The Experts below are selected from a list of 3858 Experts worldwide ranked by ideXlab platform

Olavi Pelkonen - One of the best experts on this subject based on the ideXlab platform.

Daniel L Villeneuve - One of the best experts on this subject based on the ideXlab platform.

  • extracting and benchmarking emerging Adverse Outcome Pathway knowledge
    Toxicological Sciences, 2019
    Co-Authors: Nathan Pollesch, Daniel L Villeneuve, Jason M Obrien
    Abstract:

    As the community of toxicological researchers, risk assessors, and risk managers adopt the Adverse Outcome Pathway (AOP) framework for organizing toxicological knowledge, the number and diversity of AOPs in the online AOP knowledgebase (KB) continues to grow. To track and investigate this growth, AOPs in the AOP-KB were assembled into a single network. Summary measures on the current state of the AOP-KB and the overall connectivity and structural features of the resulting network were calculated. Our results show that networking the 187 user-defined AOPs currently described in the AOP-KB resulted in the emergence of 9405 unique, previously undescribed, linear AOPs (LAOPs). To investigate patterns in this emerging knowledge, we assembled the AOP-KB network retrospectively by sequentially adding each of the 187 user-defined AOPs and found that the creation of new AOPs that borrowed components from previously existing AOPs in the KB most described emergence of new LAOPs. However, the introduction of nonadjacent key event relationships and cycles among KEs also play key roles in emergent LAOPs. We provide examples of how to identify application-specific critical paths from this large number of LAOPs. Our research shows that the global AOP network may have considerable value as a source of emergent toxicological knowledge. These findings are not only helpful for understanding the nature of this emergent information but can also be used to manage and guide future development of the AOP-KB, and how to tailor this wealth of information to specific applications.

  • ecdysone receptor agonism leading to lethal molting disruption in arthropods review and Adverse Outcome Pathway development
    Environmental Science & Technology, 2017
    Co-Authors: You Song, Daniel L Villeneuve, Kenji Toyota, Taisen Iguchi, Knut Erik Tollefsen
    Abstract:

    Molting is critical for growth, development, reproduction, and survival in arthropods. Complex neuroendocrine Pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting chemicals (EDCs). Based on several known ED mechanisms, a wide range of pesticides has been developed to combat unwanted organisms in food production activities such as agriculture and aquaculture. Meanwhile, these chemicals may also pose hazards to nontarget species by causing molting defects, and thus potentially affecting the health of the ecosystems. The present review summarizes the available knowledge on molting-related endocrine regulation and chemically mediated disruption in arthropods (with special focus on insects and crustaceans), to identify research gaps and develop a mechanistic model for assessing environmental hazards of these compounds. Based on the review, multiple targets of EDCs in the molting processes were identified and the link between mode of action ...

  • the potential of aop networks for reproductive and developmental toxicity assay development
    Reproductive Toxicology, 2015
    Co-Authors: Dries Knapen, Daniel L Villeneuve, Lucia Vergauwen, Gerald T Ankley
    Abstract:

    Historically, the prediction of reproductive and developmental toxicity has largely relied on the use of animals. The Adverse Outcome Pathway (AOP) framework forms a basis for the development of new non-animal test methods. It also provides biological context for mechanistic information from existing assays. However, a single AOP may not capture all events that contribute to any relevant toxic effect, even in single chemical exposure scenarios. AOP networks, defined as sets of AOPs sharing at least one common element, are capable of more realistically representing potential chemical effects. They provide information on interactions between AOPs and have the potential to reveal previously unknown links between biological Pathways. Analysis of these AOP networks can aid the prioritization of assay development, whether the goal is to develop a single assay with predictive utility of multiple Outcomes, or development of assays that are highly specific for a particular mode of action. This paper provides a brief overview of the AOPs related to reproductive and developmental toxicity currently available in the AOP Wiki (http://aopwiki.org), and gives an example of an AOP network based on five reproductive and developmental toxicity-related AOPs for fish to illustrate how AOP networks can be used for assay development and refinement.

  • Adverse Outcome Pathway development ii best practices
    Toxicological Sciences, 2014
    Co-Authors: Daniel L Villeneuve, Doug Crump, Natalia Garciareyero, Markus Hecker, Thomas H Hutchinson
    Abstract:

    Organization of existing and emerging toxicological knowledge into Adverse Outcome Pathway (AOP) descriptions can facilitate greater application of mechanistic data, including those derived through high-throughput in vitro, high content omics and imaging, and biomarker approaches, in risk-based decision making. The previously ad hoc process of AOP development is being formalized through development of internationally harmonized guidance and principles. The goal of this article was to outline the information content desired for formal AOP description and some rules of thumb and best practices intended to facilitate reuse and connectivity of elements of an AOP description in a knowledgebase and network context. For example, key events (KEs) are measurements of change in biological state that are indicative of progression of a perturbation toward a specified Adverse Outcome. Best practices for KE description suggest that each KE should be defined as an independent measurement made at a particular level of biological organization. The concept of “functional equivalence” can help guide both decisions about how many KEs to include in an AOP and the specificity with which they are defined. Likewise, in describing both KEs and evidence that supports a causal linkage or statistical association between them (ie, a key event relationship; KER), best practice is to build from and contribute to existing KE or KER descriptions in the AOP knowledgebase rather than creating redundant descriptions. The best practices proposed address many of the challenges and uncertainties related to AOP development and help promote a consistent and reliable, yet flexible approach.

  • Adverse Outcome Pathway aop development i strategies and principles
    Toxicological Sciences, 2014
    Co-Authors: Daniel L Villeneuve, Doug Crump, Natalia Garciareyero, Markus Hecker, Thomas H Hutchinson
    Abstract:

    An Adverse Outcome Pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an Adverse Outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components—notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.

M E Gilbert - One of the best experts on this subject based on the ideXlab platform.

  • neurodevelopment and thyroid hormone synthesis inhibition in the rat quantitative understanding within the Adverse Outcome Pathway framework
    Toxicological Sciences, 2017
    Co-Authors: Iman Hassan, Hisham A Elmasri, Patricia A Kosian, Jermaine Ford, Sigmund J Degitz, M E Gilbert
    Abstract:

    : Adequate levels of thyroid hormone (TH) are needed for proper brain development, deficiencies may lead to Adverse neurologic Outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures and decline in serum TH resulting in neurodevelopmental impairment is poorly understood. The present study developed a quantitative Adverse Outcome Pathway where serum thyroxin (T4) reduction following inhibition of thyroperoxidase in the thyroid gland are described and related to deficits in fetal brain TH and the development of a brain malformation, cortical heterotopia. Pregnant rats were exposed to 6-propylthiouracil (PTU 0, 0.1, 0.5, 1, 2, or 3 parts per million [ppm]) from gestational days 6-20, sequentially increasing PTU concentrations in maternal thyroid gland and serum as well as in fetal serum. Dams exposed to 0.5 ppm PTU and higher exhibited dose-dependent decreases in thyroidal T4. Serum T4 levels in the dam were significantly decreased with exposure to 2 and 3 ppm PTU. In the fetus, T4 decrements were first observed at a lower dose of 0.5 ppm PTU. Based on these data, fetal brain T4 levels were estimated from published literature sources, and quantitatively linked to increases in the size of the heterotopia present in the brains of offspring. These data show the potential of in vivo assessments and computational descriptions of biologic responses to predict the development of this structural brain malformation and use of quantitative Adverse Outcome Pathway approach to evaluate brain deficits that may result from exposure to other TH disruptors.

  • neurodevelopment and thyroid hormone synthesis inhibition in the rat quantitative understanding within the Adverse Outcome Pathway framework
    Toxicological Sciences, 2017
    Co-Authors: Iman Hassan, Hisham A Elmasri, Patricia A Kosian, Jermaine Ford, Sigmund J Degitz, M E Gilbert
    Abstract:

    Adequate levels of thyroid hormone (TH) are needed for proper brain development, deficiencies may lead to Adverse neurologic Outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures and decline in serum TH resulting in neurodevelopmental impairment is poorly understood. The present study developed a quantitative Adverse Outcome Pathway where serum thyroxin (T4) reduction following inhibition of thyroperoxidase in the thyroid gland are described and related to deficits in fetal brain TH and the development of a brain malformation, cortical heterotopia. Pregnant rats were exposed to 6-propylthiouracil (PTU 0, 0.1, 0.5, 1, 2, or 3 parts per million [ppm]) from gestational days 6-20, sequentially increasing PTU concentrations in maternal thyroid gland and serum as well as in fetal serum. Dams exposed to 0.5 ppm PTU and higher exhibited dose-dependent decreases in thyroidal T4. Serum T4 levels in the dam were significantly decreased with exposure to 2 and 3 ppm PTU. In the fetus, T4 decrements were first observed at a lower dose of 0.5 ppm PTU. Based on these data, fetal brain T4 levels were estimated from published literature sources, and quantitatively linked to increases in the size of the heterotopia present in the brains of offspring. These data show the potential of in vivo assessments and computational descriptions of biologic responses to predict the development of this structural brain malformation and use of quantitative Adverse Outcome Pathway approach to evaluate brain deficits that may result from exposure to other TH disruptors.

Nancy D Denslow - One of the best experts on this subject based on the ideXlab platform.

  • early phosphoproteomic changes for Adverse Outcome Pathway development in the fathead minnow pimephales promelas brain
    Scientific Reports, 2018
    Co-Authors: L C Smith, Nancy D Denslow, Candice M Lavelle, Cecilia Silvasanchez, Tara Saboattwood
    Abstract:

    Adverse Outcome Pathways (AOPs) are conceptual frameworks that organize and link contaminant-induced mechanistic molecular changes to Adverse biological responses at the individual and population level. AOPs leverage molecular and high content mechanistic information for regulatory decision-making, but most current AOPs for hormonally active agents (HAAs) focus on nuclear receptor-mediated effects only despite the overwhelming evidence that HAAs also activate membrane receptors. Activation of membrane receptors triggers non-genomic signaling cascades often transduced by protein phosphorylation leading to phenotypic changes. We utilized label-free LC-MS/MS to identify proteins differentially phosphorylated in the brain of fathead minnows (Pimephales promelas) aqueously exposed for 30 minutes to two HAAs, 17α-ethinylestradiol (EE2), a strong estrogenic substance, and levonorgestrel (LNG), a progestin, both components of the birth control pill. EE2 promoted differential phosphorylation of proteins involved in neuronal processes such as nervous system development, synaptic transmission, and neuroprotection, while LNG induced differential phosphorylation of proteins involved in axon cargo transport and calcium ion homeostasis. EE2 and LNG caused similar enrichment of synaptic plasticity and neurogenesis. This study is the first to identify molecular changes in vivo in fish after short-term exposure and highlights transduction of rapid signaling mechanisms as targets of HAAs, in addition to nuclear receptor-mediated Pathways.

  • toward an Adverse Outcome Pathway for impaired growth mitochondrial dysfunction impairs growth in early life stages of the fathead minnow pimephales promelas
    Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2018
    Co-Authors: Derek G Bolser, Christopher J Martyniuk, David A Dreier, Kevin J Kroll, Nancy D Denslow
    Abstract:

    Abstract Chemical contaminants present in the environment can affect mitochondrial bioenergetics in aquatic organisms and can have substantial effects on individual fitness. As early life stages of fish are particularly vulnerable to environmental contaminants, they are ideal models for examining the relationship between impaired mitochondrial bioenergetics (ATP-dependent respiration, basal oxidative respiration) and apical endpoints such as growth. Here, early life stages of the fathead minnow (Pimephales promelas), an ecologically relevant North American species, were used to investigate the relationship between mitochondrial bioenergetics and growth following perturbation with model mitochondrial toxicants 2,4-dinitrophenol and octylamine. Fathead minnows were exposed to 2,4-dinitrophenol and octylamine at 3 concentrations for 24 h and endpoints related to mitochondrial bioenergetics were measured with the Agilent Seahorse XFe24 Bioanalyzer. In order to link changes in mitochondrial bioenergetics to growth, fathead minnows were exposed to the same chemical contaminants for 7–14 days and growth was measured by measuring total length on a weekly basis. There was a significant correlation between decrease in average length at 14 days and basal respiration (r = 0.997, p = 0.050, n = 3), as well as maximal respiration (r = 0.998, p-value = 0.043, n = 3) for embryos exposed to 2,4 dinitrophenol. For octylamine, ATP production was highly correlated with average length at 7 days (p-value = 0.1) and spare respiratory capacity and average length at 14 days were highly correlated (p-value = 0.1). These data improve understanding of how mitochondrial toxicants impair growth in fish larvae and may be useful for developing an Adverse Outcome Pathway for growth.

  • development and application of the Adverse Outcome Pathway framework for understanding and predicting chronic toxicity i challenges and research needs in ecotoxicology
    Chemosphere, 2015
    Co-Authors: Nancy D Denslow, Cheryl A Murphy, Ksenia J Groh, Raquel N Carvalho, J K Chipman, Marlies Halder, Dick Roelofs, Alexandra Rolaki, Kristin Schirmer
    Abstract:

    To elucidate the effects of chemicals on populations of different species in the environment, efficient testing and modeling approaches are needed that consider multiple stressors and allow reliable extrapolation of responses across species. An Adverse Outcome Pathway (AOP) is a concept that provides a framework for organizing knowledge about the progression of toxicity events across scales of biological organization that lead to Adverse Outcomes relevant for risk assessment. In this paper, we focus on exploring how the AOP concept can be used to guide research aimed at improving both our understanding of chronic toxicity, including delayed toxicity as well as epigenetic and transgenerational effects of chemicals, and our ability to predict Adverse Outcomes. A better understanding of the influence of subtle toxicity on individual and population fitness would support a broader integration of sublethal endpoints into risk assessment frameworks. Detailed mechanistic knowledge would facilitate the development of alternative testing methods as well as help prioritize higher tier toxicity testing. We argue that targeted development of AOPs supports both of these aspects by promoting the elucidation of molecular mechanisms and their contribution to relevant toxicity Outcomes across biological scales. We further discuss information requirements and challenges in application of AOPs for chemical- and site-specific risk assessment and for extrapolation across species. We provide recommendations for potential extension of the AOP framework to incorporate information on exposure, toxicokinetics and situation-specific ecological contexts, and discuss common interfaces that can be employed to couple AOPs with computational modeling approaches and with evolutionary life history theory. The extended AOP framework can serve as a venue for integration of knowledge derived from various sources, including empirical data as well as molecular, quantitative and evolutionary-based models describing species responses to toxicants. This will allow a more efficient application of AOP knowledge for quantitative chemical- and site-specific risk assessment as well as for extrapolation across species in the future.

  • development and application of the Adverse Outcome Pathway framework for understanding and predicting chronic toxicity ii a focus on growth impairment in fish
    Chemosphere, 2015
    Co-Authors: Nancy D Denslow, Cheryl A Murphy, Ksenia J Groh, Raquel N Carvalho, J K Chipman, Marlies Halder, Dick Roelofs, Alexandra Rolaki, Kristin Schirmer
    Abstract:

    Adverse Outcome Pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity Outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests.

Tommy B Andersson - One of the best experts on this subject based on the ideXlab platform.

  • cytochrome p450 induction and xeno sensing receptors pregnane x receptor constitutive androstane receptor aryl hydrocarbon receptor and peroxisome proliferator activated receptor α at the crossroads of toxicokinetics and toxicodynamics
    Basic & Clinical Pharmacology & Toxicology, 2018
    Co-Authors: Jukka Hakkola, Camilla Bernasconi, Sandra Coecke, Lysiane Richert, Tommy B Andersson, Olavi Pelkonen
    Abstract:

    Pregnane X receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AHR) and peroxisome proliferator-activated receptor α (PPARα) are ligand-activated transcription factors that regulate expression of many xenobiotic-metabolizing enzymes including several cytochrome P450 (CYP) enzymes. Many xenobiotics induce CYP enzymes through these intracellular receptors and consequently affect toxicokinetics and possible metabolic activation of the receptor ligands and other xenobiotics utilizing similar metabolic Pathways. However, it is now apparent that the xenobiotic receptors regulate also many endogenous functions and signalling Pathways, and xenobiotic exposure thus may dysregulate an array of fundamental cell functions. This MiniReview surveys and discusses the multifaceted roles of xenobiotic receptors, for which CYP induction may serve as the first alert and possibly a biomarker for exposure to xenobiotics. With the current emergence of the Adverse Outcome Pathway (AOP) concept, these receptors are being and will be assigned as molecular initiating events or key events in numerous discrete toxicity Pathways.