Biology subjects

Bakulski, K.

Publications and source records attributed to Bakulski, K..

6 recordsLinked to original sources

bioRxiv2025

Identification of chemicals targeting dementia genes and pathways using the Comparative Toxicogenomics Database

IntroductionDementia is a public health challenge and exposures likely contribute to risk, though many have not been evaluated. We screened chemicals for enrichment with dementia genes and related pathways. MethodsWe obtained gene lists from the Comparative Toxicogenomics Database for 1,008 chemicals and nine dementia-related pathways (e.g., Alzheimers disease, tauopathies). We tested pairwise chemical-dementia gene enrichment using Fishers exact tests and proportional reporting ratios (PRR), accounting for multiple comparisons with false discovery rate (FDR<1x10-6). ResultsOf the chemicals tested, 742 (73.6%) were enriched for at least one dementia pathway and 15 with all nine pathways, including benzo(a)pyrene, ethanol, paraquat, and particulate matter. We observed 295 chemicals enriched for Alzheimers disease, including sodium arsenite (PRR = 57.9) and 305 enriched for tauopathies, including bisphenol A (PRR=37.7). DiscussionWe identified chemicals enriched for dementia pathways, suggesting broad classes of chemicals contribute to dementia.

genomics↗

bioRxiv2025

Environmentally Relevant Lead Exposure Alters Cell Morphology and Expression of Neural Hallmarks During SH-SY5Y Neuronal Differentiation

Lead (Pb) continues to be a public health burden, in the US and around the world, and yet the effects of historical and current exposure levels on neurogenesis are not fully understood. Here we examine the effects of a range of environmentally relevant Pb concentrations (0.16M, 1.26M, and 10M Pb) relative to control on neural differentiation in the SH-SY5Y cell model. Pb exposure began on Day 5 and continued throughout differentiation at Day 18. We assessed morphological measures related to neurogenesis at several time points during this process, including the expression of proteins key in neural differentiation ({beta}-tubulin III and GAP43), cell number and size, as well as the development of neurites. The bulk of detectable changes occurred with 10M Pb exposure, most notably that of {beta}-tubulin III and GAP43 expression. Effects with the 0.16M and 1.26M Pb exposure conditions increased as differentiation progressed, with significant reductions in cell and nuclear size as well as the number and length of neural projections by Day 18. Best benchmark concentration (BMC) analysis revealed many of these metrics to be susceptible to levels of Pb at or below historically relevant levels. This work highlights the disruption of neurite formation and protein expression as potential new mechanisms by which environmentally relevant Pb exposure impacts neurogenesis and morphology and perturb cognitive health throughout the life course.

neuroscience↗

bioRxiv2024

Placental and Immune Cell DNA Methylation Reference Panel for Bulk Tissue Cell Composition

To distinguish DNA methylation (DNAm) from cell proportion changes in whole placental tissue research, we developed a robust cell type-specific DNAm reference to estimate cell composition. We collated newly collected and existing cell type DNAm profiles quantified via Illumina EPIC or 450k microarrays. To estimate cell composition, we deconvoluted whole placental samples (n=36) with robust partial correlation based on the top 50 hyper- and hypomethylated sites per cell type. To test deconvolution performance, we evaluated RMSE in predicting principal component one of DNAm variation in 204 external placental samples. We analyzed DNAm profiles (n=368,435 sites) from 12 cell types: cytotrophoblasts (n=18), endothelial cells (n=19), Hofbauer cells (n=26), stromal cells (n=21), syncytiotrophoblasts (n=4), six lymphocyte types (n=36), and nucleated red blood cells (n=11). Median cell composition was consistent with placental biology: 60.4% syncytiotrophoblast, 17.1% stromal, 8.8% endothelial, 4.5% cytotrophoblast, 3.9% Hofbauer, 1.7% nucleated red blood cells, and 1.2% neutrophils. Our expanded reference outperformed an existing reference in predicting DNAm variation (15.4% variance explained, IQR=21.61) with cell composition estimates (RMSE:10.51 vs. 11.43, p-value<0.001). This cell type reference can robustly estimate cell composition from whole placental DNAm data to detect important cell types, reveal biological mechanisms, and improve casual inference.

genomics↗

bioRxiv2023

Placental Cell Conditioned Media Modifies Hematopoietic Stem Cell Transcriptome In Vitro

BackgroundHematopoietic stem cells are cells that differentiate into all blood cell types. Although the placenta secretes hormones, proteins and other factors important for maternal and fetal health, cross-talk between placental cells and hematopoietic stem cells is poorly understood. Moreover, toxicant impacts on placental-hematopoietic stem cell communication is understudied. The goals of this study were to determine if factors secreted from placental cells alter transcriptomic responses in hematopoietic stem cells and if monoethylhexyl phthalate (MEHP), the bioactive metabolite of the pollutant diethylhexyl phthalate, modifies these effects. MethodsWe used K-562 and BeWo cells as in vitro models of hematopoietic stem cells and placental syncytiotrophoblasts, respectively. We treated K-562 cells with medium conditioned by incubation with BeWo cells, medium conditioned with BeWo cells treated with 10 M MEHP for 24 hours, or controls treated with unconditioned medium. We extracted K-562 cell RNA, performed RNA sequencing, then conducted differential gene expression and pathway analysis by treatment group. ResultsRelative to controls, K-562 cells treated with BeWo cell conditioned medium differentially expressed 173 genes (FDR<0.05 and fold-change>2.0), including 2.4 fold upregulatation of TPM4 and 3.3 fold upregulatation of S1PR3. Upregulated genes were enriched for pathways including stem cell maintenance, cell proliferation and immune processes. Downregulated genes were enriched for terms involved in protein translation and transcriptional regulation. MEHP treatment differentially expressed eight genes (FDR<0.05), including genes involved in lipid metabolism (PLIN2, fold-change: 1.4; CPT1A, fold-change: 1.4). ConclusionK-562 cells, a model of hematopoietic stem cells, are responsive to media conditioned by placental cells, potentially impacting pathways like stem cell maintenance and proliferation.

developmental biology↗

bioRxiv2019

Developmental programming: Transcriptional regulation of visceral and subcutaneous adipose by prenatal bisphenol-A in female sheep

BackgroundBisphenol-A (BPA) exposure is widespread and early life exposure is associated with metabolic syndrome. While visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are implicated in the development of metabolic syndrome, the adipose depot-specific effects of prenatal BPA treatment are poorly understood. ObjectiveTo determine the impact of prenatal BPA exposure on the transcriptome of VAT and SAT adipose depots. MethodsRNA sequencing was performed on SAT and VAT from 21-month old control and prenatal BPA-treated female sheep. Differences in transcriptional profiling of SAT and VAT in controls and the effect of prenatal BPA treatment on individual genes and gene pathways were determined. ResultsThere were 179 differentially expressed genes (padjusted<0.05, log2-fold change >2.5) between SAT and VAT. Development and immune response pathways were upregulated in SAT, while metabolic pathways were upregulated in VAT. In SAT, BPA-treatment resulted in differential expression of 108 genes (78% upregulated with BPA) and altered pathways (immune response downregulated, RNA processing upregulated). In contrast in VAT, BPA-treatment differentially expressed 4 genes and upregulated chromatin and RNA processing pathways. ConclusionPrenatal BPA-treatment induces adult depot-specific alterations in RNA expression in inflammation, RNA processing, and chromatin, reflecting the diverse roles of SAT and VAT in regulating lipid storage and insulin sensitivity. These adipose tissue transcriptional dysregulations may contribute to the metabolic disorders observed in prenatal BPA-treated female sheep.

pharmacology and toxicology↗

bioRxiv2017

Cord blood buffy coat DNA methylation is comparable to whole cord blood methylation

BackgroundCord blood DNA methylation is associated with numerous health outcomes and environmental exposures. Whole cord blood DNA reflects all nucleated blood cell types, while centrifuging whole blood separates red blood cells by generating a white blood cell buffy coat. Both sample types are used in DNA methylation studies. Cell types have unique methylation patterns and processing can impact cell distributions, which may influence comparability.\n\nObjectivesTo evaluate differences in cell composition and DNA methylation between buffy coat and whole cord blood samples.\n\nMethodsCord blood DNA methylation was measured with the Infinium EPIC BeadChip (Illumina) in 8 individuals, each contributing buffy coat and whole blood samples. We analyzed principal components (PC) of methylation, performed hierarchical clustering, and computed correlations of mean-centered methylation between pairs. We conducted moderated t-tests on single sites and estimated cell composition.\n\nResultsDNA methylation PCs were associated with individual (PPC1=1.4x10-9; PPC2=2.9x10-5; PPC3=3.8x10-5; PPC4=4.2x10-6; PPC5=9.9x10-13), and not with sample type (PPC1-5>0.7). Samples hierarchically clustered by individual. Pearson correlations of mean-centered methylation between paired individual samples ranged from r=0.66 to r=0.87. No individual site significantly differed between buffy coat and whole cord blood when adjusting for multiple comparisons (5 sites had unadjusted P<10-5). Estimated cell type proportions did not differ by sample type (P=0.86), and estimated cell counts were highly correlated between paired samples (r=0.99).\n\nConclusionsDifferences in methylation and cell composition between buffy coat and whole cord blood are much lower than inter-individual variation, demonstrating that both sample preparation types can be analytically combined and compared.

epidemiology↗