scholarly journals Investigation of a derived adverse outcome pathway (AOP) network for endocrine-mediated perturbations

2021 ◽  
Author(s):  
Janani Ravichandran ◽  
Bagavathy Shanmugam Karthikeyan ◽  
Areejit Samal
Keyword(s):  
Adverse Outcome ◽  
Current Knowledge ◽  
Research Question ◽  
Network Connectivity ◽  
Environmental Chemicals ◽  
Connected Components ◽  
Compact Representation ◽  
Adverse Outcome Pathway ◽  
Graph Theoretic ◽  
Depth Analysis

AbstractAn adverse outcome pathway (AOP) is a compact representation of the available mechanistic information on observed adverse effects upon environmental exposure. Sharing of events across individual AOPs has led to the emergence of AOP networks. Since AOP networks are expected to be functional units of toxicity prediction, there is current interest in their development tailored to specific research question or regulatory problem. To this end, we have developed a detailed workflow to construct a comprehensive endocrine-specific AOP (ED-AOP) network. Connectivity analysis of the ED-AOP network comprising 48 AOPs reveals 7 connected components and 12 isolated AOPs. Subsequently, we apply standard network measures to perform an in-depth analysis of the two largest connected components of the ED-AOP network. Notably, the graph-theoretic analyses led to the identification of important events including points of convergence or divergence in the ED-AOP network. Detailed analysis of the largest component in the ED-AOP network gives insights on the systems-level perturbations caused by endocrine disruption, emergent paths, and stressor-event associations. In sum, the derived ED-AOP network can be used to address the current knowledge gaps in the existing regulatory framework and aid in better risk assessment of environmental chemicals.

scholarly journals Developmental biology meets toxicology: contributing reproductive mechanisms to build adverse outcome pathways

2020 ◽  
Vol 26 (2) ◽  
pp. 111-116 ◽  
Author(s):  
Monica Kam Draskau ◽  
Cassy M Spiller ◽  
Julie Boberg ◽  
Josephine Bowles ◽  
Terje Svingen
Keyword(s):  
Large Scale ◽  
Adverse Outcome ◽  
Environmental Chemicals ◽  
Basic Knowledge ◽  
Biological Knowledge ◽  
Adverse Outcome Pathway ◽  
Fundamental Knowledge ◽  
Testing Strategies ◽  
Human Reproductive

Abstract An adverse outcome pathway (AOP) is a simplified description of the sequence of mechanistic events that lead to a particular toxicological effect, from initial trigger to adverse outcome. Although designed to inform regulatory risk assessors, the AOP framework also provides a platform for innovative collaborations between experts from relevant research fields and the regulatory community. The underpinning for any AOP is basic knowledge about molecular and developmental processes; such knowledge can only be attained by solid bioscientific research. Starting with this fundamental knowledge, the objective is to devise novel testing strategies that focus on key events in a causative pathway. It is anticipated that such a knowledge-based approach will ultimately alleviate many of the burdens associated with classical chemical testing strategies that typically involve large-scale animal toxicity regimens. This hails from the notion that a solid understanding of the underlying mechanisms will allow the development and use of alternative test methods, including both in vitro and in silico approaches. This review is specifically targeted at professionals working in bioscientific fields, such as developmental and reproductive biology, and aims to (i) inform on the existence of the AOP framework and (ii) encourage new cross-disciplinary collaborations. It is hoped that fundamental biological knowledge can thus be better exploited for applied purposes: firstly, an improved understanding of how our perpetual exposure to environmental chemicals is causing human reproductive disease and, secondly, new approaches to screen for harmful chemicals more efficiently. This is not an instructional manual on how to create AOPs; rather, we discuss how to harness fundamental knowledge from the biosciences to assist regulatory toxicologists in their efforts to protect humans against chemicals that harm human reproductive development and function.

scholarly journals Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

2020 ◽  
Vol 94 (10) ◽  
pp. 3359-3379 ◽  
Author(s):  
Hanna K. L. Johansson ◽  
Pauliina Damdimopoulou ◽  
Majorie B. M. van Duursen ◽  
Julie Boberg ◽  
Delphine Franssen ◽  
...  
Keyword(s):  
Reproductive Health ◽  
Adverse Outcome ◽  
Current Knowledge ◽  
Chemical Exposure ◽  
Reproductive Hormones ◽  
Test Method ◽  
Adverse Outcome Pathway ◽  
Continuous Exposure ◽  
Reproductive Disorders ◽  
Female Reproductive Health

Abstract Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause–effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman’s reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause–effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.

scholarly journals Combined In Vitro and In Vivo Approaches to Propose a Putative Adverse Outcome Pathway for Acute Lung Inflammation Induced by Nanoparticles: A Study on Carbon Dots

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 180
Author(s):  
Maud Weiss ◽  
Jiahui Fan ◽  
Mickaël Claudel ◽  
Luc Lebeau ◽  
Françoise Pons ◽  
...  
Keyword(s):  
Carbon Dots ◽  
Lung Inflammation ◽  
Adverse Outcome ◽  
Cellular Responses ◽  
Target Cells ◽  
Inflammasome Activation ◽  
Adverse Outcome Pathway ◽  
Acute Lung Inflammation

With the growth of nanotechnologies, concerns raised regarding the potential adverse effects of nanoparticles (NPs), especially on the respiratory tract. Adverse outcome pathways (AOP) have become recently the subject of intensive studies in order to get a better understanding of the mechanisms of NP toxicity, and hence hopefully predict the health risks associated with NP exposure. Herein, we propose a putative AOP for the lung toxicity of NPs using emerging nanomaterials called carbon dots (CDs), and in vivo and in vitro experimental approaches. We first investigated the effect of a single administration of CDs on mouse airways. We showed that CDs induce an acute lung inflammation and identified airway macrophages as target cells of CDs. Then, we studied the cellular responses induced by CDs in an in vitro model of macrophages. We observed that CDs are internalized by these cells (molecular initial event) and induce a series of key events, including loss of lysosomal integrity and mitochondrial disruption (organelle responses), as well as oxidative stress, inflammasome activation, inflammatory cytokine upregulation and macrophage death (cellular responses). All these effects triggering lung inflammation as tissular response may lead to acute lung injury.

scholarly journals Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Luigi Margiotta-Casaluci ◽  
Stewart F. Owen ◽  
Belinda Huerta ◽  
Sara Rodríguez-Mozaz ◽  
Subramanian Kugathas ◽  
...  
Keyword(s):  
Predictive Power ◽  
Adverse Outcome ◽  
Plasma Concentrations ◽  
Internal Exposure ◽  
Adverse Outcome Pathway ◽  
Conceptual Tool ◽  
Fish Model ◽  
Species Specific

Abstract The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

scholarly journals Molecular Modelling Study of the PPARγ Receptor in Relation to the Mode of Action/Adverse Outcome Pathway Framework for Liver Steatosis

2014 ◽  
Vol 15 (5) ◽  
pp. 7651-7666 ◽  
Author(s):  
Ivanka Tsakovska ◽  
Merilin Al Sharif ◽  
Petko Alov ◽  
Antonia Diukendjieva ◽  
Elena Fioravanzo ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Mode Of Action ◽  
Adverse Outcome ◽  
Liver Steatosis ◽  
Adverse Outcome Pathway ◽  
Modelling Study

Anchoring molecular mechanisms to the adverse outcome pathway for skin sensitization: Analysis of existing data

2014 ◽  
Vol 44 (7) ◽  
pp. 590-599 ◽  
Author(s):  
Jochem W. van der Veen ◽  
Lya G. Soeteman-Hernández ◽  
Janine Ezendam ◽  
Rob Stierum ◽  
Frieke C. Kuper ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Adverse Outcome ◽  
Adverse Outcome Pathway ◽  
Skin Sensitization ◽  
Existing Data

Trust and Relationship Development Among Users in Dark Web Child Sexual Exploitation and Abuse Networks: A Literature Review From a Psychological and Criminological Perspective

2021 ◽  
pp. 152483802110572
Author(s):  
Juliane A. Kloess ◽  
Madeleine van der Bruggen
Keyword(s):  
Literature Review ◽  
Current Knowledge ◽  
Research Question ◽  
Sexual Exploitation ◽  
Relationship Development ◽  
Expert Advice ◽  
Future Research ◽  
Child Sexual Exploitation ◽  
Criminological Perspective ◽  
Dark Web

The increased potential and speed of the Internet has changed the nature of sexual crimes against children. It enables individuals with a sexual interest in children to meet, interact, and engage in illegal activities. The literature review presented here aims to provide an overview of the current knowledge and understanding of trust and relationship development among users of online networks that are dedicated to the sexual exploitation and abuse of children. A systematic search using six databases was conducted to identify relevant literature from a psychological and a criminological perspective. Twenty-one studies met the inclusion criteria that centered around the key aspects of the literature review’s research question, namely, (i) child sexual exploitation and abuse, (ii) Dark Web platforms, (iii) online forums and networks, and (iv) trust and relationship development. Our findings reveal that the engagement in interpersonal communication and interactions with like-minded others serves various functions, including validation, normalization, and support, as well as access to expert advice, information, and material. Dark Web networks are high-stake and risky environments, where users have to manage a continuous flow of threats, with information about others and their trustworthiness being limited. The establishment and maintenance of trust is of social and technical relevance, and users have to navigate a number of demands and commitments. Findings are discussed in relation to theoretical and practical implications, as well as directions for future research.

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