Publications by authors named "Johanna Zilliacus"

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers.

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The Adverse Outcome Pathway (AOP) framework has gained widespread acceptance in toxicological disciplines as a tool for aiding chemical hazard assessment. Despite increased activity in AOP development, progress towards a high volume of fully endorsed AOPs has been slow, partly due to the challenging task of constructing complete AOPs according to the AOP Developer's Handbook. To facilitate greater uptake of new knowledge units onto the open-source AOP-wiki platform, a pragmatic approach was recently proposed.

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The prevalence of hormone-related health issues caused by exposure to endocrine disrupting chemicals (EDCs) is a significant, and increasing, societal challenge. Declining fertility rates together with rising incidence rates of reproductive disorders and other endocrine-related diseases underscores the urgency in taking more action. Addressing the growing threat of EDCs in our environment demands robust and reliable test methods to assess a broad variety of endpoints relevant for endocrine disruption.

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Adverse Outcome Pathways (AOPs) can support both testing and assessment of endocrine disruptors (EDs). There is, however, a need for further development of the AOP framework to improve its applicability in a regulatory context. Here we have inventoried the AOP-wiki to identify all existing AOPs related to mammalian reproductive toxicity arising from disruption to the estrogen, androgen, and steroidogenesis modalities.

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Efficient and successful integration of data generated from non-animal test methods must rely on reliable and relevant data. It is important therefore to develop tools and criteria that facilitate scientifically sound, structured, and transparent evaluation of reliability and relevance of toxicity data to efficiently inform regulatory hazard and risk assessment. The (SciRAP) initiative aims to promote such overarching goals.

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Adverse outcome pathway (AOP) is a conceptual framework that links a molecular initiating event (MIE) via intermediate key events (KEs) with adverse effects (adverse outcomes, AO) relevant for risk assessment, through defined KE relationships (KERs). The aim of the present work is to describe a linear AOP, supported by experimental data, for skeletal craniofacial defects as the AO. This AO was selected in view of its relative high incidence in humans and the suspected relation to chemical exposure.

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Background: Scientific criteria to identify endocrine disruptors (ED) was recently implemented for plant protection products (PPP) and biocidal products (BP). A guidance document has been published by ECHA and EFSA in the context of ED criteria for PPPs and BPs.

Methods: In the present work, a case study was performed on Bisphenol AF (BPAF) to explore the application of the EU criteria and EFSA/ECHA guidance document for the ED assessment of a non-pesticide chemical regulated under REACH.

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Focus on risks to human health and the environment from combined exposure to multiple chemicals ("mixture risk assessment") has increased in the last couple of decades. There has been a rise in awareness and concern in the community, especially concerning unintentional environmental exposure to unknown chemical mixtures. The Horizon 2020 project EuroMix has developed methodologies and tools for mixture risk assessment with a focus on component-based approach where substances are grouped based on toxicological considerations.

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Endocrine disruptors (EDs) are exogenous compounds that interfere with the hormone system, affecting human health and environment. Specific legislative obligations have been introduced in the European Union (EU) to gradually eliminate EDs in water, industrial chemicals and pesticides. However, identification of EDs is the first and essential step towards regulation and appropriate risk management.

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A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project.

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The Science in Risk Assessment and Policy (SciRAP) web-based platform was developed to promote and facilitate structure and transparency in the evaluation of ecotoxicity and toxicity studies for hazard and risk assessment of chemicals. The platform includes sets of criteria and a colour-coding tool for evaluating the reliability and relevance of individual studies. The SciRAP method for evaluating in vivo toxicity studies was first published in 2014 and the aim of the work presented here was to evaluate and develop that method further.

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The UN Paris Agreement puts in place a legally binding mechanism to increase mitigation action over time. Countries put forward pledges called nationally determined contributions (NDC) whose impact is assessed in global stocktaking exercises. Subsequently, actions can then be strengthened in light of the Paris climate objective: limiting global mean temperature increase to well below 2 °C and pursuing efforts to limit it further to 1.

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Following its inception in 1994, the certification of European Registered Toxicologists (ERT) by EUROTOX has been recognized as ensuring professional competence as well as scientific integrity and credibility. Criteria and procedures for registration are contained in the ERT "Guidelines for Registration 2012". The register of ERT currently has over 1900 members.

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Regulatory risk assessment is traditionally based primarily on toxicity studies conducted according to standardized and internationally validated test guidelines. However, health risk assessment of endocrine disrupting chemicals (EDCs) is argued to rely on the efficient integration of findings from academic research. The aim of this review was to provide an overview of current developments to facilitate the use of academic research in regulatory risk assessment of chemicals and how certain aspects of study design and reporting are particularly important for the risk assessment process.

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The glucocorticoid receptor (GR) forms part of a multiprotein complex consisting of chaperones and proteins active in glucocorticoid signaling and other pathways. By immunoaffinity purification of GR, followed by Edman sequencing and Western blotting, we identified the FMS-like tyrosine kinase 3 (Flt3) as a GR-interacting protein in rat liver and hepatoma cells. Flt3 interacts with both non-liganded and liganded GR.

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Polyamine-modulated factor 1 (PMF-1) has been reported to interact with NF-E2 related factor 2 (Nrf-2) and activate the polyamine-induced transcription of spermidine/spermine N(1)-acetyltransferase (SSAT) gene. Polyamines are important regulators of cell growth and cell death and have been implicated in glucocorticoid-induced apoptosis. In the present study, we have identified and characterized new functional binding partners for PMF-1.

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Similarities in physiological roles of LXR (liver X receptors) and co-repressor RIP140 (receptor-interacting protein 140) in regulating energy homoeostasis and lipid and glucose metabolism suggest that the effects of LXR could at least partly be mediated by recruitment of the co-repressor RIP140. In the present study, we have elucidated the molecular basis for regulation of LXR transcriptional activity by RIP140. LXR is evenly localized in the nucleus and neither the N-terminal domain nor the LBD (ligand-binding domain) is necessary for nuclear localization.

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Glucocorticoids are widely used to treat inflammatory diseases but have a number of side effects that partly are connected to inhibition of cell proliferation. Glucocorticoids mediated their action by binding to the glucocorticoid receptor. In the present study, we have identified by two-hybrid screens the germinal center-associated protein (GANP) and MCM3-associated protein (MCM3AP), a splicing variant of GANP, as glucocorticoid receptor interacting proteins.

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Regulation of gene transcription by nuclear receptors involves association with numerous coregulators. Receptor-interacting protein 140 (RIP140) is a corepressor that negatively regulates the ligand-induced activity of several nuclear receptors, including the glucocorticoid receptor (GR). In the present study, we have characterized the role of the intranuclear localization of RIP140 in its corepressor activity.

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The receptor for parathyroid hormone (PTH) and PTH-related protein (PTHrP) regulates calcium homeostasis, bone remodeling and skeletal development. 14-3-3 proteins bind to signaling proteins and act as molecular scaffolds and regulators of subcellular localization. We show that the parathyroid hormone receptor (PTHR) interacts with 14-3-3 and the proteins colocalize within the cell.

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Apoptosis is an essential process for functions such as organ development and the immune response, and glucocorticoids are one of the important regulators of the cellular functions underlying these events. We have previously shown that the pro-apoptotic death-associated protein 3 (DAP3) directly interacts with the glucocorticoid receptor (GR), leading to the enhancement of the activity of the ligand-induced receptor. Here, we show that coexpression of DAP3 and GR results in an increased amount of cellular GR, as well as in partial translocation of DAP3 to the nucleus.

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