Dataset Information

Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes.

ABSTRACT: Inflammation is central to the mechanisms of parturition, but the lack of understanding of how it is controlled in normal parturition hampers our ability to understand how it may diverge resulting in preterm birth. Cell-free fetal DNA is found in the amniotic fluid, and it is thought to be able to activate inflammation as a danger-associated molecular pattern. Although its levels increases with gestational age, its effect has not been studied on the human fetal membranes. Thus, the aim of this study was to determine if the fetal DNA can trigger inflammation in the human fetal membranes and, thus, potentially contribute to the inflammatory load. Isolated human amniotic epithelial cells and fetal membrane explants were treated apically with fetal DNA causing the translocation of NF-KB into the nucleus of cells and throughout the cells of the explant layers with time. Fetal membrane explants were treated apically with either small or larger fragments of fetal DNA. IL-6, TNFα, and GM-CSF secretion was measured by ELISA, and pro-MMP2 and pro-MMP9 activity was measured by zymography from apical and basal media. Increased apical IL-6 secretion and basal pro-MMP2 activity was seen with small fragments of fetal DNA. When the data were disaggregated based on fetal sex, males had significant increases in IL-6 secretion and basal increased activity in pro-MMP2 and 9, whereas females had significantly increased basal secretion of TNFα. This was caused by the smaller fragments of fetal DNA, whereas the larger fragments did not cause any significant increases. Male fetal DNA had significantly lower percentages of methylation than females. Thus, when the cytokine and pro-MMP activity data were correlated with methylation percentage, IL-6 secretion significantly correlated negatively, whereas GM-CSF secretion positively correlated. These data support the role of fetal DNA as an inflammatory stimulus in the FM, as measured by increased NF-κB translocation, cytokine secretion, and increased pro-MMP activity. However, the data also suggested that the responses are different from FM tissues of male and female fetuses, and both the fragment size and methylation status of the fetal DNA can influence the magnitude and type of molecule secreted.

SUBMITTER: Saito Reis CA

PROVIDER: S-EPMC9257279 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:PurposeTo derive a prescriptive sex-specific fetal growth standard and assess clinical management and outcomes according to sex-specific growth status.Materials and methodsThis was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b), a prospective observational study of 10,038 nulliparas from eight U.S. centers who underwent ultrasounds at 14-20 and 22-29 weeks with outcomes ascertained after delivery. From these, we selected a nested cohort of lower risk participants (excluded those with chronic hypertension, pre-gestational diabetes, suspected aneuploidy, and preterm delivery) to derive a sex-specific equation for expected fetal growth using fetal weights by ultrasound and at birth. We compared the male-female discrepancy in the rate of weight <10th (small for gestational age [SGA]) and >90th (large for gestational age [LGA]) percentiles between the sex-specific and sex-neutral (Hadlock) standards. Using the full unselected cohort, we then assessed outcomes and clinical management according to sex-specific SGA and LGA status.ResultsOverall, 7280 infants in the lower risk nested cohort were used to derive a sex-specific equation with fetal sex included as an equation intercept. The sex-neutral standard diagnosed SGA more often in female newborns (21% vs. 13%, p < .001) and LGA more often in male newborns (5% vs. 3%, p < .001). The sex-specific standard resolved these disparities (SGA: 9% vs. 10%, p = .23; LGA: 13% vs. 13%, p = .58). To approximate an unselected population, 1059 participants initially excluded for risk factors for abnormal growth were then included for our secondary objective (N = 8339). In this unselected cohort, 39% (95% CI 37.0-42.0%) of the 1498 newborns classified as SGA by the sex-neutral standard were reclassified as appropriate for gestational age (AGA) by the sex-specific standard. These reclassified newborns were more likely to be delivered for growth restriction despite having lower risk of morbidity (females) or comparable risk of morbidity (males) compared to newborns considered AGA by both methods. Of the 6485 newborns considered AGA by the sex-neutral standard, 737 (11.4%, 95% CI 10.6-12.2%) were reclassified as LGA by the sex-specific standard. These reclassified newborns had higher rates of cesarean for arrest of descent, cesarean for arrest of dilation, and shoulder dystocia than newborns considered AGA by both methods. None were reclassified from LGA to AGA by the sex-specific standard.ConclusionThe Hadlock sex-neutral standard generates sex disparities in SGA and LGA at birth. Our sex-specific standard resolves these disparities and has the potential to improve accuracy of growth pathology risk stratification.

Project description:ContextNoninvasive prenatal determination of fetal sex using cell-free fetal DNA provides an alternative to invasive techniques for some heritable disorders. In some countries this testing has transitioned to clinical care, despite the absence of a formal assessment of performance.ObjectiveTo document overall test performance of noninvasive fetal sex determination using cell-free fetal DNA and to identify variables that affect performance.Data sourcesSystematic review and meta-analysis with search of PubMed (January 1, 1997-April 17, 2011) to identify English-language human studies reporting primary data. References from review articles were also searched.Study selection and data extractionAbstracts were read independently to identify studies reporting primary data suitable for analysis. Covariates included publication year, sample type, DNA amplification methodology, Y chromosome sequence, and gestational age. Data were independently extracted by 2 reviewers.ResultsFrom 57 selected studies, 80 data sets (representing 3524 male-bearing pregnancies and 3017 female-bearing pregnancies) were analyzed. Overall performance of the test to detect Y chromosome sequences had the following characteristics: sensitivity, 95.4% (95% confidence interval [CI], 94.7%-96.1%) and specificity, 98.6% (95% CI, 98.1%-99.0%); diagnostic odds ratio (OR), 885; positive predictive value, 98.8%; negative predictive value, 94.8%; area under curve (AUC), 0.993 (95% CI, 0.989-0.995), with significant interstudy heterogeneity. DNA methodology and gestational age had the largest effects on test performance. Methodology test characteristics were AUC, 0.988 (95% CI, 0.979-0.993) for polymerase chain reaction (PCR) and AUC, 0.996 (95% CI, 0.993-0.998) for real-time quantitative PCR (RTQ-PCR) (P = .02). Gestational age test characteristics were AUC, 0.989 (95% CI, 0.965-0.998) (<7 weeks); AUC, 0.994 (95% CI, 0.987-0.997) (7-12 weeks); AUC, 0.992 (95% CI, 0.983-0.996) (13-20 weeks); and AUC, 0.998 (95% CI, 0.990-0.999) (>20 weeks) (P = .02 for comparison of diagnostic ORs across age ranges). RTQ-PCR (sensitivity, 96.0%; specificity, 99.0%) outperformed conventional PCR (sensitivity, 94.0%; specificity, 97.3%). Testing after 20 weeks (sensitivity, 99.0%; specificity, 99.6%) outperformed testing prior to 7 weeks (sensitivity, 74.5%; specificity, 99.1%), testing at 7 through 12 weeks (sensitivity, 94.8%; specificity, 98.9%), and 13 through 20 weeks (sensitivity, 95.5%; specificity, 99.1%).ConclusionsDespite interstudy variability, performance was high using maternal blood. Sensitivity and specificity for detection of Y chromosome sequences was greatest using RTQ-PCR after 20 weeks' gestation. Tests using urine and tests performed before 7 weeks' gestation were unreliable.

Dataset Information

Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets