Application of
            in silico
            and
            in vitro
            methods in the development of adverse outcome pathway constructs in wildlife

There is a long history of using both in silico and in vitro methods to predict adverse effects in humans and environmental species where toxicity data are lacking. Currently, there is a great deal of interest in applying these methods to the development of so-called ‘adverse outcome pathway’ (AOP) constructs. The AOP approach provides a framework for organizing information at the chemical and biological level, allowing evidence from both in silico and in vitro studies to be rationally combined to fill gaps in knowledge concerning toxicological events. Fundamental to this new paradigm is a greater understanding of the mechanisms of toxicity and, in particular, where these mechanisms may be conserved across taxa, such as between model animals and related wild species. This presents an opportunity to make predictions across diverse species, where empirical data are unlikely to become available as is the case for most species of wildlife.

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Identification of mitochondrial toxicants by combined in silico and in vitro studies – A structure-based view on the adverse outcome pathway

Computational Toxicology ◽

10.1016/j.comtox.2020.100123 ◽

2020 ◽

Vol 14 ◽

pp. 100123 ◽

Cited By ~ 1

Author(s):

Florentina Troger ◽

Johannes Delp ◽

Melina Funke ◽

Wanda van der Stel ◽

Claire Colas ◽

...

Keyword(s):

In Silico ◽

Adverse Outcome ◽

In Vitro Studies ◽

Adverse Outcome Pathway

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Development of an adverse outcome pathway for cranio-facial malformations: A contribution from in silico simulations and in vitro data

Food and Chemical Toxicology ◽

10.1016/j.fct.2020.111303 ◽

2020 ◽

Vol 140 ◽

pp. 111303 ◽

Cited By ~ 1

Author(s):

Francesca Metruccio ◽

Luca Palazzolo ◽

Francesca Di Renzo ◽

Maria Battistoni ◽

Elena Menegola ◽

...

Keyword(s):

In Silico ◽

Adverse Outcome ◽

Adverse Outcome Pathway ◽

Vitro Data ◽

In Vitro Data

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Semen Cuscutae-Fructus Lycii improves spermatogenic dysfunction by repairing the blood-testis barrier in rats according to in silico and in vitro methods

Journal of Ethnopharmacology ◽

10.1016/j.jep.2021.114022 ◽

2021 ◽

pp. 114022

Author(s):

Yutian Zhu ◽

Lei Dong ◽

Jingshang Wang ◽

Qiuning Liu ◽

Hongxuan Tong ◽

...

Keyword(s):

In Silico ◽

In Vitro Methods ◽

Fructus Lycii ◽

Blood Testis Barrier

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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 ◽

10.3390/nano11010180 ◽

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.

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

Scientific Reports ◽

10.1038/srep21978 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 33

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.

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Synaptic Plasticity In Vitro and In Silico: Insights into an Intracellular Signaling Maze

Physiology ◽

10.1152/physiol.00009.2006 ◽

2006 ◽

Vol 21 (4) ◽

pp. 289-296 ◽

Cited By ~ 5

Author(s):

Sriram M. Ajay ◽

Upinder S. Bhalla

Keyword(s):

Experimental Data ◽

Synaptic Plasticity ◽

Neuronal Activity ◽

In Silico ◽

Intracellular Signaling ◽

Signaling Networks ◽

Functional Roles ◽

Current State ◽

History Of

Synaptic plasticity provides a record of neuronal activity and is a likely basis for memory. The early apparent simplicity of the process of synaptic plasticity has been lost in a flood of experimental data that now implicates some 200 signaling molecules in cellular memory. It is now clear that these signaling networks perform surprisingly sophisticated cellular decisions that weigh factors such as input patterns, location of stimulus, history of activity, and context. Computer models have followed experiments into this maze of molecular detail, often matching closely with their experimental counterparts, but perhaps losing simplicity in the process. Here, we suggest that the merger of models and experiment have begun to restore the earlier simplicity by outlining a few key functional roles for signaling networks in synaptic plasticity. In this review, we discuss the current state of understanding of synaptic plasticity in terms of models and experiments.

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