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In past times, the analysis of endocrine disrupting properties of chemicals has mainly been focused on (anti-)estrogenic or (anti-)androgenic properties, as well as on aspects of steroidogenesis and the modulation of thyroid signaling. More recently, disruption of energy metabolism and related signaling pathways by exogenous substances, so-called metabolism-disrupting chemicals (MDCs) have come into focus. While general effects such as body and organ weight changes are routinely monitored in animal studies, there is a clear lack of mechanistic test systems to determine and characterize the metabolismdisrupting potential of chemicals. In order to contribute to filling this gap, one of the project within EU-funded Partnership for the Assessment of Risks of Chemicals (PARC) aims at developing novel in vitro methods for the detection of endocrine metabolic disruptors. Efforts will comprise projects related to specific signaling pathways, for example, involving mTOR or xenobioticsensing nuclear receptors, studies on hepatocytes, adipocytes and pancreatic beta cells covering metabolic and morphological endpoints, as well as metabolism-related zebrafish-based tests as an alternative to classic rodent bioassays. This paper provides an overview of the approaches and methods of these PARC projects and how this will contribute to the improvement of the toxicological toolbox to identify substances with endocrine disrupting properties and to decipher their mechanisms of action. [ABSTRACT FROM AUTHOR]

Early numeracy is a robust predictor of later mathematical abilities. So far, early numeracy has typically been presented as a unitary or two-factorial construct. Nevertheless, there is recent evidence suggesting that it may also be reflected by more basic numerical competences. However, the structure and stability of such a multifactorial model of early numeracy over time has not been investigated yet. In the present study, we used data from a large, longitudinal sample (N = 1292) in the United States with assessments of math ability in prekindergarten and kindergarten to evaluate both the factorial structure of early numeracy and its stability over time. Confirmatory factor analysis identified four distinct basic numerical competences making up early numeracy in prekindergarten: patterning/geometry, number sense, arithmetic, and data analysis/statistics. Stability as tested by means of measurement invariance indicated configural invariance of these four factors from prekindergarten to kindergarten. This reflected that early numeracy in kindergarten was made up by the same four basic numerical competences as in prekindergarten and thus seemed rather stable over the course of preschool. These findings may not only have implications for research on numerical cognition but particularly for diagnostic processes or the development of interventions in educational practice.

Visual-spatial abilities (VSA) are considered a building block of early numerical development. They are intuitively acquired in early childhood and differentiate in further development. However, when children enter school, there already are considerable individual differences in children’s visual-spatial and numerical abilities. To better understand this diversity, it is necessary to empirically evaluate the development as well as the latent structure of early VSA as proposed by the 2 by 2 taxonomy of Newcombe and Shipley (2015). In the present study, we report on a tablet-based assessment of VSA using the digital application (app) MaGrid in kindergarten children aged 4–6 years. We investigated whether the visual-spatial tasks implemented in MaGrid are sensitive to replicate previously observed age differences in VSA and thus a hierarchical development of VSA. Additionally, we evaluated whether the selected tasks conform to the taxonomy of VSA by Newcombe and Shipley (2015) applying a confirmatory factor analysis (CFA) approach. Our results indicated that the hierarchical development of VSA can be measured using MaGrid. Furthermore, the CFA substantiated the hypothesized factor structure of VSA in line with the dimensions proposed in the taxonomy of Newcombe and Shipley (2015). Taken together, the present results advance our knowledge to the (hierarchical) development as well as the latent structure of early VSA in kindergarten children.

1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are secondary plant metabolites that occur as food contaminants. Upon consumption, they can cause severe liver damage. PAs have been shown to induce apoptosis, to have cytotoxic and genotoxic effects, and to impair bile acid homeostasis in the human hepatoma cell line HepaRG. The major mode of action of PAs is DNA- and protein-adduct formation. Beyond that, nuclear receptor activation has only been observed for one receptor and two PAs, yielding the possibility that other cellular mediators are involved in PA-mediated toxicity. Here, the mode of action of Senecionine (Sc), a prominent and ubiquitous representative of hepatotoxic PAs, was investigated by analyzing 7 hepatic microRNAs (miRNAs) in HepaRG cells. Ultimately, 11 target genes that were predicted with Ingenuity Pathway Analysis software (IPA) were found to be significantly downregulated, while their assigned miRNAs showed significant upregulation of gene expression. According to IPA, these targets are positively correlated with apoptosis and cellular death and are involved in diseases such as hepatocellular carcinoma. Subsequent antagomiR-inhibition analysis revealed a significant correlation between PA-induced miRNA-4434 induction and P21-Activated Kinase-1 (PAK1) downregulation. PAK1 downregulation is usually associated with cell cycle arrest, suggesting a new function of Sc-mediated toxicity in human liver cells.

Abstract Background Even though a continuously high number of in vitro studies on nanoparticles are being published, the issue of correct dose matter is often not sufficiently taken into account. Due to their size, the diffusion of nanoparticles is slower, as compared to soluble chemicals, and they sediment slowly. Therefore, the administered dose of particles in in vitro experiments is not necessarily the same (effective) dose that comes into contact with the cellular system. This can lead to misinterpretations of experimental toxic effects and disturbs the meaningfulness of in vitro studies. In silico calculations of the effective nanoparticle dose can help circumventing this problem. Results This study addresses more complex in vitro models like the human intestinal cell line Caco-2 or the human liver cell line HepaRG, which need to be differentiated over a few weeks to reach their full complexity. During the differentiation time the cells grow up the wall of the cell culture dishes and therefore a three-dimensional-based in silico model of the nanoparticle dose was developed to calculate the administered dose received by different cell populations at the bottom and the walls of the culture dish. Moreover, the model can perform calculations based on the hydrodynamic diameter which is measured by light scattering methods, or based on the diffusion coefficient measured by nanoparticle tracking analysis (NTA). This 3DSDD (3D-sedimentation-diffusion-dosimetry) model was experimentally verified against existing dosimetry models and was applied to differentiated Caco-2 cells incubated with silver nanoparticles. Conclusions The 3DSDD accounts for the 3D distribution of cells in in vitro cell culture dishes and is therefore suitable for differentiated cells. To encourage the use of dosimetry calculating software, our model can be downloaded from the supporting information.