Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that are widely involved in various physiological functions. They are widely expressed through the ...reproductive system. Their roles in the metabolism and function of sex steroids and thus the etiology of reproductive disorders receive great concern. Various kinds of exogenous chemicals, especially environmental pollutants, exert their adverse impact on the reproductive system through disturbing the PPAR signaling pathway. Chemicals could bind to PPARs and modulate the transcription of downstream genes containing PPRE (peroxisome proliferator response element). This will lead to altered expression of genes related to metabolism of sex steroids and thus the abnormal physiological function of sex steroids. In this review, various kinds of environmental ligands are summarized and discussed. Their interactions with three types of PPARs are classified by various data from transcript profiles, PPRE reporter in cell line, in silico docking, and gene silencing. The review will contribute to the understanding of the roles of PPARs in the reproductive toxicology of environmental chemicals.
Abstract
Objective
To investigate the predictive value of pre-induction digital examination, sonographic measurements and parity for the prediction of non-reassuring fetal status and cord arterial pH ...< 7.2 prior to the induction of labor (IOL).
Method
This was a prospective observational study, including 384 term pregnancies undergoing IOL. Before the IOL, the Bishop score (BS) by digital examination, sonographic Doppler parameters and the estimated fetal weight (EFW) was assessed. The fetal cord arterial was sampled to measure the pH at delivery. Multivariate logistic regression analysis was performed to identify independent predictors of non-reassuring fetal status and low cord arterial pH.
Results
Forty four cases (11.5%) had non-reassuring fetal status, and 76 cases (19.8%) had fetal cord arterial pH < 7.2. In the non-reassuring fetal status group, the incidence of cord arterial pH < 7.2 was significantly higher than that in the normal fetal heart rate group (χ
2
= 6.401,
p
= 0.011). Multivariate analysis indicated that significant independent predictors of non-reassuring fetal status were nulliparity (adjusted odds ratio AOR: 3.746,
p
= 0.003), EFW < 10
th
percentile (AOR: 3.764,
p
= 0.003) and cerebroplacental ratio (CPR) < 10
th
centile (AOR:4.755,
p
< 0.001). In the prediction of non-reassuring fetal status, the performance of the combination of nulliparity and EFW < 10th percentile was improved by the addition of CPR < 10th percentile (AUC: 0.681, (95%CI: 0.636 to 0.742) vs 0.756, (95%CI:0.713 to 0.795)), but the difference was not significant (DeLong test: z = 1.039,
p
= 0.053).. None of the above variables were predictors of cord arterial pH < 7.2.
Conclusion
The risk of fetal acidosis has increased in cases of non-reassuring fetal status. Nulliparity, small for gestational age and CPR < 10th centile are independent predictors for non-reassuring fetal status in term fetuses, though the addition of CPR < 10th centile could not significantly improve the screening accuracy.
Endometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which ...involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear.
We employed multi-omics approaches on two cohorts of endometriosis patients with 39 samples. GO terms and KEGG pathways enrichment analyses were used to investigate the functional changes involved in endometriosis. Pearson's correlation coefficient analysis was conducted to explore the relationship between global proteome and ubiquitylome in endometriosis. The protein expression levels of ubiquitin-, fibrosis-related proteins, and E3 ubiquitin-protein ligase TRIM33 were validated via Western blot. Transfecting human endometrial stroma cells (hESCs) with TRIM33 small interfering RNA (siRNA) in vitro to explore how TRIM33 affects fibrosis-related proteins.
Integration of proteomics and transcriptomics showed genes with concurrent change of both mRNA and protein level which involved in ECM production in ectopic endometria. Ubiquitylomics distinguished 1647 and 1698 ubiquitinated lysine sites in the ectopic (EC) group compared to the normal (NC) and eutopic (EU) groups, respectively. Further multi-omics integration highlighted the essential role of ubiquitination in key fibrosis regulators in endometriosis. Correlation analysis between proteome and ubiquitylome showed correlation coefficients of 0.32 and 0.36 for ubiquitinated fibrosis proteins in EC/NC and EC/EU groups, respectively, indicating positive regulation of fibrosis-related protein expression by ubiquitination in ectopic lesions. We identified ubiquitination in 41 pivotal proteins within the fibrosis-related pathway of endometriosis. Finally, the elevated expression of TGFBR1/α-SMA/FAP/FN1/Collagen1 proteins in EC tissues were validated across independent samples. More importantly, we demonstrated that both the mRNA and protein levels of TRIM33 were reduced in endometriotic tissues. Knockdown of TRIM33 promoted TGFBR1/p-SMAD2/α-SMA/FN1 protein expressions in hESCs but did not significantly affect Collagen1/FAP levels, suggesting its inhibitory effect on fibrosis in vitro.
This study, employing multi-omics approaches, provides novel insights into endometriosis ubiquitination profiles and reveals aberrant expression of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, emphasizing their critical involvement in fibrosis pathogenesis and potential therapeutic targets.
Change in the composition of intestinal microbiota is associated with metabolic disorders such as gestational diabetes mellitus (GDM).
To understand how the microbiota impacts the development of ...gestational diabetes mellitus, we profiled the intestinal microbiome of 54 pregnant women, including 27 GDM subjects, by employing 16S rRNA gene sequencing. Additionally, we conducted targeted metabolomics assays to validate the identified pathways with overrepresented metabolites.
We evaluated the patterns of changing abundances of operational taxonomic units (OTU) between GDM and the healthy counterparts over three timepoints. Based on the significant OTUs, we inferred 132 significantly altered metabolic pathways in GDM. And identified two overrepresented metabolites of pregnancy hormone, butyrate and mevalonate, as potential intermediary metabolites of intestinal microbiota in GDM. Finally, we validated the impacts of the intestinal microbiota on GDM by demonstrating consistent changes of the serum levels of progesterone, estradiol, butyrate, and mevalonate in an independent cohort.
Our findings confirm that alterations in the microbiota play a role in the development of GDM by impacting the metabolism of pregnancy hormones. This provides a novel perspective on the pathogenesis of GDM and introduces potential biomarkers that can be used for early diagnosis and prevention of the disease.
Progesterone (P
) is required for the preparation of the endometrium for a successful pregnancy. P
resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often ...leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P
-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1
;Pgr-Cre (Cfp1
) mice showed impaired P
responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P
response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1
ectopic lesions showed P
resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P
targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P
-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.
Background Since public awareness of cystic fibrosis (CF) has increased, more children have been diagnosed with CF in China. This study aimed to investigate medical and other challenges faced by ...pediatric CF patients in China. Method Treatments and treatment outcomes were retrospectively analyzed for 46 pediatric CF patients diagnosed from August 2009 to June 2019. Pre- and post-treatment results were compared using independent samples t-test. Results Of 46 pediatric CF study patients, four died and five were lost to follow-up. Thirty-seven patients were monitored for 0.03 to 9.21 years; patients exhibited fewer attacks of respiratory tract infections after diagnosis (4.49 + or - 2.13 episodes/year before diagnosis vs 1.97 + or - 1.87 times/year after 1-year treatment, p < 0.05), significantly reduced sputum production and experienced 1.62 + or - 1.71 exacerbations/year. Patient mean body mass index was 16.87 + or - 3.53 and pancreatic malfunction persisted in 15 patients. For 17 children, no significant differences in lung function were found at follow-up as compared to lung function at diagnosis (FEV.sub.1: 82.45% + or - 16.56% vs 75.26% + or - 22.34%, FVC: 87.18% + or - 13.64% vs 86.99% + or - 19.95%, FEF.sub.75%: 46.51% + or - 28.78% vs 36.63% + or - 24.30%, P = 0.27, 0.97, 0.20, respectively). Pseudomonas aeruginosa (17/27) and bronchiectasis (22/22) were found during follow-up evaluation. Twenty-four patients (64.8%) maintained good adherence to therapies. Overall, azithromycin and tobramycin treatments were administered for 0.5-62 months and 0.5-48 months, respectively, and triggered no obvious adverse reactions. Conclusion No obvious declines in clinical presentation or lung function were found in Chinese pediatric CF patients after receiving standard therapeutic and active treatments, although malnutrition and low compliance were persistent challenges. Keywords: Cystic fibrosis, Follow-up, Chinese children
Ciliated and secretory cells are two major cell types that comprise the oviduct epithelia. Accumulating evidences support a role of oviductal multiciliated epithelia for embryo transport, however the ...mechanisms underlying this specialized cell type differentiation remain elusive. Here, we report that CDC42 depletion in oviduct epithelia hampers the morphogenesis of multiciliated cell, and results in embryo retention, leading to early pregnancy failure. Utilizing the oviduct organoid model, we further observed that CDC42 guides secretory cells transition into multiciliated cells independent of its GTPase activity and the well-known Notch pathway. Further exploration uncovered the AKT as a novel indispensable regulator for multiciliated cells differentiation, whose activity was maintained by CDC42 through interacting with the p110β. Consistently, re-activating AKT partially incites multiciliated cells differentiation in Cdc42 knockout oviductal organoids. Finally, low levels of CDC42 and phospho-AKT with reduced multiciliated cells in the oviduct are observed in women with ectopic pregnancy. Collectively, we provide previously unappreciated evidence that CDC42-AKT signaling is a critical determinant for morphogenesis of oviduct multiciliated cell, which possesses the clinical application in understanding the pathology of ectopic pregnancy and facilitating the development of prevention strategies.
To explore the circular RNA (circRNA) profile in cumulus cells from endometriosis-associated infertility patients.
The expression of circRNAs was profiled by high-throughput sequencing. Sanger ...sequencing was performed to identify the backsplicing site. Six candidate circRNAs and their parental genes were measured in 30 samples by quantitative reverse transcription-polymerase chainreaction (qRT-PCR). Bioinformatics analysis was performed to predict the functions.
A total of 55 upregulated and 41 downregulated differentially expressed circRNAs were detected. Kyoto Encyclopedia of Genes and Genomes data indicated that these target genes were mainly involved in cumulus cell growth- and differentiation-related pathways. Hsa_circ_0072391, hsa_circ_0007299 and hsa_circ_0057799 were significantly increased, and hsa_circ_001533 was significantly decreased in endometriosis-associated infertility patients.
The differentially expressed circRNAs might be potentially involved in pathophysiology of endometriosis-associated infertility.
In recent decades, there has been increasing attention toward the quality of life of breast cancer (BC) survivors. Meeting the growing expectations of fertility preservation and the generation of ...biological offspring remains a great challenge for these patients. Conventional strategies for fertility preservation such as oocyte and embryo cryopreservation are not suitable for prepubertal cancer patients or in patients who need immediate cancer therapy. Ovarian tissue cryopreservation (OTC) before anticancer therapy and autotransplantation is an alternative option for these specific indications but has a risk of retransplantation malignant cells. An emerging strategy to resolve these issues is by constructing an artificial ovary combined with stem cells, which can support follicle proliferation and ensure sex hormone secretion. This promising technique can meet both demands of improving the quality of life and meanwhile fulfilling their expectation of biological offspring without the risk of cancer recurrence.
Backgrounds: Urban energy consumption is one of the important causes of air pollution. The epidemiological risk assessment guided by air pollution is of great significance to the promotion of urban ...environmental protection. Objectives: The work researched the acute impact of exposure to air pollution on preterm birth (PTB) in Xiamen city from 2015 to 2018. Furthermore, the economic losses were assessed as well. Methods: Association of air pollution and PTB with economic losses were assessed using the generalized additive model. Results: A total of 1991 PTB visits, who are inhabitant in Xiamen, have been investigated. An interquartile range (IQR) (10 μg/m3) increase of PM10, NO2, and SO2 in the current day corresponded to the increase of 0.64% 95% CI: −1.22, 2.54%, 0.52% 95% CI: −5.21, 6.61%, and 2.33% 95% CI: −6.41, 11.58% in daily PTB visits. Especially, PTB visits were significantly related with PM10 and NO2 in Lag 1 and NO2 and SO2 in Lag 2. Furthermore, for multipollutants, an IQR increase in PM2.5, O3, and CO, after adjustment with SO2, was related with 5.04% 95% CI: −5.90, 17.24, 2.49% 95% CI: −6.07, 11.81, and 7.10% 95% CI: −2.79, 18.00 increase of PTB morbidity, respectively. The estimates of the number of excess PTBs attributed to typical pollutants PM10 and SO2 were ∼2400 and 1200 people, respectively, every year. The highest excess PTBs was estimated to occur as a result of PM10 and SO2 effects. Conclusions: Although Xiamen has a relatively low level of air pollution, short-term exposure to NO2, SO2, and PM10 was linked to the increase of PTB visits.
PDF
