An Advancement in Developmental and Reproductive Toxicity (DART) Risk Assessment: Evaluation of a Bioactivity and Exposure-Based NAM Toolbox
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PROVIDER: PRJEB94457 | ENA |
REPOSITORIES: ENA
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Project description:Advancing systemic toxicity risk assessment: Evaluation of a NAM-based toolbox approach
| PRJEB94531 | ENA
Project description:As complex mixtures, botanicals present unique challenges when assessing safe use, particularly when endpoint gaps exist that cannot be fully resolved by existing toxicological literature. Obtaining data for developmental and reproductive toxicity (DART) can be particularly difficult as this is a frequent data gap for botanicals. Here we explore in vitro receptor binding and enzyme activity assays as well gene expression studies as alternative tools to inform on DART relevent modes of action. Botanicals suspected to have DART effects in addition to herbs with a significant history of use were tested at biologically relevant doses to probe activity at a molecular level. Additionally, gene expression changes in a number of different cell types were analysed using the connectivity mapping approach (CMap) to identify modes of action through a functional read across approach. Together, these two data streams increase the confidence in predictions of biological mode of action and inform potential DART risk by way of potency comparisons and/or a margin of internal exposure approach.
2020-05-01 | GSE144235 | GEO
Project description:Working with primary human myogenic progenitors (hMPs), we developed a high-content screen to discover molecules that enhanced myogenic function and identified NAM and PN as modulators of myogenic proliferation and differentiation. We characterized genome-wide expression profiles of NAM-, PN-treated and NAM/PN-treated hMPs with the goal to uncover the mechanisms of action of NAM and PN and the potential additivity from the combination at the molecular level in hMPs.
2024-11-18 | GSE264285 | GEO
Project description:For many years, a method that allowed systemic toxicity safety assessments to be conducted without generating new animal test data, seemed out of reach. However, several different research groups and regulatory authorities are beginning to use a variety of in silico, in chemico, and in vitro techniques to inform safety decisions. To manage this transition to animal-free safety assessments responsibly, it is important to ensure that the level of protection offered by a safety assessment based on new approach methodologies (NAMs), is at least as high as that provided by a safety assessment based on traditional animal studies. To this end, we have developed an evaluation strategy to assess both the level of protection and the utility offered by a NAM-based systemic safety "toolbox." The toolbox comprises physiologically based kinetic models to predict internal exposures, and bioactivity NAMs designed to give broad coverage across many different toxicity modes of action. The output of the toolbox is the calculation of a bioactivity:exposure ratio (analogous to a margin of internal exposure), which can be used to inform decision-making. In this work, we have expanded upon an initial pilot study of 10 chemicals with an additional 38 chemicals and 70 consumer exposure scenarios. We found that, for the majority of these (>90%), the NAM-based workflow is protective of human health, enabling us to make animal-free safety decisions for systemic toxicity and preventing unnecessary animal use. We have also identified critical areas for improvement to further increase our confidence in the robustness of the approach.
| S-EPMC11879040 | biostudies-literature
Project description:m6A is a widespread RNA modification which plays important roles in the regulation of gene expression. Methods for the global detection of m6A rely on immunoprecipitation of methylated transcripts using m6A antibodies. However, these methods are costly and require large amounts of input RNA, making them prohibitive for many experiments. Here, we describe DART-seq, an antibody-free method for m6A detection which enables transcriptome-wide mapping of m6A residues using low amounts of input material. DART-seq can be used to obtain global m6A maps using as little as 10 nanograms of total RNA and at single-molecule resolution. This method offers several improvements over current techniques and will facilitate detection of m6A in limiting cell and tissue types.
2019-09-23 | GSE125780 | GEO
Project description:To further explore the effect of NAM on the TGFβ1-induced hESC-derived corneal endothelial progenitor cells, we have employed whole RNA microarray expression profiling as a discovery platform to identify genes and mechanism of NAM on the EnMT and senescence. hESC-derived endothelial progenotors were culured under 30ng/ml TGFβ1 with or without 50 mM NAM. The cultures were incubated for 72 hours at 37 ºC in a humidified incubator with 5% CO2.
2022-01-05 | GSE183786 | GEO
Project description:We aimed to identify specific biomarkers of IFN-beta bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFN-beta. Nine genes followed patterns in gene expression over time similar to the MX1 and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments revealed specific induction of selected biomarkers by IFN-beta but not IFN-gamma, and several markers, in particular USP18 and HERC5, were significantly induced at lower IFN-beta concentrations and more selective than the MX1 as biomarkers of IFN-beta bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p=0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFN-beta bioactivity, and to further explore their implication in MS pathogenesis. Number of samples: 32. We analyzed PBMC from 8 patients at baseline and after 3, 12 and 24 months of IFN-beta treatment
2010-12-18 | E-GEOD-26104 | biostudies-arrayexpress
Project description:Soybean nested association mapping (NAM) parent lines were compared by CGH to catalog structurally variant (e.g. deletion and duplication) regions among these genotypes. The CGH comparisons reveal reveal putative deletions and duplications among the 41 lines.
2014-03-30 | GSE56351 | GEO
Project description:Background : Candida albicans is a diploid pathogenic fungus not yet amenable to routine genetic investigations. Understanding aspects of the regulation of its biological functions and the assembly of its protein complexes would lead to further insight into the biology of this common disease-causing microbial agent. Results: We have developed a toolbox allowing in vivo protein tagging by PCR-mediated homologous recombination with TAP, HA and MYC tags. The transformation cassettes were designed to accommodate a common set of integration primers. The tagged proteins can be used to perform tandem affinity purification (TAP) or chromatin immunoprecipitation coupled with microarray analysis (ChIP-CHIP). Tandem affinity purification of C. albicans Nop1 revealed the high conservation of the small processome composition in yeasts. Data obtained with in vivo TAP-tagged Tbf1, Cbf1 and Mcm1 recapitulates previously published genome-wide location profiling by ChIP-CHIP. We also designed a new reporter system for in vivo analysis of transcriptional activity of gene loci in C. albicans. Conclusion: This toolbox provides a basic setup to perform purification of protein complexes and increase the number of annotated transcriptional regulators and genetic circuits in C. albicans. Two independent biological replicates of ChIP-CHIP of Mcm1-TAP in yeast and hyphal states. ChIP-CHIP of Cbf1-TAP and Tbf1-TAP.
2010-05-16 | E-GEOD-13427 | biostudies-arrayexpress