migration. Chitosan did not affect sperm motility in vitro or in vivo, suggesting reinforcement of the mucus physical barrier as the primary mechanism of action. The chitosan formulations did not damage or irritate the ewe vaginal epithelium, in contrast to nonoxynol-9 spermicide. The demonstration that cervical mucus can be reinforced topically to create an effective barrier to sperm may therefore form the technological basis for muco-cervical barrier contraceptives with the potential to become an alternative to hormonal contraceptives.
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| 6. |
- Sigurgeirsson, Benjamín, et al.
(författare)
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Comprehensive RNA sequencing of healthy human endometrium at two time points of the menstrual cycle
- 2016
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Endometrial receptivity is crucial for implantation and establishment of a normal pregnancy. The shift from proliferative to receptive endometrium is still far from understood. In this paper we comprehensively present the transcriptome of the human endometrium by comparing endometrial biopsies from proliferative phase with consecutive biopsies 7-9 days after ovulation. The results show a clear difference in expression between the two time points using both total and small RNA sequencing. 3297 mRNAs, 516 long non-coding RNAs and 102 small non-coding RNAs were identified as statistically differentially expressed between the two time points. We show a thorough description of the change in mRNA between the two time points and display lncRNAs, snoRNAs and snRNAs not previously reported in the healthy human endometrium. In conclusion this paper reports in detail the shift in RNA expression from the proliferative to receptive endometrium.
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| 7. |
- Sigurgeirsson, Benjamin, et al.
(författare)
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Comprehensive RNA sequencing of healthy human endometrium at two time points of the menstrual cycle
- 2017
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Ingår i: Biology of Reproduction. - : SOC STUDY REPRODUCTION. - 0006-3363 .- 1529-7268. ; 96:1, s. 24-33
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial receptivity is crucial for implantation and establishment of a normal pregnancy. The shift from proliferative to receptive endometrium is still far from being understood. In this paper, we comprehensively present the transcriptome of the human endometrium by comparing endometrial biopsies from proliferative phase with consecutive biopsies 7-9 days after ovulation. The results show a clear difference in expression between the two time points using both total and small RNA sequencing. A total of 3,297 messenger RNAs (mRNAs), 516 long noncoding RNAs (lncRNAs), and 102 small noncoding RNAs were identified as statistically differentially expressed between the two time points. We show a thorough description of the change in mRNA between the two time points and display lncRNAs, small nucleolar RNAs, and small nuclear RNAs not previously reported in the healthy human endometrium. In conclusion, this paper reports in detail the shift in RNA expression from the proliferative to receptive endometrium. Summary Sentence Messenger RNA, sncRNA, and lncRNA show a clear difference in expression between proliferative phase and 7-9 days after ovulation, thoroughly described together with lncRNA, snoRNA, and snRNA not previously reported in healthy human endometrium.
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| 8. |
- Solders, Martin, et al.
(författare)
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Maternal Adaptive Immune Cells in Decidua Parietalis Display a More Activated and Coinhibitory Phenotype Compared to Decidua Basalis
- 2017
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-9678 .- 1687-966X. ; 2017
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Martin Solders et al. The maternal part of the placenta, the decidua, consists of maternal immune cells, decidual stromal cells, and extravillous fetal trophoblasts. In a successful pregnancy, these cell compartments interact to provide an intricate balance between fetal tolerance and antimicrobial defense. These processes are still poorly characterized in the two anatomically different decidual tissues, basalis and parietalis. We examined immune cells from decidua basalis and parietalis from term placentas (n=15) with flow cytometry. By using multivariate discriminant analysis, we found a clear separation between the two decidual compartments based on the 81 investigated parameters. Decidua parietalis lymphocytes displayed a more activated phenotype with a higher expression of coinhibitory markers than those isolated from basalis and contained higher frequencies of T regulatory cells. Decidua basalis contained higher proportions of monocytes, B cells, and mucosal-associated invariant T (MAIT) cells. The basalis B cells were more immature, and parietalis MAIT cells showed a more activated phenotype. Conventional T cells, NK cells, and MAIT cells from both compartments potently responded with the production of interferon-γ and/or cytotoxic molecules in response to stimulation. To conclude, leukocytes in decidua basalis and parietalis displayed remarkable phenotypic disparities, indicating that the corresponding stromal microenvironments provide different immunoregulatory signals.
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| 9. |
- Svensson, Daniel, et al.
(författare)
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Inhibition of MicroRNA-125a Promotes Human Endothelial Cell Proliferation and Viability through an Antiapoptotic Mechanism.
- 2014
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Ingår i: Journal of Vascular Research. - : S. Karger AG. - 1423-0135 .- 1018-1172. ; 51:3, s. 239-245
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Tidskriftsartikel (refereegranskat)abstract
- The microRNA-125a (miR-125a) is highly expressed in endothelial cells, but its role in vascular biology is not known. Endothelial cell proliferation and viability play an important role in endothelial healing, and we hypothesize that miR-125a regulates this process. The aim of the present study was to investigate if miR-125a controls human endothelial cell proliferation, viability and endothelial healing, and to assess the mechanisms involved. We showed that overexpression of miR-125a by transfection with miR-125a mimic reduced human umbilical vein endothelial cell (HUVEC) proliferation and viability, and stimulated apoptosis as demonstrated by a miR-125a-induced increase of the proportion of annexin V-positive cells monitored by flow cytometry. Moreover, we showed that the miR-125a mimic downregulated the antiapoptotic Bcl2 protein and upregulated caspase 3, suggesting that these two proteins represent molecular targets for miR-125a. Accordingly, transfection with miR-125a inhibitor, downregulating miR-125a expression, promoted HUVEC proliferation and viability, and reduced apoptosis. Importantly, transfection with miR-125a inhibitor promoted HUVEC tube formation in Matrigel, suggesting that reduction of miR-125a has a proangiogenic effect. In conclusion, downregulation of miR-125a through local transfection with miR-125a inhibitor might be a new way to enhance endothelial cell proliferation and viability, thereby promoting the reendothelialization observed in response to intimal injury. © 2014 S. Karger AG, Basel.
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| 10. |
- 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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