An integral perspective of canonical cigarette and e-cigarette-related cardiovascular toxicity based on the adverse outcome pathway framework.
Journal of advanced research
BACKGROUND:Nowadays, cigarette smoking remains the leading cause of chronic disease and premature death, especially cardiovascular disease. As an emerging tobacco product, e-cigarettes have been advocated as alternatives to canonical cigarettes, and thus may be an aid to promote smoking cessation. However, recent studies indicated that e-cigarettes should not be completely harmless to the cardiovascular system. AIM OF REVIEW:This review aimed to build up an integral perspective of cigarettes and e-cigarettes-related cardiovascular toxicity. KEY SCIENTIFIC CONCEPTS OF REVIEW:This review adopted the adverse outcome pathway (AOP) framework as a pivotal tool and aimed to elucidate the association between the molecular initiating events (MIEs) induced by cigarette and e-cigarette exposure to the cardiovascular adverse outcome. Since the excessive generation of reactive oxygen species (ROS) has been widely approved to play a critical role in cigarette smoke-related CVD and may also be involved in e-cigarette-induced toxic effects, the ROS overproduction and subsequent oxidative stress are regarded as essential parts of this framework. As far as we know, this should be the first AOP framework focusing on cigarette and e-cigarette-related cardiovascular toxicity, and we hope our work to be a guide in exploring the biomarkers and novel therapies for cardiovascular injury.
10.1016/j.jare.2022.08.012
Adverse outcome pathway of fine particulate matter leading to increased cardiovascular morbidity and mortality: An integrated perspective from toxicology and epidemiology.
Yu Yang,Sun Qinglin,Li Tianyu,Ren Xiaoke,Lin Lisen,Sun Mengqi,Duan Junchao,Sun Zhiwei
Journal of hazardous materials
Fine particulate matter (PM) exposure is a major threat to public health, and is listed as one of the leading factors associated with global premature mortality. Among the adverse health effects on multiple organs or tissues, the influence of PM exposure on cardiovascular system has drawn more and more attention. Although numerous studies have investigated the mechanisms responsible for the cardiovascular toxicity of PM, the various mechanisms have not been integrated due to the variety of the study models, different levels of toxicity assessment endpoints, etc. Adverse Outcome Pathway (AOP) framework is a useful tool to achieve this goal so as to facilitate comprehensive understanding of toxicity assessment of PM on cardiovascular system. This review aims to illustrate the causal mechanistic relationships of PM-triggered cardiovascular toxicity from different levels (from molecular/cellular/organ to individual/population) by using AOP framework. Based on the AOP Wiki and published literature, we propose an AOP framework focusing on the cardiovascular toxicity induced by PM exposure. The molecular initiating event (MIE) is identified as reactive oxygen species generation, followed by the key events (KEs) of oxidative damage and mitochondria dysfunction, which induces vascular endothelial dysfunction via vascular endothelial cell autophagy dysfunction, vascular fibrosis via vascular smooth muscle cell activation, cardiac dysregulation via myocardial apoptosis, and cardiac fibrosis via fibroblast proliferation and myofibroblast differentiation, respectively; all of the above cardiovascular injuries ultimately elevate cardiovascular morbidity and mortality in the general population. As far as we know, this is the first work on PM-related cardiovascular AOP construction. In the future, more work needs to be done to explore new markers in the safety assessment of cardiovascular toxicity induced by PM.
10.1016/j.jhazmat.2022.128368
Adverse outcome pathway from activation of the AhR to breast cancer-related death.
Environment international
Adverse outcome pathways (AOPs) are formalized and structured linear concepts that connect one molecular initiating event (MIE) to an adverse outcome (AO) via different key events (KE) through key event relationships (KER). They are mainly used in eco-toxicology toxicology, and regulatory health issues. AOPs must respond to specific guidelines from the Organization for Economic Co-operation and Development (OECD) to weight the evidence between each KE. Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer related death (AO), through different KEs, constituting a new AOP. An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, angiogenesis, and invasion. These KEs promote an increased tumor growth, angiogenesis and migration which leads to breast cancer metastasis and breast cancer related death. The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines. The confidence in our AOP was considered strong. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast cancer-related death with an innovative use of an artificial intelligence literature search.
10.1016/j.envint.2022.107323
An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition.
Archives of toxicology
Epidemiological studies have observed an association between pesticide exposure and the development of Parkinson's disease, but have not established causality. The concept of an adverse outcome pathway (AOP) has been developed as a framework for the organization of available information linking the modulation of a molecular target [molecular initiating event (MIE)], via a sequence of essential biological key events (KEs), with an adverse outcome (AO). Here, we present an AOP covering the toxicological pathways that link the binding of an inhibitor to mitochondrial complex I (i.e., the MIE) with the onset of parkinsonian motor deficits (i.e., the AO). This AOP was developed according to the Organisation for Economic Co-operation and Development guidelines and uploaded to the AOP database. The KEs linking complex I inhibition to parkinsonian motor deficits are mitochondrial dysfunction, impaired proteostasis, neuroinflammation, and the degeneration of dopaminergic neurons of the substantia nigra. These KEs, by convention, were linearly organized. However, there was also evidence of additional feed-forward connections and shortcuts between the KEs, possibly depending on the intensity of the insult and the model system applied. The present AOP demonstrates mechanistic plausibility for epidemiological observations on a relationship between pesticide exposure and an elevated risk for Parkinson's disease development.
10.1007/s00204-017-2133-4
Application of adverse outcome pathway networks to integrate mechanistic data informing the choice of a point of departure for hydrogen sulfide exposure limits.
Goyak Katy O,Lewis R Jeffrey
Critical reviews in toxicology
Acute exposure to hydrogen sulfide initiates a series of hallmark biological effects that occur progressively at increasing exposure levels: odor perception, conjunctivitis, olfactory paralysis, "knockdown," pulmonary edema, and apnea. Although effects of exposure to high concentrations of hydrogen sulfide are clear, effects associated with chronic, low-level exposure in humans is under debate, leading to uncertainty in the critical effect used in regulatory risk assessments addressing low dose exposures. This study integrates experimental animal, observational epidemiology, and occupational exposure evidence by applying a pathway-based approach. A hypothesized adverse outcome pathway (AOP) network was developed from 34 studies, composed of 4 AOPs sharing 1 molecular initiating events (MIE) and culminating in 4 adverse outcomes. A comparative assessment of effect levels and weight of evidence identified an AOP leading to a biologically-plausible, low-dose outcome relative to the other outcomes (nasal lesions, 30 ppm versus olfactory paralysis, >100 ppm; neurological effects, >80 ppm; pulmonary edema, >80 ppm). This AOP (i.e. AOP1) consists of the following key events: cytochrome oxidase inhibition (>10 ppm), neuronal cell loss (>30 ppm), and olfactory nasal lesions (defined as both neuronal cell loss and basal cell hyperplasia; >30 ppm) in rodents. The key event relationships in this pathway were supported by moderate empirical evidence and have high biological plausibility due to known mechanistic understanding and consistency in observations for diverse chemicals.
10.1080/10408444.2021.1897085
Construction of an adverse outcome pathway framework based on integrated data to evaluate arsenic-induced non-alcoholic fatty liver disease.
Environment international
Arsenic is a recognized environmental pollutant naturally occurring in aquifers through geological processes. Toxicological studies have revealed that liver is the main target organ harmed by arsenic exposure. However, systematic studies of non-alcoholic fatty liver disease (NAFLD) are not comprehensive, and information regarding threats and risk assessment remains insufficient. This research aimed to examine the association between arsenic exposure and NAFLD and uncover the role of molecular initiating events and key events in disease development using the Adverse Outcome Pathway (AOP). Data from 8,104 adults in the National Health and Nutrition Examination Survey were used to explore the relationship between urinary arsenic and NAFLD. In a logistic regression model, urinary inorganic arsenic levels positively correlated with NAFLD (odds ratio = 1.12, 95 % confidence interval = 1.07-1.16). Subsequently, to gain a deeper understanding of arsenic-induced NAFLD, an AOP framework was constructed, revealing that arsenic exposure led to elevate levels of TNF-α, which regulated the NF-κB pathway and led to hepatic lipid deposition, causing NAFLD. This AOP was assessed as "high" according to the Organization for Economic Co-operation and Development users' handbook, and in vitro and in vivo models validated the AOP framework. In summary, this study highlights the potential mechanisms of arsenic-induced NAFLD. We combined the AOP with classical toxicological approaches with a view of establishing, rapidly and accurately, the lowest level at which environmental arsenic exposure can have adverse effects on the body, thereby contributing to risk assessment strategies for arsenic exposure through iterative and animal modeling at the population level.
10.1016/j.envint.2023.108381
An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non)genotoxic Carcinogenesis.
Chemical research in toxicology
Nongenotoxic (NGTX) carcinogens induce cancer via other mechanisms than direct DNA damage. A recognized mode of action for NGTX carcinogens is induction of oxidative stress, a state in which the amount of oxidants in a cell exceeds its antioxidant capacity, leading to regenerative proliferation. Currently, carcinogenicity assessment of environmental chemicals primarily relies on genetic toxicity end points. Since NGTX carcinogens lack genotoxic potential, these chemicals may remain undetected in such evaluations. To enhance the predictivity of test strategies for carcinogenicity assessment, a shift toward mechanism-based approaches is required. Here, we present an adverse outcome pathway (AOP) network for chemically induced oxidative stress leading to (NGTX) carcinogenesis. To develop this AOP network, we first investigated the role of oxidative stress in the various cancer hallmarks. Next, possible mechanisms for chemical induction of oxidative stress and the biological effects of oxidative damage to macromolecules were considered. This resulted in an AOP network, of which associated uncertainties were explored. Ultimately, development of AOP networks relevant for carcinogenesis in humans will aid the transition to a mechanism-based, human relevant carcinogenicity assessment that involves a substantially lower number of laboratory animals.
10.1021/acs.chemrestox.2c00396
Adverse outcome pathway of developmental neurotoxicity resulting from prenatal exposures to cannabis contaminated with organophosphate pesticide residues.
Leung Maxwell C K,Silva Marilyn H,Palumbo Amanda J,Lohstroh Peter N,Koshlukova Svetlana E,DuTeaux Shelley B
Reproductive toxicology (Elmsford, N.Y.)
There is growing concern that increased use of medical and recreational cannabis may result in increased exposure to contaminants on the cannabis, such as pesticides. Several states are moving towards implementing robust regulation of the sales, cultivation, and manufacture of cannabis products. However, there are challenges with creating health-protective regulations in an industry that, to date, has been largely unregulated. The focus of this publication is a theoretical examination of what may happen when women are exposed pre-conceptually or during pregnancy to cannabis contaminated with pesticides. We propose an adverse outcome pathway of concomitant prenatal exposure to cannabinoids and the organophosphate pesticide chlorpyrifos by curating what we consider to be the key events at the molecular, cellular, and tissue levels that result in developmental neurotoxicity. The implications of this adverse outcome pathway underscore the need to elucidate the potential developmental neurotoxicity that may result from prenatal exposure to pesticide-contaminated cannabis.
10.1016/j.reprotox.2019.01.004
A meta-analysis-based adverse outcome pathway for the male reproductive toxicity induced by microplastics and nanoplastics in mammals.
Journal of hazardous materials
The male reproductive toxicity of microplastics (MPs) and nanoplastics (NPs) has attracted great attention, but the latent mechanisms remain fragmented. This review performed the adverse outcome pathway (AOP) analysis and meta-analysis in 39 relevant studies, with the AOP analysis to reveal the cause-and-effect relationships of MPs/NPs-induced male reproductive toxicity and the meta-analysis to quantify the toxic effects. In the AOP framework, increased reactive oxygen species (ROS) is the molecular initiating event (MIE), which triggered several key events (KEs) at different levels. At the cellular level, the KEs included oxidative stress, mitochondrial dysfunction, sperm DNA damage, endoplasmic reticulum stress, apoptosis and autophagy of testicular cells, repressed expression of steroidogenic enzymes and steroidogenic acute regulatory protein, disrupted hypothalamic-pituitary-testicular (HPT) axis, and gut microbiota alteration. These KEs further induced the reduction of testosterone, impaired blood-testis barrier (BTB), testicular inflammation, and impaired spermatogenesis at tissue/organ levels. Ultimately, decreased sperm quality or quantity was noted and proved by meta-analysis, which demonstrated that MPs/NPs led to a decrease of 5.99 million/mL in sperm concentration, 14.62% in sperm motility, and 23.56% in sperm viability, while causing an increase of 10.65% in sperm abnormality rate. Overall, this is the first AOP for MPs/NPs-mediated male reproductive toxicity in mammals. The innovative integration of meta-analysis into the AOP analysis increases the rigorism of the results.
10.1016/j.jhazmat.2023.133375