Ionizing radiation (IR) impact cellular and molecular processes that require chromatin remodelling relevant for cellular integrity. However, the cellular implications of ionizing radiation (IR) delivered per time unit (dose rate) are still debated. This study investigates whether the dose rate is relevant for inflicting changes to the epigenome, represented by chromatin accessibility, or whether it is the total dose that is decisive. CBA/CaOlaHsd mice were whole-body exposed to either chronic low dose rate (2.5 mGy/h for 54 d) or the higher dose rates (10 mGy/h for 14 d and 100 mGy/h for 30 h) of gamma radiation (60Co, total dose: 3 Gy). Chromatin accessibility was analysed in liver tissue samples using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-Seq), both one day after and over three months post-radiation (>100 d). The results show that the dose rate contributes to radiation-induced epigenomic changes in the liver at both sampling timepoints. Interestingly, chronic low dose rate exposure to a high total dose (3 Gy) did not inflict long-term changes to the epigenome. In contrast to the acute high dose rate given to the same total dose, reduced accessibility at transcriptional start sites (TSS) was identified in genes relevant for the DNA damage response and transcriptional activity. Our findings link dose rate to essential biological mechanisms that could be relevant for understanding long-term changes after ionizing radiation exposure. However, future studies are needed to comprehend the biological consequence of these findings.
Ploidy affects the amount of DNA per cell. Because phosphorus (P) is required for building DNA, polyploids should have higher P content and be more sensitive to dietary P limitation. Such differences could be due to some combination of differential incorporation and excretion of P. We tested these predictions using diploids and polyploids of the zooplankter Daphnia pulex. After manipulating the P content of natural seston, we fed it to diploids and polyploids and quantified growth and %P. Although neither growth nor %P differed significantly with ploidy, polyploids tended to grow faster on P-spiked seston. Laboratory experiments on four genotypes using Scenedesmus algae cultured under low (LoP) and high (HiP) phosphorus supplies revealed significant P treatment by ploidy interactions in both growth and %P, with polyploids growing faster in HiP, and containing more P in LoP. Radiotracer assays revealed that polyploids incorporated significantly more 33P and excreted significantly less 33P compared with diploids. Ploidy-specific P use could interact with environmental P supply to affect the fitness of genotypes differing in ploidy level. Further, these results indicate unique ecological functions (i.e. P recycling) of lineages differing in ploidy level that should be generally applicable to taxa that have undergone whole-genome duplications.
Abstract Motivation The AOP-Wiki, a knowledge database for Adverse Outcome Pathways (AOPs), requires an efficient way to present an overview of its content for the reconstruction of networks by experts in a given domain. We have developed the AOP-networkFinder, a user-friendly tool that retrieves AOPs of interest, allows network generation and cleaning, and finally visualizes networks built around the retrieved AOPs. Our tool constructs AOP networks by connecting AOPs that use the same Key Events (KEs) in a versatile but controlled manner. Genes related to these KEs are also displayed. The constructed networks can then be exported as images or to Cytoscape for further fine-tuning and statistical analysis. Results The AOP-networkFinder allows users to comprehensively identify relationships between KEs and visualize the overall structure of an AOP both quickly and easily. This is immensely beneficial to researchers who need to understand the complex interplay between different KEs and the overall pathway they are studying and helps them to build further networks of interest while logging relevant information about changes within the network. These efforts are in line with the FAIR principles, which are crucial attributes for any developed databases and tools for optimizing (re)use in a dynamically changing landscape of AOP-Wiki. Availability and implementation The AOP-networkFinder is an open-source application and is available online at aop-networkfinder.no, in the ‘Computational Toxicology at Norwegian Institute of Public Health’ Zenodo community at DOI 10.5281/zenodo.11068434, in the GitHub repository at github.com/folkehelseinstituttet/AOPnetworkFinder_v1, as well as in a Docker image at hub.docker.com/r/nurre123/aop_network_finder. The software is available under the GNU Affero General Public License (AGPL), v3.0. The tool uses the AOP-Wiki SPARQL endpoint to retrieve AOP data.
Currently, the world is facing a pandemic from the rapid spread of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes the COVID-19 disease. At the time of writing, there...
Exposure to phthalates is widespread in Europe. Phthalates are considered endocrine disrupting compounds and are classified as toxic for reproduction. However how phthalates affect the transcriptome in humans remains largely unknown. To investigate the effects of phthalate exposure on the transcriptomic profile we conducted RNA sequencing on peripheral blood samples from the Norwegian EuroMix cohort. We compared gene expression changes between participants with high, medium, and low exposure of six phthalates and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH). Comparing high and low exposure groups, DINCH was the compound that showed the highest number of differentially expressed genes (126 genes) followed by mono-n-butyl phthalate (MnBP; 89 genes) and mono-iso-nonyl phthalate (MiBP; 70 genes). Distributions between up- or down-regulated genes were similar across the different phthalates and DINCH. All phthalates including DINCH shared common differentially expressed genes ranging from 3 to 37 overlaps. Enriched Gene Ontology (GO) and biological pathway analysis revealed that most of the differentially expressed genes were associated with general cellular metabolism GO terms. MnBP and DINCH, particularly, showed a marked enrichment in various immunological function pathways including neutrophil degranulation, adaptive immune system and signaling by interleukins. Furthermore, the association between genes involved in the peroxisome proliferator activated receptor (PPAR) signaling pathway and phthalates, including DINCH, was evaluated. In total, 15 genes showed positive or negative associations across 5 phthalates and DINCH. MnBP and MiBP were the phthalate metabolites with the highest number of associations: 8 and 4 PPAR signaling pathway genes, respectively. Overall, we have performed an association study between phthalate exposure levels and modulation of transcriptomic profiles in human peripheral blood cells. DINCH, which is often mentioned as a substitute for phthalates, had comparable effects on differential gene expression in peripheral blood cells as phthalates.
Background: Per- and polyfluoroalkyl substances (PFASs) constitute a large group of compounds that are water, stain, and oil repellent. Numerous sources contribute to the blood levels of PFASs in the European population. The main contributor for perfluorooctanoic acid (PFOA) is food/drinking water, house dust, consumer products and personal care products (PCPs).Objectives: The purpose of the present work is to calculate the dietary and dermal external exposure to PFOA, estimate the aggregated internal exposure from diet and PCPs using a PBPK model, and compare estimates with measured concentrations.Methods: Detailed information on diet and PCP use from the EuroMix study is combined with concentration data of PFOA in food, drinking water and PCPs in a probabilistic exposure assessment. A physiologically based pharmacokinetic model (PBPK) was further refined by incorporating a dermal exposure pathway, and changes in the kidney and faecal excretion.Results: The aggregated internal exposure using the PBPK model shows that the major contributor to the internal exposure is diet for both males and females. The estimated internal exposure of PFOA for the EuroMix population was in the same range but lower than the measured blood concentrations using the lower bound (LB) external exposure estimates, showing that the LB estimates are underestimations. For seven females the internal exposure of PFOA were higher from PCPs than from diet.Conclusion: PCPs and diet contributed in the same range to the internal PFOA exposure for several women participating in EuroMix. This calls for additional studies on exposure to PFOA and possibly other PFASs from PCPs, especially for women. Overall, PBPK modelling was shown as valuable tool in understanding the sources of PFOA exposure and in guiding risk assessments and regulatory decisions.
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