Biology subjects

De Witte, L. D.

Publications and source records attributed to De Witte, L. D..

3 recordsLinked to original sources

bioRxiv2024

High-dimensional mediation analysis to elucidate the role of metabolites in the association between PFAS exposure and reduced SARS-CoV-2 IgG in pregnancy

We previously found that per- and polyfluoroalkyl substances (PFAS) mixture exposure is inversely associated with SARS-CoV-2 IgG (IgG) antibody levels in pregnant individuals. Here, we aim to identify metabolites mediating this relationship to elucidate the underlying biological pathways. This cross-sectional study included 59 pregnant participants from a US-based pregnancy cohort. Untargeted metabolomic profiling was performed using Liquid Chromatography-High Resolution Sass spectrometry (LC-HRMS), and weighted Quantile Sum (WQS) regression was applied to assess the PFAS and metabolites mixture effects on IgG. Metabolite indices positively or negatively associated with IgG levels were constructed separately and their mediation effects were examined independently and jointly. The PFAS- index was negatively associated with IgG levels (beta=-0.315, p<0.001), with PFHpS and PFHxS as major contributors. Two metabolite-indices were constructed, one positively (beta=1.249, p<0.001) and one negatively (beta=-1.200, p<0.001) associated with IgG. Key contributors for these indices included trigonelline, adipate, p-octopamine, and n-acetylproline. Analysis of a single mediator showed that 74.6% (95% CI: 45.9%, 98.0%) and 68.6% (95% CI: 41.8%, 94.1%) of the PFAS index-IgG total effect were mediated by the negative and positive metabolites-indices, respectively. Joint analysis of the metabolite-indices indicated a cumulative mediation effect of 83.8% (95% CI: 58.1%, 98.7%). Enriched pathways associated with these metabolites indices were phenylalanine, tyrosine, and tryptophan biosynthesis and arginine metabolism. We observed significant mediation effects of plasma metabolites on the PFAS-IgG relationship, suggesting that PFAS is associated with alteration in the balance of plasma metabolites that contributes to reduced plasma IgG production.

bioinformatics↗

bioRxiv2024

A microglia-containing cerebral organoid model to study early life immune challenges

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs. How the maternal as well as the fetal immune system affect human neurodevelopment and contribute to NDDs remains unclear. An important reason for this knowledge gap is the fact that the impact of exposure to prenatal risk factors has been challenging to study in the human context. Here, we characterized a model of cerebral organoids (CO) with integrated microglia (COiMg). These organoids express typical microglial markers and respond to inflammatory stimuli. The presence of microglia influences cerebral organoid development, including cell density and neural differentiation, and regulates the expression of several ciliated mesenchymal cell markers. Moreover, COiMg and organoids without microglia show similar but also distinct responses to inflammatory stimuli. Additionally, IFN-{gamma} induced significant transcriptional and structural changes in the cerebral organoids, that appear to be regulated by the presence of microglia. Specifically, interferon-gamma (IFN-{gamma}) was found to alter the expression of genes linked to autism. This model provides a valuable tool to study how inflammatory perturbations and microglial presence affect neurodevelopmental processes.

neuroscience↗

bioRxiv2022

Maternal cytokine response after SARS-CoV-2 infection during pregnancy

ObjectiveDysregulation of the immune system during pregnancy is associated with adverse pregnancy outcomes. Recent studies report cytokine changes during the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We examine whether there is a lasting association between SARS-CoV-2 infection during pregnancy and peripheral blood cytokine levels. Study designWe conducted a case-control study at the Mount Sinai health system in NYC including 100 SARS-CoV-2 IgG antibody positive people matched to 100 SARS-CoV-2 IgG antibody negative people on age, race/ethnicity, parity, and insurance status. Blood samples were collected at a median gestational age of 34 weeks. Levels of 14 cytokines were measured. ResultsIndividual cytokine levels and cytokine cluster Eigenvalues did not differ significantly between groups, indicating no persisting maternal cytokine changes after SARS-CoV-2 infection during pregnancy. ConclusionOur findings suggest that the acute inflammatory response after SARS-CoV-2 infection may be restored to normal values during pregnancy.

immunology↗