Exposure to Perfluoroalkyl Substances During Pregnancy and Fetal BDNF Level: A Prospective Cohort Study.
Yu Guoqi,Luo Fei,Nian Min,Li Shuman,Liu Bin,Feng Liping,Zhang Jun
Frontiers in endocrinology
Background:Humans are widely exposed to environmental perfluoroalkyl substances (PFAS), which may affect fetal neurodevelopment. Brain-derived neurotrophic factor (BDNF) is an important factor in neurodevelopment, but its role in PFAS-induced neurotoxicity is unclear. We investigated the association between prenatal PFAS exposure and fetal BDNF level in the umbilical cord blood in a large prospective cohort. Methods:A total of 725 pregnant women who participated in the Shanghai Birth Cohort were included. 10 PFAS were measured by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples of early pregnancy. The BDNF level was determined by ELISA. The concentration of total mercury (Hg) in the umbilical cord blood was tested by cold vapor atomic absorption spectrometry (AAS) and included as a main confounder, along with other covariates. Multiple linear regression was used to explore the associations between PFAS concentrations and BDNF level. Quantile-based g-computation was applied to explore the joint and independent effects of PFAS on BDNF level. Results:The mean BDNF level in the total population was 10797 (±4713) pg/ml. Male fetuses had a higher level than female fetuses (<0.001). A significant positive association was observed between PFHxS and BDNF level after adjusting for potential confounders [β=1285 (95% CI: 453, 2118, =0.003)]. No association was observed between other PFAS congeners and BDNF level. Results of the mixed exposure model showed that the joint effects of PFAS mixture were not associated with BDNF [β=447 (95% CI: -83, 978, =0.10)], while the positive association with PFHxS exposure remained significant after controlling for other PFAS [β=592 (95% CI: 226, 958, =0.002)]. The above associations were more prominent in male [β=773 (95% CI: 25, 1520, = 0.04)] than female fetuses [β=105 (95% CI: -791, 1002, = 0.82)] for the mixed effects. Conclusions:Prenatal exposure to PFHxS was associated with an increased BDNF level in the umbilical blood, especially in male fetuses.
10.3389/fendo.2021.653095
From Qualitative to Quantitative AOP: A Case Study of Neurodegeneration.
Frontiers in toxicology
Adverse outcome pathways (AOPs) include a sequence of events that connect a molecular-level initiating event with an adverse outcome at the cellular level for human health endpoints, or at the population level for ecological endpoints. When there is enough quantitative understanding of the relationships between key events in an AOP, a mathematical model may be developed to connect key events in a quantitative AOP (qAOP). Ideally, a qAOP will reduce the time and resources spent for chemical toxicity testing and risk assessment and enable the extrapolation of data collected at the molecular-level by assays, for example, to predict whether an adverse outcome may occur. Here, we review AOPs in the AOPWiki, an AOP repository, to determine best practices that would facilitate conversion from AOP to qAOP. Then, focusing on a particular case study, acetylcholinesterase inhibition leading to neurodegeneration, we describe specific methods and challenges. Examples of challenges include the availability and collection of quantitative data amenable to model development, the lack of studies that measure multiple key events, and model accessibility or transferability across platforms. We conclude with recommendations for improving key event and key event relationship descriptions in the AOPWiki that facilitate the transition of qualitative AOPs to qAOPs.
10.3389/ftox.2022.838729
Providing Biological Plausibility for Exposure-Health Relationships for the Mycotoxins Deoxynivalenol (DON) and Fumonisin B1 (FB1) in Humans Using the AOP Framework.
Toxins
Humans are chronically exposed to the mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1), as indicated by their widespread presence in foods and occasional exposure in the workplace. This exposure is confirmed by human biomonitoring (HBM) studies on (metabolites of) these mycotoxins in human matrices. We evaluated the exposure-health relationship of the mycotoxins in humans by reviewing the available literature. Since human studies did not allow the identification of unequivocal chronic health effects upon exposure to DON and FB1, the adverse outcome pathway (AOP) framework was used to structure additional mechanistic evidence from in vitro and animal studies on the identified adverse effects. In addition to a preliminary AOP for DON resulting in the adverse outcome (AO) 'reduced body weight gain', we developed a more elaborated AOP for FB1, from the molecular initiating event (MIE) 'inhibition of ceramide synthases' leading to the AO 'neural tube defects'. The mechanistic evidence from AOPs can be used to support the limited evidence from human studies, to focus FB1- and DON-related research in humans to identify related early biomarkers of effect. In order to establish additional human exposure-health relationships in the future, recommendations are given to maximize the information that can be obtained from HBM.
10.3390/toxins14040279
Linking Bisphenol S to Adverse Outcome Pathways Using a Combined Text Mining and Systems Biology Approach.
Carvaillo Jean-Charles,Barouki Robert,Coumoul Xavier,Audouze Karine
Environmental health perspectives
BACKGROUND:Available toxicity data can be optimally interpreted if they are integrated using computational approaches such as systems biology modeling. Such approaches are particularly warranted in cases where regulatory decisions have to be made rapidly. OBJECTIVES:The study aims at developing and applying a new integrative computational strategy to identify associations between bisphenol S (BPS), a substitute for bisphenol A (BPA), and components of adverse outcome pathways (AOPs). METHODS:The proposed approach combines a text mining (TM) procedure and integrative systems biology to comprehensively analyze the scientific literature to enrich AOPs related to environmental stressors. First, to identify relevant associations between BPS and different AOP components, a list of abstracts was screened using the developed text-mining tool AOP-helpFinder, which calculates scores based on the graph theory to prioritize the findings. Then, to fill gaps between BPS, biological events, and adverse outcomes (AOs), a systems biology approach was used to integrate information from the AOP-Wiki and ToxCast databases, followed by manual curation of the relevant publications. RESULTS:Links between BPS and 48 AOP key events (KEs) were identified and scored via 31 references. The main outcomes were related to reproductive health, endocrine disruption, impairments of metabolism, and obesity. We then explicitly analyzed co-mention of the terms BPS and obesity by data integration and manual curation of the full text of the publications. Several molecular and cellular pathways were identified, which allowed the proposal of a biological explanation for the association between BPS and obesity. CONCLUSIONS:By analyzing dispersed information from the literature and databases, our novel approach can identify links between stressors and AOP KEs. The findings associating BPS and obesity illustrate the use of computational tools in predictive toxicology and highlight the relevance of the approach to decision makers assessing substituents to toxic chemicals. https://doi.org/10.1289/EHP4200.
10.1289/EHP4200
AOP-DB: A database resource for the exploration of Adverse Outcome Pathways through integrated association networks.
Pittman Maureen E,Edwards Stephen W,Ives Cataia,Mortensen Holly M
Toxicology and applied pharmacology
The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability to, automatically and on a large scale, integrate AOP knowledge with publically available sources of biological high-throughput data and its derived associations. To support the discovery and development of putative (existing) and potential AOPs, we introduce the AOP-DB, an exploratory database resource that aggregates association relationships between genes and their related chemicals, diseases, pathways, species orthology information, ontologies, and gene interactions. These associations are mined from publically available annotation databases and are integrated with the AOP information centralized in the AOP-Wiki, allowing for the automatic characterization of both putative and potential AOPs in the context of multiple areas of biological information, referred to here as "biological entities". The AOP-DB acts as a hypothesis-generation tool for the expansion of putative AOPs, as well as the characterization of potential AOPs, through the creation of association networks across these biological entities. Finally, the AOP-DB provides a useful interface between the AOP framework and existing chemical screening and prioritization efforts by the US Environmental Protection Agency.
10.1016/j.taap.2018.02.006
AOP4EUpest: mapping of pesticides in adverse outcome pathways using a text mining tool.
Jornod Florence,Rugard Marylène,Tamisier Luc,Coumoul Xavier,Andersen Helle R,Barouki Robert,Audouze Karine
Bioinformatics (Oxford, England)
MOTIVATION:Exposure to pesticides may lead to adverse health effects in human populations, in particular vulnerable groups. The main long-term health concerns are neurodevelopmental disorders, carcinogenicity as well as endocrine disruption possibly leading to reproductive and metabolic disorders. Adverse outcome pathways (AOP) consist in linear representations of mechanistic perturbations at different levels of the biological organization. Although AOPs are chemical-agnostic, they can provide a better understanding of the Mode of Action of pesticides and can support a rational identification of effect markers. RESULTS:With the increasing amount of scientific literature and the development of biological databases, investigation of putative links between pesticides, from various chemical groups and AOPs using the biological events present in the AOP-Wiki database is now feasible. To identify co-occurrence between a specific pesticide and a biological event in scientific abstracts from the PubMed database, we used an updated version of the artificial intelligence-based AOP-helpFinder tool. This allowed us to decipher multiple links between the studied substances and molecular initiating events, key events and adverse outcomes. These results were collected, structured and presented in a web application named AOP4EUpest that can support regulatory assessment of the prioritized pesticides and trigger new epidemiological and experimental studies. AVAILABILITY AND IMPLEMENTATION:http://www.biomedicale.parisdescartes.fr/aop4EUpest/home.php. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.
10.1093/bioinformatics/btaa545
Linking Mitochondrial Dysfunction to Organismal and Population Health in the Context of Environmental Pollutants: Progress and Considerations for Mitochondrial Adverse Outcome Pathways.
Dreier David A,Mello Danielle F,Meyer Joel N,Martyniuk Christopher J
Environmental toxicology and chemistry
Mitochondria are key targets of many environmental contaminants, because specific chemicals can interact directly with mitochondrial proteins, lipids, and ribonucleic acids. These direct interactions serve as molecular initiating events that impede adenosine triphosphate production and other critical functions that mitochondria serve within the cell (e.g., calcium and metal homeostasis, apoptosis, immune signaling, redox balance). A limited but growing number of adverse outcome pathways (AOPs) have been proposed to associate mitochondrial dysfunction with effects at organismal and population levels. These pathways involve key events such as altered membrane potential, mitochondrial fission/fusion, and mitochondrial DNA damage, among others. The present critical review and analysis reveals current progress on AOPs involving mitochondrial dysfunction, and, using a network-based computational approach, identifies the localization of mitochondrial molecular initiating events and key events within multiple existing AOPs. We also present 2 case studies, the first examining the interaction between mitochondria and immunotoxicity, and the second examining the role of early mitochondrial dysfunction in the context of behavior (i.e., locomotor activity). We discuss limitations in our current understanding of mitochondrial AOPs and highlight opportunities for clarifying their details. Advancing our knowledge of key event relationships within the AOP framework will require high-throughput datasets that permit the development and testing of chemical-agnostic AOPs, as well as high-resolution research that will enhance the mechanistic testing and validation of these key event relationships. Given the wide range of chemicals that affect mitochondria, and the centrality of energy production and signaling to ecologically important outcomes such as pathogen defense, homeostasis, growth, and reproduction, a better understanding of mitochondrial AOPs is expected to play a significant, if not central, role in environmental toxicology. Environ Toxicol Chem 2019;38:1625-1634. © 2019 SETAC.
10.1002/etc.4453
Towards a systematic use of effect biomarkers in population and occupational biomonitoring.
Zare Jeddi Maryam,Hopf Nancy B,Viegas Susana,Price Anna Bal,Paini Alicia,van Thriel Christoph,Benfenati Emilio,Ndaw Sophie,Bessems Jos,Behnisch Peter A,Leng Gabriele,Duca Radu-Corneliu,Verhagen Hans,Cubadda Francesco,Brennan Lorraine,Ali Imran,David Arthur,Mustieles Vicente,Fernandez Mariana F,Louro Henriqueta,Pasanen-Kase Robert
Environment international
Effect biomarkers can be used to elucidate relationships between exposure to environmental chemicals and their mixtures with associated health outcomes, but they are often underused, as underlying biological mechanisms are not understood. We aim to provide an overview of available effect biomarkers for monitoring chemical exposures in the general and occupational populations, and highlight their potential in monitoring humans exposed to chemical mixtures. We also discuss the role of the adverse outcome pathway (AOP) framework and physiologically based kinetic and dynamic (PBK/D) modelling to strengthen the understanding of the biological mechanism of effect biomarkers, and in particular for use in regulatory risk assessments. An interdisciplinary network of experts from the European chapter of the International Society for Exposure Science (ISES Europe) and the Organization for Economic Co-operation and Development (OECD) Occupational Biomonitoring activity of Working Parties of Hazard and Exposure Assessment group worked together to map the conventional framework of biomarkers and provided recommendations for their systematic use. We summarized the key aspects of this work here, and discussed these in three parts. Part I, we inventory available effect biomarkers and promising new biomarkers for the general population based on the H2020 Human Biomonitoring for Europe (HBM4EU) initiative. Part II, we provide an overview AOP and PBK/D modelling use that improved the selection and interpretation of effect biomarkers. Part III, we describe the collected expertise from the OECD Occupational Biomonitoring subtask effect biomarkers in prioritizing relevant mode of actions (MoAs) and suitable effect biomarkers. Furthermore, we propose a tiered risk assessment approach for occupational biomonitoring. Several effect biomarkers, especially for use in occupational settings, are validated. They offer a direct assessment of the overall health risks associated with exposure to chemicals, chemical mixtures and their transformation products. Promising novel effect biomarkers are emerging for biomonitoring of the general population. Efforts are being dedicated to prioritizing molecular and biochemical effect biomarkers that can provide a causal link in exposure-health outcome associations. This mechanistic approach has great potential in improving human health risk assessment. New techniques such as in silico methods (e.g. QSAR, PBK/D modelling) as well as 'omics data will aid this process. Our multidisciplinary review represents a starting point for enhancing the identification of effect biomarkers and their mechanistic pathways following the AOP framework. This may help in prioritizing the effect biomarker implementation as well as defining threshold limits for chemical mixtures in a more structured way. Several ex vivo biomarkers have been proposed to evaluate combined effects including genotoxicity and xeno-estrogenicity. There is a regulatory need to derive effect-based trigger values using the increasing mechanistic knowledge coming from the AOP framework to address adverse health effects due to exposure to chemical mixtures. Such a mechanistic strategy would reduce the fragmentation observed in different regulations. It could also stimulate a harmonized use of effect biomarkers in a more comparable way, in particular for risk assessments to chemical mixtures.
10.1016/j.envint.2020.106257
Gene Expression Thresholds Derived From Short-term Exposures Identify Rat Liver Tumorigens.
Hill Thomas,Rooney John,Abedini Jaleh,El-Masri Hisham,Wood Charles E,Corton J Christopher
Toxicological sciences : an official journal of the Society of Toxicology
Traditional methods for cancer risk assessment are resource-intensive, retrospective, and not feasible for the vast majority of environmental chemicals. In this study, we investigated whether quantitative genomic data from short-term studies may be used to set protective thresholds for potential tumorigenic effects. We hypothesized that gene expression biomarkers measuring activation of the key early events in established pathways for rodent liver cancer exhibit cross-chemical thresholds for tumorigenesis predictive for liver cancer risk. We defined biomarker thresholds for 6 major liver cancer pathways using training sets of chemicals with short-term genomic data (3-29 days of exposure) from the TG-GATES (n = 77 chemicals) and DrugMatrix (n = 86 chemicals) databases and then tested these thresholds within and between datasets. The 6 pathway biomarkers represented genotoxicity, cytotoxicity, and activation of xenobiotic, steroid, and lipid receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Thresholds were calculated as the maximum values derived from exposures without detectable liver tumor outcomes. We identified clear response values that were consistent across training and test sets. Thresholds derived from the TG-GATES training set were highly predictive (97%) in a test set of independent chemicals, whereas thresholds derived from the DrugMatrix study were 96%-97% predictive for the TG-GATES study. Threshold values derived from an abridged gene list (2/biomarker) also exhibited high predictive accuracy (91%-94%). These findings support the idea that early genomic changes can be used to establish threshold estimates or "molecular tipping points" that are predictive of later-life health outcomes.
10.1093/toxsci/kfaa102
A toxicity pathway-oriented approach to develop adverse outcome pathway: AHR activation as a case study.
Jin Yuan,Feng Meiyao,Ma Wanli,Wei Yanhong,Qi Guangshuai,Luo Jiao,Xu Lin,Li Xinmei,Li Chuanhai,Wang Ying,Li Daochuan,Chen Jing,Zhao Yanjie,Hou Yufei,Zhao Qianwen,Jiang Lidan,Xie Mengyue,Zheng Yuxin,Yu Dianke
Environmental pollution (Barking, Essex : 1987)
With numerous new chemicals introduced into the environment everyday, identification of their potential hazards to the environment and human health is a considerable challenge. Developing adverse outcome pathway (AOP) framework is promising in helping to achieve this goal as it can bring In Vitro testing into toxicity measurement and understanding. To explore the toxic mechanism underlying environmental chemicals via the AOP approach, an integration of adequate experimental data with systems biology understanding is preferred. Here, we describe a novel method to develop reliable and sensible AOPs that relies on chemical-gene interactions, toxicity pathways, molecular regulations, phenotypes, and outcomes information obtained from comparative toxicogenomics database (CTD) and Ingenuity Pathway Analysis (IPA). Using Benzo(a)pyrene (BaP), a highly studied chemical as a stressor, we identified the pivotal IPA toxicity pathways, the molecular initiating event (MIE), and candidate key events (KEs) to structure AOPs in the liver and lung, respectively. Further, we used the corresponding CTD information of multiple typical AHR-ligands, including 2,3,7,8-tetrachlorodibenzoparadioxin (TCDD), valproic acid, quercetin, and particulate matter, to validate our AOP networks. Our approach is likely to speed up AOP development as providing a time- and cost-efficient way to collect all fragmented bioinformation in published studies. It also facilitates a better understanding of the toxic mechanism of environmental chemicals, and potentially brings new insights into the screening of critical paths in the AOP network.
10.1016/j.envpol.2020.115733
AOPERA: A proposed methodology and inventory of effective tools to link chemicals to adverse outcome pathways.
Rycroft Taylor E,Foran Christy M,Thrash Adam,Cegan Jeffrey C,Zollinger Robert,Linkov Igor,Perkins Edward J,Garcia-Reyero Natàlia
ALTEX
New approaches, like the Adverse Outcome Pathway (AOP) framework, have been developed to describe how chemicals cause toxicity by linking in vitro assays to adverse health outcomes. However, approaches, tools and resources for development of AOPs have not been well described. Here we review information resources for AOP development and define a streamlined process for linking a chemical to an existing AOP. We propose a four step process to facilitate AOP development: link the uncharacterized chemical directly to Molecular Initiating Events, Key Events, or Adverse Outcomes; identify analogs with toxicological information for the uncharacterized chemical; link the characterized chemical (initial chemical if characterized, a characterized analog if initial chemical is not) to Molecular Initiating Events, Key Events, or Adverse Outcomes; and identify AOPs that contain the Molecular Initiating Events, Key Events, or Adverse Outcomes that were found in Steps 1 and 3. The process and library of informational resources proposed and tested here served as the foundation for an informational online tool (AOPERA) that helps practitioners identify their current-state knowledge gaps, navigate the four-step process, and connect to relevant resources. AOPERA can be found at https://igbb.github.io/AOPERA_HTML. Additionally, we anticipate that by simplifying and standardizing the process of linking a chemical to a known AOP, we will lower the barrier to entry for this objective and increase its accessibility to new practitioners. In turn, this may increase the demand for new or improved AOPs to which practitioners can link chemicals, thereby contributing to the expansion of the library of known AOPs.
10.14573/altex.1906201
A Set of Six Gene Expression Biomarkers Identify Rat Liver Tumorigens in Short-term Assays.
Toxicological sciences : an official journal of the Society of Toxicology
Chemical-induced liver cancer occurs in rodents through well-characterized adverse outcome pathways. We hypothesized that measurement of the 6 most common molecular initiating events (MIEs) in liver cancer adverse outcome pathways in short-term assays using only gene expression will allow early identification of chemicals and their associated doses that are likely to be tumorigenic in the liver in 2-year bioassays. We tested this hypothesis using transcript data from a rat liver microarray compendium consisting of 2013 comparisons of 146 chemicals administered at doses with previously established effects on rat liver tumor induction. Five MIEs were measured using previously characterized gene expression biomarkers composed of gene sets predictive for genotoxicity and activation of 1 or more xenobiotic receptors (aryl hydrocarbon receptor, constitutive activated receptor, estrogen receptor, and peroxisome proliferator-activated receptor α). Because chronic injury can be important in tumorigenesis, we also developed a biomarker for cytotoxicity that had a 96% balanced accuracy. Characterization of the genes in each biomarker set using the unsupervised TXG-MAP network model demonstrated that the genes were associated with distinct functional coexpression modules. Using the Toxicological Priority Index to rank chemicals based on their ability to activate the MIEs showed that chemicals administered at tumorigenic doses clearly gave the highest ranked scores. Balanced accuracies using thresholds derived from either TG-GATES or DrugMatrix data sets to predict tumorigenicity in independent sets of chemicals were up to 93%. These results show that a MIE-directed approach using only gene expression biomarkers could be used in short-term assays to identify chemicals and their doses that cause tumors.
10.1093/toxsci/kfaa101
Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds.
Wheeldon Ryan P,Bernacki Derek T,Dertinger Stephen D,Bryce Steven M,Bemis Jeffrey C,Johnson George E
Environmental and molecular mutagenesis
Genetic toxicology data have traditionally been utilized for hazard identification to provide a binary call for a compound's risk. Recent advances in the scientific field, especially with the development of high-throughput methods to quantify DNA damage, have influenced a change of approach in genotoxicity assessment. The in vitro MultiFlow® DNA Damage Assay is one such method which multiplexes γH2AX, p53, phospho-histone H3 biomarkers into a single-flow cytometric analysis (Bryce et al., [2016]: Environ Mol Mutagen 57:546-558). This assay was used to study human TK6 cells exposed to each of eight topoisomerase II poisons for 4 and 24 hr. Using PROAST v65.5, the Benchmark Dose approach was applied to the resulting flow cytometric datasets. With "compound" serving as covariate, all eight compounds were combined into a single analysis, per time point and endpoint. The resulting 90% confidence intervals, plotted in Log scale, were considered as the potency rank for the eight compounds. The in vitro MultiFlow data showed a maximum confidence interval span of 1Log, which indicates data of good quality. Patterns observed in the compound potency rank were scrutinized by using the expert rule-based software program Derek Nexus, developed by Lhasa Limited. Compound sub-classification and structural alerts were considered contributory to the potencies observed for the topoisomerase II poisons studied herein. The Topo II poison Adverse Outcome Pathway was evaluated with MultiFlow endpoints serving as Key Events. The step-wise approach described herein can be considered as a foundation for risk assessment of compounds within a specific mode of action of interest. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.
10.1002/em.22360
Adverse outcome pathway-driven identification of rat liver tumorigens in short-term assays.
Rooney John,Hill Thomas,Qin Chunhua,Sistare Frank D,Corton J Christopher
Toxicology and applied pharmacology
Chemicals induce liver cancer in rodents through well characterized adverse outcome pathways (AOPs). We hypothesized that measurement of molecular initiating events (MIEs) and downstream key events (KEs) in liver cancer AOPs in short-term assays will allow early identification of chemicals and their associated doses that are likely to be tumorigenic in the liver in two-year bioassays. We tested this hypothesis using the rat in vivo TG-GATES study data to measure MIEs (genotoxicity, cytotoxicity, AhR, CAR, ER, PPARα) and associated KEs (oxidative stress, cell proliferation, liver to body weights) across 77 chemicals that could be linked to doses with previously established effects on rat liver tumor induction. Gene expression biomarkers for MIEs generally considered to be rodent specific and human irrelevant (CAR, PPARα) and for MIEs that would be considered of greater risk at human relevant exposures (ER, AhR) were built using microarray comparisons from the livers of rats treated with prototypical activators of the receptors. The genotoxicity biomarker, also a potentially human relevant MIE, was comprised of 7 p53-responsive genes known to be induced upon DNA damage. The ability of the biomarkers to accurately predict MIE activation ranged from 91% to 98%. The Toxicological Priority Index (ToxPi) was used to rank chemicals based on their ability to activate MIEs/KEs. Chemicals administered at tumorigenic doses clearly gave the highest ranked scores. Our AOP-directed approach could be used in short term assays to identify chemicals and their doses that would be predicted to cause liver tumors in rats.
10.1016/j.taap.2018.07.023
Application of the adverse outcome pathway framework to genotoxic modes of action.
Sasaki Jennifer C,Allemang Ashley,Bryce Steven M,Custer Laura,Dearfield Kerry L,Dietz Yasmin,Elhajouji Azeddine,Escobar Patricia A,Fornace Albert J,Froetschl Roland,Galloway Sheila,Hemmann Ulrike,Hendriks Giel,Li Heng-Hong,Luijten Mirjam,Ouedraogo Gladys,Peel Lauren,Pfuhler Stefan,Roberts Daniel J,Thybaud Véronique,van Benthem Jan,Yauk Carole L,Schuler Maik
Environmental and molecular mutagenesis
In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114-134, 2020. © 2019 Wiley Periodicals, Inc.
10.1002/em.22339
The role of ethyl acrylate induced GSH depletion in the rodent forestomach and its impact on MTD and in vivo genotoxicity in developing an adverse outcome pathway (AOP).
Ellis-Hutchings R,Giuliani J,Hayashi M,Masumori S,McClymont E L,Murphy S,Wiench K
Regulatory toxicology and pharmacology : RTP
Adverse outcome pathways (AOP) and mode of action (MOA) frameworks help evaluate the toxicity findings of animal studies and their relevance to humans. To effectively use these tools to improve hazard identification and risk assessments for ethyl acrylate (EA), knowledge gaps in metabolism and genotoxicity were identified and addressed. For EA, hypothesized early key events relate to its irritation potential: concentration dependent irritation and cytotoxicity, progressing to regenerative proliferation and forestomach carcinogenicity after repeated oral bolus application in rodents. The current research quantitated glutathione (GSH) depletion to assess a kinetically-derived maximum tolerated dose (MTD) in the target tissue and used this information to conduct an in vivo genotoxicity study using current methods. In the mouse forestomach, gavage doses of EA caused GSH depletion to 47% of control at 20 mg/kg and 28% at 100 mg/kg. Cellular redox changes and histopathology support saturation of metabolism and an MTD of ∼50 mg/kg. No increases in point mutations or deletions occurred in the stomach or liver following a 28 day treatment of gpt delta transgenic mice at gavage doses up to 50 mg/kg/day. These results provide valuable information for evaluating AOP molecular initiating events or MOA key events for EA and other GSH depleting materials.
10.1016/j.yrtph.2017.11.012
A strategy to validate a selection of human effect biomarkers using adverse outcome pathways: Proof of concept for phthalates and reproductive effects.
Baken Kirsten A,Lambrechts Nathalie,Remy Sylvie,Mustieles Vicente,Rodríguez-Carrillo Andrea,Neophytou Christiana M,Olea Nicolas,Schoeters Greet
Environmental research
Human biomonitoring measures the concentrations of environmental chemicals or their metabolites in body fluids or tissues. Complementing exposure biomarkers with mechanistically based effect biomarkers may further elucidate causal pathways between chemical exposure and adverse health outcomes. We combined information on effect biomarkers previously implemented in human observational studies with mechanisms of action reported in experimental studies and with information from published Adverse Outcome Pathways (AOPs), focusing on adverse reproductive effects of phthalate exposure. Phthalates constitute a group of chemicals that are ubiquitous in consumer products and have been related to a wide range of adverse health effects. As a result of a comprehensive literature search, we present an overview of effect biomarkers for reproductive toxicity that are substantiated by mechanistic information. The activation of several receptors, such as PPARα, PPARγ, and GR, may initiate events leading to impaired male and female fertility as well as other adverse effects of phthalate exposure. Therefore, these receptors appear as promising targets for the development of novel effect biomarkers. The proposed strategy connects the fields of epidemiology and toxicology and may strengthen the weight of evidence in observational studies that link chemical exposures to health outcomes.
10.1016/j.envres.2019.05.013
Semantic characterization of adverse outcome pathways.
Wang Rong-Lin
Aquatic toxicology (Amsterdam, Netherlands)
This study was undertaken to systematically assess the utilities and performance of ontology-based semantic analysis in adverse outcome pathway (AOP) research. With an increasing number of AOPs developed by scientific domain experts to organize toxicity information and facilitate chemical risk assessment, there is a pressing need for objective approaches to evaluate the biological coherence and quality of these AOPs. Powered by ontologies covering a wide range of biological domains, abundant phenotypic data annotated ontologically, and some sophisticated knowledge computing tools, semantic analysis has great potential in this area of application. With the events in the AOP-Wiki first annotated into logical definitions and then grouped into phenotypic profiles by individual AOPs, the coherence and quality of AOPs were assessed at several levels: paired key event relationships (KER), all possible event pair combinations within AOPs, and the phenotypic profiles of AOPs, genes, biological pathways, human diseases, and selected chemicals. The semantic similarities were assessed at all these levels based on a unified cross-species vertebrate phenotype ontology encompassing the logical definitions of AOP events as well as many other domain ontologies. A substantial number of KERs and AOPs in the AOP-Wiki were found to be semantically coherent. These same coherent AOPs also mapped to many more genes, pathways, and diseases biologically aligned with the intended chain of events therein leading to their respective adverse outcomes. Significantly, these findings imply that semantic analysis should also have utilities in developing future AOPs by selecting candidate events from either the existing AOP-Wiki events or a broader collection of ontology terms semantically similar to the molecular initiating events or adverse outcomes of interest. In addition, semantic analysis enabled AOP networks to be constructed at the level of phenotypic profiles based on similarities, complementing those based on event sharing by bringing genes, pathways, diseases, and chemicals into the networks too-thus greatly expanding the biological scope and our understanding of AOPs.
10.1016/j.aquatox.2020.105478
The potential connections of adverse outcome pathways with the hazard identifications of typical organophosphate esters based on toxicity mechanisms.
Yan Zhenfei,Jin Xiaowei,Liu Daqing,Hong Yajun,Liao Wei,Feng Chenglian,Bai Yingchen
Chemosphere
Following the world-wide ban of brominated flame retardants (BFRs), organophosphate esters (OPEs), which could potentially affect human health and ecosystem safety, have been frequently detected in various environmental media. However, the knowledge regarding the underlying toxicity effects of OPEs remains limited. In order to address these issues, this study reviewed the related reports which have been published in recent years. This analysis process included 12 OPEs, 10 model organisms, and 15 cell lines, which were used to systematically examine the mechanisms of endocrine disruption, neurotoxicity, hepatotoxicity, and cardiotoxicity, as well as reproductive and developmental toxicity. Subsequently, an adverse outcome pathway (AOP) framework of the toxicological effects of OPEs was built. The results demonstrated that multiple different pathways may lead to a single same adverse outcome (AO), and there was a certain degree of correlation among the different AOs. It was found that among all the 12 OPEs, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) may potentially be the most toxic. In addition, rather than the parent chemicals, the metabolites of OPEs may also have different degrees of toxicity effects on aquatic organisms and humans. Overall, the results of the present study also suggested that an AOP framework should be built via fully utilizing the existing toxicity data of OPEs based on in vivo-in vitro-in silico to completely and deeply understand the toxic mechanisms of OPEs. This improved knowledge could then provide a theoretical basis for ecological risk assessments and water quality criteria research in the near future.
10.1016/j.chemosphere.2020.128989
Organizing mechanism-related information on chemical interactions using a framework based on the aggregate exposure and adverse outcome pathways.
Price Paul S,Jarabek Annie M,Burgoon Lyle D
Environment international
This paper presents a framework for organizing and accessing mechanistic data on chemical interactions. The framework is designed to support the assessment of risks from combined chemical exposures. The framework covers interactions between chemicals that occur over the entire source-to-outcome continuum including interactions that are studied in the fields of chemical transport, environmental fate, exposure assessment, dosimetry, and individual and population-based adverse outcomes. The framework proposes to organize data using a semantic triple of a chemical (subject), has impact (predicate), and a causal event on the source-to-outcome continuum of a second chemical (object). The location of the causal event on the source-to-outcome continuum and the nature of the impact are used as the basis for a taxonomy of interactions. The approach also builds on concepts from the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP). The framework proposes the linking of AEPs of multiple chemicals and the AOP networks relevant to those chemicals to form AEP-AOP networks that describe chemical interactions that cannot be characterized using AOP networks alone. Such AEP-AOP networks will aid the construction of workflows for both experimental design and the systematic review or evaluation performed in risk assessments. Finally, the framework is used to link the constructs of existing component-based approaches for mixture toxicology to specific categories in the interaction taxonomy.
10.1016/j.envint.2020.105673
Applying evidence-based methods to the development and use of adverse outcome pathways
ALTEX
The workshop “Application of evidence-based methods to construct mechanistic frameworks for the development and use of non-animal toxicity tests” was organized by the Evidence-based Toxicology Collaboration and hosted by the Grading of Recommendations Assessment, Development and Evaluation Working Group on June 12, 2019. The purpose of the workshop was to bring together international regulatory bodies, risk assessors, academic scientists, and industry to explore how systematic review methods and the adverse outcome pathway framework could be combined to develop and use mechanistic test methods for predicting the toxicity of chemical substances in an evidence-based manner. The meeting covered the history of biological frameworks, the way adverse outcome pathways are currently developed, the basic principles of systematic methodology, including systematic reviews and evidence maps, and assessment of certainty in models, and adverse outcome pathways in particular. Specific topics were discussed via case studies in small break-out groups. The group concluded that adverse outcome pathways provide an important framework to support mechanism-based assessment in environmental health. The process of their development has a few challenges that could be addressed with systematic methods and automation tools. Addressing these challenges will increase the transparency of the evidence behind adverse outcome pathways and the consistency with which they are defined; this in turn will increase their value for supporting public health decisions. It was suggested to explore the details of applying systematic methods to adverse outcome pathway development in a series of case studies and workshops.
10.14573/altex.2101211
The use of adverse outcome pathways in the safety evaluation of food additives.
Vinken Mathieu,Kramer Nynke,Allen Timothy E H,Hoffmans Yvette,Thatcher Natalie,Levorato Sara,Traussnig Heinz,Schulte Stefan,Boobis Alan,Thiel Anette,Rietjens Ivonne M C M
Archives of toxicology
In the last decade, adverse outcome pathways have been introduced in the fields of toxicology and risk assessment of chemicals as pragmatic tools with broad application potential. While their use in the pharmaceutical and cosmetics sectors has been well documented, their application in the food area remains largely unexplored. In this respect, an expert group of the International Life Sciences Institute Europe has recently explored the use of adverse outcome pathways in the safety evaluation of food additives. A key activity was the organization of a workshop, gathering delegates from the regulatory, industrial and academic areas, to discuss the potentials and challenges related to the application of adverse outcome pathways in the safety assessment of food additives. The present paper describes the outcome of this workshop followed by a number of critical considerations and perspectives defined by the International Life Sciences Institute Europe expert group.
10.1007/s00204-020-02670-0