Application of text mining to develop AOP-based mucus hypersecretion genesets and confirmation with in vitro and clinical samples

AbstractMucus hypersecretion contributes to lung function impairment observed in COPD (chronic obstructive pulmonary disease), a tobacco smoking-related disease. A detailed mucus hypersecretion adverse outcome pathway (AOP) has been constructed from literature reviews, experimental and clinical data, mapping key events (KEs) across biological organisational hierarchy leading to an adverse outcome. AOPs can guide the development of biomarkers that are potentially predictive of diseases and support the assessment frameworks of nicotine products including electronic cigarettes. Here, we describe a method employing manual literature curation supported by a focused automated text mining approach to identify genes involved in 5 KEs contributing to decreased lung function observed in tobacco-related COPD. KE genesets were subsequently confirmed by unsupervised clustering against 3 different transcriptomic datasets including (1) in vitro acute cigarette smoke and e-cigarette aerosol exposure, (2) in vitro repeated incubation with IL-13, and (3) lung biopsies from COPD and healthy patients. The 5 KE genesets were demonstrated to be predictive of cigarette smoke exposure and mucus hypersecretion in vitro, and less conclusively predict the COPD status of lung biopsies. In conclusion, using a focused automated text mining and curation approach with experimental and clinical data supports the development of risk assessment strategies utilising AOPs.

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An Adverse Outcome Pathway for Decreased Lung Function Focusing on Mechanisms of Impaired Mucociliary Clearance Following Inhalation Exposure

Frontiers in Toxicology ◽

10.3389/ftox.2021.750254 ◽

2021 ◽

Vol 3 ◽

Author(s):

Karsta Luettich ◽

Monita Sharma ◽

Hasmik Yepiskoposyan ◽

Damien Breheny ◽

Frazer J. Lowe

Keyword(s):

Lung Function ◽

Mucociliary Clearance ◽

Adverse Outcome ◽

Beat Frequency ◽

Inhalation Exposure ◽

Ciliary Beat Frequency ◽

Immune Defense ◽

Adverse Outcome Pathway ◽

Functional Components

Adverse outcome pathways (AOPs) help to organize available mechanistic information related to an adverse outcome into key events (KEs) spanning all organizational levels of a biological system(s). AOPs, therefore, aid in the biological understanding of a particular pathogenesis and also help with linking exposures to eventual toxic effects. In the regulatory context, knowledge of disease mechanisms can help design testing strategies using in vitro methods that can measure or predict KEs relevant to the biological effect of interest. The AOP described here evaluates the major processes known to be involved in regulating efficient mucociliary clearance (MCC) following exposures causing oxidative stress. MCC is a key aspect of the innate immune defense against airborne pathogens and inhaled chemicals and is governed by the concerted action of its functional components, the cilia and airway surface liquid (ASL). The AOP network described here consists of sequences of KEs that culminate in the modulation of ciliary beat frequency and ASL height as well as mucus viscosity and hence, impairment of MCC, which in turn leads to decreased lung function.

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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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Application of an adverse outcome pathway-based in vitro testing battery for neurotoxicity evaluation

Toxicology Letters ◽

10.1016/s0378-4274(21)00370-2 ◽

2021 ◽

Vol 350 ◽

pp. S51

Author(s):

K. Koch ◽

M. Elgamal ◽

S. Masjosthusmann ◽

I. Lauria ◽

R Hartmann ◽

...

Keyword(s):

Adverse Outcome ◽

Adverse Outcome Pathway ◽

In Vitro Testing

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Adverse Outcome Pathway Development for Assessment of Lung Carcinogenicity by Nanoparticles

Frontiers in Toxicology ◽

10.3389/ftox.2021.653386 ◽

2021 ◽

Vol 3 ◽

Author(s):

Penny Nymark ◽

Hanna L. Karlsson ◽

Sabina Halappanavar ◽

Ulla Vogel

Keyword(s):

Lung Cancer ◽

Risk Assessment ◽

Adverse Outcome ◽

Animal Experiments ◽

Engineered Nanoparticles ◽

Alternative Methods ◽

Weight Of Evidence ◽

Adverse Outcome Pathway ◽

Alternative Mechanism

Lung cancer, one of the most common and deadly forms of cancer, is in some cases associated with exposure to certain types of particles. With the rise of nanotechnology, there is concern that some engineered nanoparticles may be among such particles. In the absence of epidemiological evidence, assessment of nanoparticle carcinogenicity is currently performed on a time-consuming case-by-case basis, relying mainly on animal experiments. Non-animal alternatives exist, including a few validated cell-based methods accepted for regulatory risk assessment of nanoparticles. Furthermore, new approach methodologies (NAMs), focused on carcinogenic mechanisms and capable of handling the increasing numbers of nanoparticles, have been developed. However, such alternative methods are mainly applied as weight-of-evidence linked to generally required animal data, since challenges remain regarding interpretation of the results. These challenges may be more easily overcome by the novel Adverse Outcome Pathway (AOP) framework, which provides a basis for validation and uptake of alternative mechanism-focused methods in risk assessment. Here, we propose an AOP for lung cancer induced by nanosized foreign matter, anchored to a selection of 18 standardized methods and NAMs for in silico- and in vitro-based integrated assessment of lung carcinogenicity. The potential for further refinement of the AOP and its components is discussed in relation to available nanosafety knowledge and data. Overall, this perspective provides a basis for development of AOP-aligned alternative methods-based integrated testing strategies for assessment of nanoparticle-induced lung cancer.

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Applying the adverse outcome pathway (AOP) for food sensitization to support in vitro testing strategies

Trends in Food Science & Technology ◽

10.1016/j.tifs.2019.01.014 ◽

2019 ◽

Vol 85 ◽

pp. 307-319 ◽

Cited By ~ 2

Author(s):

Daniel Lozano-Ojalvo ◽

Sara Benedé ◽

Celia M. Antunes ◽

Simona L. Bavaro ◽

Grégory Bouchaud ◽

...

Keyword(s):

Adverse Outcome ◽

Adverse Outcome Pathway ◽

In Vitro Testing ◽

Testing Strategies ◽

Food Sensitization ◽

In Vitro Testing Strategies

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Amelioration of Cigarette Smoke-Induced Mucus Hypersecretion and Viscosity by Dendrobium officinale Polysaccharides In Vitro and In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/8217642 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Rui Chen ◽

Yingmin Liang ◽

Mary Sau Man Ip ◽

Kalin Yanbo Zhang ◽

Judith Choi Wo Mak

Keyword(s):

Gene Expression ◽

Cigarette Smoke ◽

Secretory Granules ◽

Dendrobium Officinale ◽

In Vivo Models ◽

Mucus Hypersecretion ◽

Mucin Gene ◽

Starting Point

Chronic obstructive pulmonary disease (COPD), characterized by oxidative stress and inflammation, is one of the leading causes of death worldwide, in which cigarette smoke (CS) is the major risk factor. Dendrobium officinale polysaccharides (DOPs) are the main active ingredients extracted from Dendrobium officinale, which have been reported to have antioxidant and anti-inflammatory activity as well as inhibition of mucin gene expression. This study is aimed at investigating the effect of DOPs on CS-induced mucus hypersecretion and viscosity in vitro and in vivo. For in vitro study, primary normal human bronchial epithelial cells (HBECs) differentiated at the air-liquid interface (ALI) culture for 28 days were stimulated with cigarette smoke medium (CSM) in the absence or presence of various concentrations of DOPs or N-acetylcysteine (NAC) for 24 hours. For in vivo study, male Sprague-Dawley rats were randomized to sham air (SA) as control group or CS group for 56 days. At day 29, rats were subdivided and given water as control, DOPs, or NAC as positive control as a mucolytic drug via oral gavage for the remaining duration. Samples collected from apical washing, cell lysates, bronchoalveolar lavage (BAL), and lung tissues were evaluated for mucin gene expression, mucus secretion, and viscosity. DOPs ameliorated the CS-induced mucus hypersecretion and viscosity as shown by the downregulation of MUC5AC mRNA, MUC5AC secretary protein, and mucus viscosity via inhibition of mucus secretory granules in both in vitro and in vivo models. DOPs produced its effective effects on the CS-induced mucus hypersecretion and viscosity via the inhibition of the mucus secretory granules. These findings could be a starting point for considering the potential role of DOPs in the management of the smoking-mediated COPD. However, further research is needed.

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Omics-based in vitro verification of an adverse outcome pathway of cholestatic liver injury

Toxicology Letters ◽

10.1016/j.toxlet.2017.07.905 ◽

2017 ◽

Vol 280 ◽

pp. S254

Author(s):

Robim M. Rodrigues ◽

Laxmikanth Kollipara ◽

Umesh Chaudhari ◽

Agapios Sachinidis ◽

René P. Zahedi ◽

...

Keyword(s):

Liver Injury ◽

Adverse Outcome ◽

Adverse Outcome Pathway ◽

Cholestatic Liver Injury

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An adverse outcome pathway for lung surfactant function inhibition leading to decreased lung function

Current Research in Toxicology ◽

10.1016/j.crtox.2021.05.005 ◽

2021 ◽

Author(s):

Emilie Da Silva ◽

Ulla Vogel ◽

Karin S. Hougaard ◽

Jesus Pérez-Gil ◽

Yi Y. Zuo ◽

...

Keyword(s):

Lung Function ◽

Adverse Outcome ◽

Lung Surfactant ◽

Adverse Outcome Pathway

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

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa001 ◽

2020 ◽

Vol 26 (2) ◽

pp. 111-116 ◽

Cited By ~ 3

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.

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