Template-type: ReDIF-Paper 1.0 Author-Name: OECD Title: Users' Handbook supplement to the Guidance Document for developing and assessing Adverse Outcome Pathways Abstract: This document is a supplement to the Guidance Document for developing and assessing Adverse Outcome Pathways (AOPs). It provides focused and practical instructions for both AOP developers and reviewers and is intended to assist in identifying, organising and evaluating critical information on key events (KEs) as well as linkages between KEs within the AOP (i.e. AOP development). It also provides explicit guidance on how to assess the weight of evidence (WoE) supporting the overall AOP and its relevance for life stage, sex and taxonomy (i.e. AOP evaluation). This handbook is not intended to provide a review or summary of the literature informing the AOP concept. Instead, it focuses on practical aspects of AOP development and assessment. It has been developed by a subgroup of the OECD Extended Advisory Group for Molecular Screening and Toxicogenomics (EAGMST). Keywords: AOP assessment, AOP development, handbook, weight of evidence Creation-Date: 2018-02-14 Number: 1 Handle: RePEc:oec:envaad:1-EN Template-type: ReDIF-Paper 1.0 Author-Name: Brigitte Landesmann Author-Workplace-Name: European Commission Title: Adverse Outcome Pathway on Protein Alkylation Leading to Liver Fibrosis Abstract: Liver fibrosis is an important human health issue associated with chemical exposure. It is a typical result of chronic toxic injury and one of the considered endpoints for regulatory purposes. This AOP describes the linkage between hepatic injury caused by protein alkylation and the formation of liver fibrosis. Fibrogenesis is a long-term and complex process for which an adequate cell model is not available and an in vitro evaluation of fibrogenic potential is therefore not feasible yet. This systematic and coherent display of currently available mechanistic-toxicological information can serve as a knowledge-based repository for identification/selection/development of in vitro methods suitable for measuring key events and their relationships along the AOP and to facilitate the use of alternative data for regulatory purposes. Identified uncertainties and knowledge gaps can indicate priorities for future research. Keywords: hepatotoxicity, liver fibrosis, protein alkylation Creation-Date: 2016-08-04 Number: 2 Handle: RePEc:oec:envaad:2-EN Template-type: ReDIF-Paper 1.0 Author-Name: Carole Yauk Author-Workplace-Name: Environmental Health Science and Research Bureau, Health Canada Author-Name: Iain Lambert Author-Workplace-Name: Carleton University Author-Name: Francesco Marchetti Author-Workplace-Name: Environmental Health Science and Research Bureau, Health Canada Author-Name: George Douglas Author-Workplace-Name: Environmental Health Science and Research Bureau, Health Canada Title: Adverse Outcome Pathway on Alkylation of DNA in Male Pre-Meiotic Germ Cells Leading to Heritable Mutations Abstract: Germ cell/heritable mutations are important regulatory endpoints for international agencies interested in protecting the health of future generations. However, germ cell mutation analysis has been hampered by a lack of efficient tools. The motivation for developing this AOP was to provide context for new assays in this field, identify research gaps and facilitate the development of new methods. In this AOP, a compound capable of alkylating DNA is delivered to the testes causing germ cell mutations and subsequent mutations in the offspring of the exposed parents. Although there are some gaps surrounding some mechanistic aspects of this AOP, the overarching AOP is widely accepted and applies broadly to any species that produces sperm. Keywords: DNA adducts, DNA alkylation, DNA repair, heritable mutations, male pre-meiotic germ cells Creation-Date: 2016-08-04 Number: 3 Handle: RePEc:oec:envaad:3-EN Template-type: ReDIF-Paper 1.0 Author-Name: Daniel L. Villeneuve Author-Workplace-Name: US Environmental Protection Agency (EPA) Title: Adverse Outcome Pathway on Aromatase Inhibition Leading to Reproductive Dysfunction (in Fish) Abstract: This adverse outcome pathway details the linkage between inhibition of gonadal aromatase activity in females and reproductive dysfunction, as measured through the adverse effect of reduced cumulative fecundity and spawning. Initial development of this AOP draws heavily on evidence collected using repeat-spawning fish species. Cumulative fecundity is the most apical endpoint considered in the OECD 229 Fish Short Term Reproduction Assay. The OECD 229 assay serves as screening assay for endocrine disruption and associated reproductive impairment (OECD 2012). Cumulative fecundity is one of several variables known to be of demographic significance in forecasting fish population trends. Therefore, this AOP has utility in supporting the application of measures of aromatase, or in silico predictions of the ability to inhibit aromatase, as a means to identify chemicals with known potential to adversely affect fish populations and potentially other oviparous vertebrates. Keywords: aromatase inhibition, Fish Short Term Reproduction Assay, reduced cumulative fecundity, repeat-spawning fish species, reproductive toxicity Creation-Date: 2016-08-06 Number: 4 Handle: RePEc:oec:envaad:4-EN Template-type: ReDIF-Paper 1.0 Author-Name: Magdalini Sachana Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Author-Name: Sharon Munn Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Author-Name: Anna Bal-Price Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Title: Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities Abstract: It is well documented and accepted that learning and memory processes rely on physiological functioning of the glutamate receptor N-methyl-D-aspartate (NMDAR). Both animal and human studies investigating NMDA itself, experiments with NMDAR antagonists and mutant mice lacking NMDAR subunits strongly support this statement (Rezvani, 2006). Activation of NMDARs results in long-term potentiation (LTP), which is related to increased synaptic strength, plasticity and memory formation in the hippocampus (Johnston et al., 2009). LTP induced by activation of NMDA receptors has been found to be elevated in the developing rodent brain compared to the mature brain, partially due to 'developmental switch' of the NMDAR 2A and 2B subunits (Johnston et al., 2009). Activation of the NMDAR also enhances brain derived neurotrophic factor (BDNF) release, which promotes neuronal survival, differentiation and synaptogenesis (Tyler et al., 2002; Johnston et al., 2009). Consequently, the blockage of NMDAR by chemical substances during synaptogenesis disrupts neuronal network formation resulting in the impairment of learning and memory processes (Toscano and Guilarte, 2005). This AOP is relevant to developmental neurotoxicity (DNT). The molecular initiating event (MIE) is described as the chronic binding of antagonist to NMDAR in neurons during synaptogenesis (development) in hippocampus (one of the critical brain structures for learning and memory formation). One of the chemicals that blocks NMDAR after chronic exposure is lead (Pb2+), a well-known developmental neurotoxicant. Keywords: developmental neurotoxicity, impairment of learning and memory, N-methyl-D-aspartate receptor (NMDAR) Creation-Date: 2016-08-13 Number: 5 Handle: RePEc:oec:envaad:5-EN Template-type: ReDIF-Paper 1.0 Author-Name: Magdalini Sachana Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Author-Name: Sharon Munn Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Author-Name: Anna Bal-Price Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Title: Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment Abstract: Under physiological conditions activation of glutamate ionotropic receptors such as N-methyl-D-aspartate (NMDARs), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPARs) and kainate (KARs) is responsible for basal excitatory synaptic transmission and synaptic plasticity. However, sustained over-activation of these receptors can induce excitotoxic neuronal cell death. Increased Ca2+ influx through NMDARs promotes many pathways of toxicity due to generation of free radical species, reduced ATP production, endoplasmic reticulum (ER) stress and protein aggregation. Neuronal injury induced by over-activation of these receptors and the excessive Ca2+ influx is considered an early key event of excitotoxicity. The proposed AOP is relevant to adult neurotoxicity. The MIE has been defined as a direct binding of agonists to NMDARs or indirect, through prior activation of AMPARs and/or KARs resulting in sustained NMDARs over-activation causing excitotoxic neuronal cell death, mainly in hippocampus and cortex, two brain structures fundamental for learning and memory processes. Keywords: adult neurotoxicity, excitotoxicity, impairment of learning and memory in adults, ionotropic glutamate receptors Creation-Date: 2016-09-09 Number: 6 Handle: RePEc:oec:envaad:6-EN Template-type: ReDIF-Paper 1.0 Author-Name: Anna Bal-Price Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Author-Name: Marcel Leist Author-Workplace-Name: University of Konstanz Author-Name: Stefan Schildknecht Author-Workplace-Name: University of Konstanz Author-Name: Florianne Tschudi-Monnet Author-Workplace-Name: University of Lausanne Author-Name: Alicia Paini Author-Workplace-Name: Joint Research Centre, European Commission, Ispra Author-Name: Andrea Terron Author-Workplace-Name: European Food Safety Authority Title: Adverse Outcome Pathway on Inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits Abstract: This AOP describes the linkage between inhibition of complex I (CI) of the mitochondrial respiratory chain and motor deficit as in parkinsonian disorders. Binding of an inhibitor to CI has been defined as the molecular initiating event (MIE) that triggers mitochondrial dysfunction, impaired proteostasis, which then cause degeneration of dopaminergic (DA) neurons. Neuroinflammation is triggered early in the neurodegenerative process and exacerbates it significantly. These causatively linked cellular key events result in motor deficit symptoms, typical for parkinsonian disorders, including Parkinson's disease (PD), described as the Adverse Outcome (AO). The weight-of-evidence supporting the relationship between the described key events is based mainly on effects observed after an exposure to the chemicals rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This AOP could apply for chemicals having structural similarities to the stressors, chemicals binding to CI and supports the mechanistic biological plausibility in the process of evaluation and integration of the epidemiological studies into the risk assessment. Creation-Date: 2018-10-12 Number: 7 Handle: RePEc:oec:envaad:7-EN Template-type: ReDIF-Paper 1.0 Author-Name: Florianne Tschudi-Monnet Author-Workplace-Name: University of Lausanne Author-Name: Rex FitzGerald Author-Workplace-Name: Universität Basel Title: Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging Abstract: This AOP links chronic NMDA receptors inhibition during brain development to neurodegeneration in hippocampus and cortex with amyloid plaque deposition and tau hyperphosphorylation, and impairment of learning and memory, which are considered as hallmark of Alzheimer's disease. It makes use of some KEs and KERs from AOP 13 and introduces Neuroinflammation as KE, which is involved in several neurodegenerative diseases. This AOP is based on the hypothesis of Landrigan and coworkers (2005) proposing an early origin of neurodegenerative diseases in later life. The chemical initiator used in this AOP for the empirical support is lead (Pb). In adults, cumulative lifetime Pb exposure is also associated with decline in cognition, suggesting that long-term exposure during development or occupational exposure increases the risk to develop neurodegenerative disease. The long latency period between exposure and late-onset of effects gives a very broad life-stage applicability. The gap of knowledge is mainly due to limited quantitative evaluations. Creation-Date: 2018-10-12 Number: 8 Handle: RePEc:oec:envaad:8-EN Template-type: ReDIF-Paper 1.0 Author-Name: Daniel L. Villeneuve Author-Workplace-Name: US Environmental Protection Agency (EPA) Title: Adverse Outcome Pathway on Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish) Abstract: This AOP details the linkage between binding and activation of androgen receptor (AR) in females and reductions in cumulative fecundity and spawning. AR-mediated activities are among the major concerns in endocrine disruptor screening programs. Cumulative fecundity is the apical endpoint considered in the OECD 229 Fish Short Term Reproduction Assay. It is also one of several variables with demographic significance in forecasting fish population trends. Therefore, this AOP supports the use of measures of AR activation as a means to identify chemicals with potential to adversely affect fish populations. At present, this AOP is largely supported by evidence from small laboratory model fish species. While many aspects of the biology underlying this AOP are largely conserved across oviparous vertebrates, its relevance to vertebrate classes other than fish, or to fish species employing different reproductive strategies has not been established. Thus, the applicability domain should be carefully considered when evaluating fit-for-purpose. Creation-Date: 2018-10-12 Number: 9 Handle: RePEc:oec:envaad:9-EN Template-type: ReDIF-Paper 1.0 Author-Name: Kurt A. Gust Author-Workplace-Name: U.S. Army Engineer Research and Development Center Author-Name: Mitchell S. Wilbanks Author-Workplace-Name: U.S. Army Engineer Research and Development Center Author-Name: Zachary A. Collier Author-Workplace-Name: U.S. Army Engineer Research and Development Center Author-Name: Lyle D. Burgoon Author-Workplace-Name: U.S. Army Engineer Research and Development Center Author-Name: Edward J. Perkins Author-Workplace-Name: U.S. Army Engineer Research and Development Center Title: Adverse Outcome Pathway on antagonist binding to PPARα leading to body-weight loss Abstract: The present AOP describes antagonistic chemical binding to the peroxisome proliferator-activated receptor α (PPARα), resulting in preferential binding a co-repressor to the overall PPARα signalling complex causing a chain of events that includes: antagonism of PPARα nuclear signalling, decreased transcriptional expression of PPARα-regulated genes that support energy metabolism, inhibited metabolic energy production (decreased fatty acid beta oxidation and ketogenesis), and increase in catabolism of muscle protein, culminating with starvation-like weight loss. The AOP is likely to be synergised during fasting, starvation or malnutrition events. The adverse outcome of this AOP is body-weight loss, which within the context of dynamic energy budget theory, decreases energy allocations to organismal maturation and reproduction and has been demonstrated to negatively affect ecological fitness. Creation-Date: 2019-07-30 Number: 10 Handle: RePEc:oec:envaad:10-EN Template-type: ReDIF-Paper 1.0 Author-Name: Ping Gong Author-Workplace-Name: U.S. Army Engineer Research and Development Center Author-Name: Edward J. Perkins Author-Workplace-Name: U.S. Army Engineer Research and Development Center Title: Adverse Outcome Pathway on binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain Abstract: This AOP begins with the interaction of chemicals to the picrotoxin binding site of the ionotropic GABA receptor complex causing blockage of the ion channel. As a result, decrease in inward chloride conductance occurs, followed by a reduction in postsynaptic inhibition, reflected as reduced frequency and amplitude of spontaneous inhibitory postsynaptic current or abolishment of GABA-induced firing action. Consequently, the resistance of excitatory neurons to fire is decreased, resulting in the generation of a large excitatory postsynaptic potential (EPSP) that causes voltage-gated Na+ to open, which results in action potentials. The depolarisation is followed by a period of hyper-polarisation mediated by Ca2+-dependent K+ channels or GABA-activated Cl− influx, which becomes smaller, gradually disappears, and is replaced by a depolarisation known as “paroxysmal depolarizing shift” (PDS). A PDS is an indication of epilepsy at the cellular level and initiates the adverse outcome at the organismal level of epileptic seizure. Creation-Date: 2019-07-30 Number: 11 Handle: RePEc:oec:envaad:11-EN Template-type: ReDIF-Paper 1.0 Author-Name: Jon Doering Author-Workplace-Name: US Environmental Protection Agency (EPA) Author-Name: Markus Hecker Author-Workplace-Name: University of Saskatchewan Author-Name: Daniel L. Villeneuve Author-Workplace-Name: US Environmental Protection Agency (EPA) Author-Name: Xiaowei Zhang Author-Workplace-Name: Nanjing University Title: Adverse Outcome Pathway on aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2 Abstract: This AOP details the linkage between activation of the aryl hydrocarbon receptor (AhR) and early life stage mortality in oviparous vertebrates. It can be initiated mostly by dioxin-like compounds, which are able to bind to the AhR causing heterodimerisation with the aryl hydrocarbon nuclear translocator (ARNT) and interaction with dioxin-responsive elements on the DNA causing an up-regulation in dioxin responsive genes. One dioxin-responsive gene is cyclooxygenase 2 (COX-2), which has roles in development of the cardiovascular system. Up-regulation in expression of COX-2 causes alteration in cardiovascular development and function resulting in reduced heart pumping efficiency, reduced blood flow, and eventual cardiac collapse and death. Comparable apical manifestations of activation of the AhR have been recorded across freshwater and marine teleost and non-teleost fishes, as well as birds. Despite conservation in the AOP across taxa, great differences in sensitivity to perturbation exist both among and within taxonomic groups. Creation-Date: 2019-07-30 Number: 12 Handle: RePEc:oec:envaad:12-EN Template-type: ReDIF-Paper 1.0 Author-Name: Kevin M. Crofton Author-Workplace-Name: R3Fellows LLC Author-Name: Mary Gilbert Author-Workplace-Name: US Environmental Protection Agency (EPA) Author-Name: Katie Paul Friedman Author-Workplace-Name: US Environmental Protection Agency (EPA) Author-Name: Barbara Demeneix Author-Workplace-Name: National History Museum Author-Name: Mary Sue Marty Author-Workplace-Name: Dow Chemical Company Author-Name: R. Thomas Zoeller Author-Workplace-Name: University of Massachusetts Title: Adverse Outcome Pathway on inhibition of Thyroperoxidase and subsequent adverse neurodevelopmental outcomes in mammals Abstract: This AOP describes one adverse outcome that may result from the inhibition of thyroperoxidase (TPO) during mammalian development. Chemical inhibition of TPO results in decreased thyroid hormone (TH) synthesis, and subsequent reduction in circulating concentrations of THs. THs are essential for normal human brain development, both prenatally and postnatally, modulating genes critical for a normal neuroanatomical development, with subsequent effects on neurophysiology, and finally neurological function. Therefore, chemicals that interfere with TH synthesis have the potential to cause TH insufficiency that may result in adverse neurodevelopmental effects in offspring. Herein, we discuss the implications of developmental TPO inhibition for hippocampal anatomy, function, and ultimately neural function. The hippocampus is known to be critically involved in cognitive, emotional, and memory function. The adverse consequences of TH insufficiency depend both on severity and developmental timing, indicating that exposure to TPO inhibitors may produce different effects at different developmental windows of exposure. Creation-Date: 2019-07-30 Number: 13 Handle: RePEc:oec:envaad:13-EN Template-type: ReDIF-Paper 1.0 Author-Name: Alexandra Rolaki Author-Workplace-Name: European Commission, Joint Research Centre Author-Name: Francesca Pistollato Author-Workplace-Name: European Commission, Joint Research Centre Author-Name: Sharon Munn Author-Workplace-Name: European Commission, Joint Research Centre Author-Name: Anna Bal-Price Author-Workplace-Name: European Commission, Joint Research Centre Title: Adverse Outcome Pathway on inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment Abstract: The thyroid hormones (TH) are essential for brain development, maturation, and function as they regulate the early key developmental processes. Normal human brain development and cognitive function relays on sufficient production of TH during the perinatal period. The function of Na+/I- symporter (NIS) is critical for the physiological production of TH levels in the serum. The present AOP describes causative links between inhibition of NIS function leading to the decreased levels of TH in the blood and consequently in the brain, causing learning and memory deficit in children. Learning and memory depend upon the coordinated action of different brain regions and neurotransmitter systems creating functionally integrated neural networks. Hippocampus and cortex are the most critical brain structures involved in the process of cognitive functions. The function of NIS and its essentiality for TH synthesis is well known across species, however, quantitative information of KERs is limited. Creation-Date: 2019-07-30 Number: 14 Handle: RePEc:oec:envaad:14-EN Template-type: ReDIF-Paper 1.0 Author-Name: Amani Farhat Author-Workplace-Name: Environment and Climate Change Canada Author-Name: Gillian Manning Author-Workplace-Name: Environment and Climate Change Canada Author-Name: Jason O’Brien Author-Workplace-Name: Environment and Climate Change Canada Author-Name: Sean W. Kennedy Author-Workplace-Name: Environment and Climate Change Canada Title: Adverse Outcome Pathway on Aryl hydrocarbon receptor activation leading to uroporphyria Abstract: Hepatic uroporphyria is a disorder where the disturbance of heme biosynthesis results in accumulation and excretion of uroporphyrin, heptacarboxyl- and hexacarboxyl porphyrin: collectively referred to as highly carboxylated porphyrins (HCPs). The disorder is due to a homozygous mutation in uroporphyrinogen decarboxylase (UROD), an enzyme involved in the heme biosynthesis pathway, or may be chemically induced, which involves the inhibition of UROD. This AOP describes the linkages leading to chemically induced porphyria through the activation of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. AHR activation leads to the induction of cytochrome P450 1A2, a phase I metabolising enzyme, which in turn results in excessive oxidation of uroporphyrinogen. This oxidation produces a UROD inhibitor, preventing the conversion of uroporphyrinogen to coprouroporphyrinogen and increasing the synthesis of the UROD inhibitor in a positive feedback loop. The accumulation of uroporphyrinogen leads to its preferential oxidation and accumulation of HCP in various organs (Uroporphyria). Creation-Date: 2019-07-30 Number: 15 Handle: RePEc:oec:envaad:15-EN Template-type: ReDIF-Paper 1.0 Author-Name: Amani Farhat Author-Workplace-Name: Environment and Climate Change Canada Author-Name: Sean W. Kennedy Author-Workplace-Name: Environment and Climate Change Canada Title: Adverse Outcome Pathway on Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF Abstract: Interference with endogenous developmental processes that are regulated by the aryl hydrocarbon receptor (AHR), through sustained exogenous activation, causes molecular, structural, and functional cardiac abnormalities in avian, mammalian and piscine embryos; this cardiotoxicity ultimately leads to severe oedema and embryo death in birds and fish and some strains of rat. There have been numerous proposed mechanisms of action for this toxicity profile, many of which include the dysregulation of vascular endothelial growth factor (VEGF). This AOP describes the indirect suppression of VEGF expression through the sequestration of the aryl hydrocarbon receptor nuclear translocator (ARNT) by AHR. ARNT is common dimerization partner for both AHR and hypoxia inducible factor alpha (HIF-1α), which stimulates angiogenesis through the transcriptional regulation of VEGF. The suppression of VEGF thereby reduces cardiomyocyte and endothelial cell proliferation, altering cardiovascular morphology and reducing cardiac output, which ultimately leads to congestive heart failure and death. Creation-Date: 2019-07-30 Number: 16 Handle: RePEc:oec:envaad:16-EN Template-type: ReDIF-Paper 1.0 Author-Name: Shihori Tanabe Author-Workplace-Name: National Institute of Health Sciences Author-Name: Akihiko Hirose Author-Workplace-Name: National Institute of Health Sciences Author-Name: Takashi Yamada Author-Workplace-Name: National Institute of Health Sciences Title: Adverse Outcome Pathway on histone deacetylase inhibition leading to testicular atrophy Abstract: The present AOP describes inhibition of histone deacetylase resulting in testicular atrophy. Histone deacetylase inhibitors (HDIs) are approved as anti-cancer drugs since HDIs have apoptotic effects in cancer cells. The intracellular mechanisms of induction of the spermatocyte apoptosis by HDIs are suggested as histone deacetylase (HDAC) inhibition as MIE, histone acetylation increase, disrupted cell cycle, apoptosis, and spermatocyte depletion as KEs. The adverse outcome has been defined as testicular atrophy. The HDIs inhibit deacetylation of the histone, leading to an increase in histone acetylation. The apoptosis induced by disrupted cell cycle leads to spermatocyte depletion and testis atrophy. Testicular toxicity is of interest for human health risk assessment especially in terms of reproductive and developmental toxicity, however, the testicular toxicity has not been fully elucidated. This AOP may be one of the pathways induced by HDIs, which suggests the pathway networks of protein hyperacetylations. Creation-Date: 2021-10-15 Number: 17 Handle: RePEc:oec:envaad:17-EN Template-type: ReDIF-Paper 1.0 Author-Name: Hiroyuki Komatsu Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Junichiro Sugimoto Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Ken Goto Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Kiyoshi Kushima Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Naohisa Tsutsui Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Shigeru Hisada Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Shiho Ito Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Tadashi Kosaka Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Takumi Ohishi Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Yasuharu Otsubo Author-Workplace-Name: The Japanese Society of Immunotoxicology Author-Name: Yoshihiro Takahashi Author-Workplace-Name: The Japanese Society of Immunotoxicology Title: Adverse Outcome Pathway on inhibition of calcineurin activity leading to impaired T-cell dependent antibody response Abstract: The present AOP describes the inhibition of calcineurin activity resulting in impaired T-Cell Dependent Antibody Response (TDAR). Calcineurin (CN), a protein phosphatase, is known to impair immune function when its phosphatase activation is inhibited. CN inhibitors (CNIs) inhibit CN phosphatase activity to suppress many kinds of immune functions and have been used in the medical domain to prevent hyper immune reactions. However, CNIs are reported to also induce immunosuppression-derived adverse effects such as increased frequency and/or severity of infections and increased tumor incidences. CNIs might affect several T-cell derived immune functions to induce compromised host. Among the affected immune functions, T-cell dependent antibody response (TDAR) is an important factor to resist infections and thought to be the useful endpoint on evaluating immunotoxicity of chemicals; therefore, this AOP describes the linkage between the inhibition of CN activity and impairment of TDAR. Creation-Date: 2021-10-15 Number: 18 Handle: RePEc:oec:envaad:18-EN Template-type: ReDIF-Paper 1.0 Author-Name: Francina Webster Author-Workplace-Name: Health Canada Author-Name: Iain B. Lambert Author-Workplace-Name: Carleton University Author-Name: Carole L. Yauk Author-Workplace-Name: University of Ottawa Title: Adverse Outcome Pathway on Cyp2E1 activation leading to liver cancer Abstract: The present AOP describes the prolonged activation of Cyp2E1 resulting in liver cancer. Cyp2E1 is a cytochrome P450 mono-oxygenase that bioactivates over 85 substrates, thereby creating electrophilic metabolites and oxidative stress. Mono-oxygenation of these substrates to their reactive metabolites, and the accompanying oxidative stress produced during metabolism, pose health risks because they lead to hepatotoxicity and, often, to liver cancer. The MIE occurs when Cyp2E1 binds a substrate. The Cyp2E1 catalytic cycle is prone to decoupling, which produces oxidative stress (KE1), and mono-oxidation of substrates produces reactive metabolites. Both reactive oxygen species and metabolites cause cytotoxicity (KE2). However, following injury, the liver is able to regenerate itself through an increase in cellular proliferation (KE3). Under conditions of chronic activation of Cyp2E1, excessive chronic increases in levels of reactive oxygen species and cell death, and subsequent dysregulated cellular proliferation, leads to tumour formation (AO). Creation-Date: 2021-10-15 Number: 19 Handle: RePEc:oec:envaad:19-EN Template-type: ReDIF-Paper 1.0 Author-Name: Florianne Tschudi-Monnet Author-Name: Marie-Gabrielle Zurich Author-Name: Carolina Nunes Author-Name: Jenny Sandström Author-Name: Rex FitzGerald Author-Name: Michael Aschner Author-Name: Joao Rocha Title: Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leading to impairment of learning and memory Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between binding to proteins involved in protection against oxidative stress and impairment in learning and memory. Production, binding and degradation of Reactive Oxygen Radicals are tightly regulated in the body, and an imbalance between production and protection may cause oxidative stress, which is common to many toxicity pathways. Oxidative stress may lead to an imbalance in glutamate neurotransmission, which is involved in learning and memory. Oxidative stress may also cause cellular injury and death. During brain development and in particular during the establishment of neuronal connections and networks, such perturbations may lead to functional impairment in learning and memory. The weight-of-evidence supporting the relationship between the key events described in this AOP is based mainly on developmental effects observed after an exposure to mercury, a heavy metal known for its strong affinity to many proteins having anti-oxidant properties. This AOP is referred to as AOP 17 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Brain development, Oxidative stress, Seleno-proteins Creation-Date: 2022-12-15 Number: 20 Handle: RePEc:oec:envaad:20-EN Template-type: ReDIF-Paper 1.0 Author-Name: Olavi Pelkonen Author-Name: Andrea Terron Author-Name: Antonio F. Hernandez Author-Name: Pablo Menendez Author-Name: Susanne Hougaard Bennekou Title: Inhibitor binding to topoisomerase II leading to infant leukaemia Abstract: This Adverse Outcome Pathway (AOP) describes the linkages between the perturbation of the normal topoisomerase II enzyme function and infant leukaemia. Infant leukaemia is a rare haematological disease (1 in 106 newborns, accounting for 10% of all childhood acute lymphoblastic leukaemias) of developmental origin, manifesting soon after birth (< 1 year old). The present AOP describes how interference of stressors with DNA topoisomerase II enzyme can possibly result in DNA double-strand break and chromosomal rearrangement during intrauterine development and lead to infant leukaemia, manifesting soon after birth. The proposed AOP is supported by a number of evidences by means of using etoposide as a model compound to empirically support the linkage between the proposed molecular initiating event and the adverse outcome. This AOP also identifies several knowledge gaps, the main ones being the identification of the initiating cell and the investigation of TopoII poisons in a robust model; thus, the present AOP may be modified in future on the basis of new evidence. This AOP is referred to as AOP 202 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Genotoxicity, Infant leukaemia, Topoisomerase II Creation-Date: 2022-12-15 Number: 21 Handle: RePEc:oec:envaad:21-EN Template-type: ReDIF-Paper 1.0 Author-Name: Lucia Vergauwen Author-Name: Evelyn Stinckens Author-Name: Daniel L. Villeneuve Author-Name: Dries Knapen Title: Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between Deiodinase 2 inhibition and increased mortality via reduced posterior swim bladder inflation. The swim bladder is a gas-filled organ found in many bony fish species and typically consists of two gas-filled chambers. The posterior chamber inflates during early development (embryo), while the anterior chamber inflates during late development (larva). Both chambers are important for fish to control buoyancy and the anterior chamber has an additional role in hearing. This AOP is part of a network of 5 AOPs describing how disruption of the thyroid hormone system can affect developmental processes involved in swim bladder inflation. The network includes three molecular initiating events representing the inhibition of enzymes that are important for thyroid hormone synthesis and activation. It describes how inhibition of thyroperoxidase and/or deiodinase, leads to reduced swim bladder inflation, resulting in reduced swimming performance, increased mortality and ultimately, decreased population trajectory in fish. This AOP network is currently mainly based on experimental evidence from studies on fish species with a two-chambered swim bladder. This AOP is referred to as AOP 155 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Deiodinase 2, Fish toxicity, swim bladder Creation-Date: 2022-12-15 Number: 22 Handle: RePEc:oec:envaad:22-EN Template-type: ReDIF-Paper 1.0 Author-Name: Lucia Vergauwen Author-Name: Evelyn Stinckens Author-Name: Daniel L. Villeneuve Author-Name: Dries Knapen Title: Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between Deiodinase 2 inhibition and increased mortality via reduced anterior swim bladder inflation. The swim bladder is a gas-filled organ found in many bony fish species and typically consists of two gas-filled chambers. The posterior chamber inflates during early development (embryo), while the anterior chamber inflates during late development (larva). Both chambers are important for fish to control buoyancy and the anterior chamber has an additional role in hearing. This AOP is part of a network of 5 AOPs describing how disruption of the thyroid hormone system can affect developmental processes involved in swim bladder inflation. The network includes three molecular initiating events representing the inhibition of enzymes that are important for thyroid hormone synthesis and activation. It describes how inhibition of thyroperoxidase and/or deiodinase, leads to reduced swim bladder inflation, resulting in reduced swimming performance, increased mortality and ultimately, decreased population trajectory in fish. This AOP network is currently mainly based on experimental evidence from studies on fish species with a two-chambered swim bladder. This AOP is referred to as AOP 156 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Creation-Date: 2022-12-15 Number: 23 Handle: RePEc:oec:envaad:23-EN Template-type: ReDIF-Paper 1.0 Author-Name: Lucia Vergauwen Author-Name: Evelyn Stinckens Author-Name: Daniel L. Villeneuve Author-Name: Dries Knapen Title: Deiodinase 1 inhibition leading to increased mortality via reduced posterior swim bladder inflation Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between Deiodinase 1 inhibition and increased mortality via reduced posterior swim bladder inflation. The swim bladder is a gas-filled organ found in many bony fish species and typically consists of two gas-filled chambers. The posterior chamber inflates during early development (embryo), while the anterior chamber inflates during late development (larva). Both chambers are important for fish to control buoyancy and the anterior chamber has an additional role in hearing. This AOP is part of a network of 5 AOPs describing how disruption of the thyroid hormone system can affect developmental processes involved in swim bladder inflation. The network includes three molecular initiating events representing the inhibition of enzymes that are important for thyroid hormone synthesis and activation. It describes how inhibition of thyroperoxidase and/or deiodinase, leads to reduced swim bladder inflation, resulting in reduced swimming performance, increased mortality and ultimately, decreased population trajectory in fish. This AOP network is currently mainly based on experimental evidence from studies on fish species with a two-chambered swim bladder. This AOP is referred to as AOP 157 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Deiodinase 1, Fish toxicity, swim bladder Creation-Date: 2022-12-15 Number: 24 Handle: RePEc:oec:envaad:24-EN Template-type: ReDIF-Paper 1.0 Author-Name: Lucia Vergauwen Author-Name: Evelyn Stinckens Author-Name: Daniel L. Villeneuve Author-Name: Dries Knapen Title: Deiodinase 1 inhibition leading to increased mortality via reduced anterior swim bladder inflation Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between Deiodinase 1 inhibition and increased mortality via reduced anterior swim bladder inflation. The swim bladder is a gas-filled organ found in many bony fish species and typically consists of two gas-filled chambers. The posterior chamber inflates during early development (embryo), while the anterior chamber inflates during late development (larva). Both chambers are important for fish to control buoyancy and the anterior chamber has an additional role in hearing. This AOP is part of a network of 5 AOPs describing how disruption of the thyroid hormone system can affect developmental processes involved in swim bladder inflation. The network includes three molecular initiating events representing the inhibition of enzymes that are important for thyroid hormone synthesis and activation. It describes how inhibition of thyroperoxidase and/or deiodinase, leads to reduced swim bladder inflation, resulting in reduced swimming performance, increased mortality and ultimately, decreased population trajectory in fish. This AOP network is currently mainly based on experimental evidence from studies on fish species with a two-chambered swim bladder. This AOP is referred to as AOP 158 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Deiodinase 1, Fish toxicity, swim bladder Creation-Date: 2022-12-15 Number: 25 Handle: RePEc:oec:envaad:25-EN Template-type: ReDIF-Paper 1.0 Author-Name: Lucia Vergauwen Author-Name: Evelyn Stinckens Author-Name: Daniel L. Villeneuve Author-Name: Dries Knapen Title: Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflation Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between Thyroperoxidase inhibition and increased mortality via reduced anterior swim bladder inflation. The swim bladder is a gas-filled organ found in many bony fish species and typically consists of two gas-filled chambers. The posterior chamber inflates during early development (embryo), while the anterior chamber inflates during late development (larva). Both chambers are important for fish to control buoyancy and the anterior chamber has an additional role in hearing. This AOP is part of a network of 5 AOPs describing how disruption of the thyroid hormone system can affect developmental processes involved in swim bladder inflation. The network includes three molecular initiating events representing the inhibition of enzymes that are important for thyroid hormone synthesis and activation. It describes how inhibition of thyroperoxidase and/or deiodinase, leads to reduced swim bladder inflation, resulting in reduced swimming performance, increased mortality and ultimately, decreased population trajectory in fish. This AOP network is currently mainly based on experimental evidence from studies on fish species with a two-chambered swim bladder. This AOP is referred to as AOP 159 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Fish toxicity, swim bladder, Thyroperoxidase Creation-Date: 2022-12-15 Number: 26 Handle: RePEc:oec:envaad:26-EN Template-type: ReDIF-Paper 1.0 Author-Name: Simon Schmid Author-Name: You Song Author-Name: Knut Erik Tollefsen Title: Chitin synthase 1 inhibition leading to mortality Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between Chitin synthase 1 inhibition and mortality in arthropods. In order to grow and develop, arthropods need to shed their exoskeleton (or cuticle) periodically and replace it with a new one in a process called molting. Successful molting, and therefore a successful development necessitates stability and integrity of the cuticle to support muscular contractions involved in the shedding of the old cuticle. Arthropods heavily rely on chitin synthesis as chitin is one of the main constituents of the cuticle. The cuticular chitin synthase (CHS-1) is the key enzyme in the biosynthetic pathway and arthropods are therefore especially dependent on its proper function. The present AOP describes the effects of CHS-1 chemical inhibition on the molting process leading to increased mortality in arthropods. Knowledge gaps still exist in the process and this AOP may help guiding assay development for further experimental studies, addressing these gaps. This AOP is referred to as AOP 360 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Chitin synthesis, Developmental toxicity, Invertebrate toxicology Creation-Date: 2022-12-15 Number: 27 Handle: RePEc:oec:envaad:27-EN Template-type: ReDIF-Paper 1.0 Author-Name: You Song Author-Name: Daniel L. Villeneuve Title: Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased cell proliferation Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between uncoupling of oxidative phosphorylation (OXPHOS) and growth inhibition via decreased cell proliferation. The mitochondrial OXPHOS machinery is a key physiological process responsible for producing the primary cellular energy, adenosine triphosphate (ATP). Uncoupling of OXPHOS is a well-known mechanism of action of many chemicals and can affect many ATP-dependent biological functions. Cell proliferation in particular, as a major process to achieve organismal growth, is positively correlated with the cellular ATP level and highly susceptible to energy depletion. This AOP causally links uncoupling of OXPHOS to growth inhibition, through ATP depletion and reduced cell proliferation with strong weight of evidence support. This AOP is of high regulatory relevance, as it is considered applicable to both human health and ecological risk assessments. The AOP also forms the core of a larger AOP network addressing uncoupling of OXPHOS mediated growth inhibition. This AOP is referred to as AOP 263 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Adenosine triphosphate, Cell proliferation, oxidative phosphorylation Creation-Date: 2022-12-15 Number: 28 Handle: RePEc:oec:envaad:28-EN Template-type: ReDIF-Paper 1.0 Author-Name: Eunnara Cho Author-Name: Ashley Allemang Author-Name: Marc Audebert Author-Name: Vinita Chauhan Author-Name: Stephen Dertinger Author-Name: Giel Hendriks Author-Name: Mirjam Luijten Author-Name: Francesco Marchetti Author-Name: Sheroy Minocherhomji Author-Name: Stefan Pfuhler Author-Name: Daniel J. Roberts Author-Name: Kristina Trenz Author-Name: Carole L. Yauk Title: Oxidative DNA damage leading to chromosomal aberrations and mutations Abstract: This Adverse Outcome Pathway (AOP) describes the linkage between oxidative DNA damage and irreversible genomic damage (chromosomal aberrations and mutations). DNA damage is considered an important contributor to the adverse health effects of many environmental toxicants and this AOP may thus be of widespread use to the regulatory community. Although increase in oxidative DNA damage is the molecular initiating event for this AOP, there are numerous upstream key events that can also lead to DNA oxidation. Thus, this AOP may be expanded upstream, and could be incorporated into a variety of AOP networks. Furthermore, the AOP points to critical research gaps required to establish the quantitative associations and modulating factors that connect KEs across the AOP, and highlights the utility of novel test methods in understanding and evaluating the implications of oxidative DNA damage. This AOP is referred to as AOP 296 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Creation-Date: 2023-07-11 Number: 29 Handle: RePEc:oec:envaad:29-EN Template-type: ReDIF-Paper 1.0 Author-Name: Yutaka Kimura Author-Name: Setsuya Aiba Author-Name: Takao Ashikaga Author-Name: Takumi Ohishi Author-Name: Kiyoshi Kushima Title: Adverse Outcome Pathway on impaired interleukin-1 receptor type I (IL-1R1) signaling leading to impaired T-cell dependent antibody response Abstract: Stressors that exhibit immunosuppression might act by different mechanisms, i.e. alter the number of cells involved in the immune response, the ability of the cells to produce cytokines, chemokines, antibodies or growth factors, the composition of the subpopulations of cells present at the site of the response, or the function of the cells. This Adverse Outcome Pathway (AOP) describes how impairment of the signaling receptor IL-1R1 in T cells can lead to impaired T cell activation and antibody production, leading to increased susceptibility to infection. The AOP focuses on the blocking of binding of IL-1 to IL-1R1, leading to the Inhibition of Nuclear factor kappa B (NF-kB). This AOP is referred to as AOP 277 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Creation-Date: 2023-10-23 Number: 30 Handle: RePEc:oec:envaad:30-EN Template-type: ReDIF-Paper 1.0 Author-Name: Thomas B. Knudsen Author-Name: Katerine Saili Author-Name: Jill Franzosa Author-Name: Nancy Baker Author-Name: Richard Spencer Author-Name: Tamara Tal Author-Name: Nicole Kleinstreuer Author-Name: Tuula Heinonen Author-Name: Rob Ellis-Hutchings Author-Name: Neil Vargesson Author-Name: Maria Bondesson Title: Disruption of VEGFR signaling leading to developmental defects Abstract: The cardiovascular system is the first functional organ system to develop in the vertebrate embryo, reflecting its critical role during normal development and pregnancy. This Adverse Outcome Pathway focuses on the regulation and disruption of vasculogenesis-angiogenesis during embryonic development via disruption of the Vascular Endothelial Growth Factor (VEGF) signaling pathway. This pathway is a critical regulatory system for assembly of embryonic blood vessels. Genetic studies have shown that perturbing the VEGF signaling system can invoke varying degrees of adverse consequences, ranging from congenital angiodysplasia to fetal malformations and embryolethality. This AOP is referred to as AOP 43 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Creation-Date: 2023-10-23 Number: 31 Handle: RePEc:oec:envaad:31-EN Template-type: ReDIF-Paper 1.0 Author-Name: Samantha Sherman Author-Name: Zakara Said Author-Name: Baki Sadi Author-Name: Carole Yauk Author-Name: Danielle Beaton Author-Name: Ruth Wilkins Author-Name: Robert Stainforth Author-Name: Nadine Adam Author-Name: Vinita Chauhan Title: Adverse Outcome Pathway on deposition of energy leading to lung cancer Abstract: The present Adverse Outcome Pathway (AOP) describes the linkage between lung cancer initiated from the Deposition of Energy (DoE) into a cell by a prototypic stressor such as radon gas. The multiple ionization events from DoE can directly break DNA double strands and initiate the activation of repair machinery through non-homologous end joining, an efficient, but error-prone process. When double strand breaks occur in DNA regions that transcribe critical genes, mutations generated by faulty repair may alter the function of these genes or cause chromosomal aberrations. These events alter the functions of many gene products and affect cell growth, cycling, and apoptosis. Cell proliferation is then promoted by escaping the regulatory control and forming hyperplasia in lung epithelial cells, leading eventually to lung cancer. Although the weight of evidence for this AOP is strong, uncertainties remain on dose-effect relationships across KEs, particularly for DoE delivered at low doses and dose-rates. Creation-Date: 2023-10-23 Number: 32 Handle: RePEc:oec:envaad:32-EN Template-type: ReDIF-Paper 1.0 Author-Name: Sabina Halappanavar Author-Name: Monita Sharma Author-Name: Silvia Solorio-Rodriguez Author-Name: Hakan Wallin Author-Name: Ulla Vogel Author-Name: Kristie Sullivan Author-Name: Amy J. Clippinger Title: Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosis Abstract: Lung fibrosis is a dysregulated or exaggerated tissue repair process resulting in the thickening or scarring of lung tissue. It involves the presence of sustained or repeated exposure to a stressor and intricate dynamics between several inflammatory and immune response cells, and the microenvironment of the alveolar-capillary region consisting of both immune and non-immune cells, and the lung interstitium. This AOP is applicable to a broad group of stressors of diverse properties e.g. metal dusts, pharmacological products, fibres, microorganisms, chemicals, including novel technology-enabled stressors such as nanomaterials. This AOP is referred to as AOP 173 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Inflammation, Lung fibrosis, Nanomaterials, Pulmonary fibrosis Creation-Date: 2023-12-12 Number: 33 Handle: RePEc:oec:envaad:33-EN Template-type: ReDIF-Paper 1.0 Author-Name: Kelvin J. Santana Rodriguez Author-Name: Daniel L. Villeneuve Author-Name: Kathleen M. Jensen Author-Name: Gerald T. Ankley Author-Name: David H. Miller Title: Adverse Outcome Pathway on Aromatase inhibition leading to male-biased sex ratio via impacts on gonad differentiation Abstract: This adverse outcome pathway links inhibition of aromatase activity in teleost fish during gonadogenesis to increased differentiation to testis resulting in a male-biased sex ratio in the population, and ultimately, reduced population sustainability. Most gonochoristic fish species develop either as males or females and do not change sex throughout their life span. However, in species where sexual differentiation is controlled at least to some degree by environmental factors, there can be a window of development during gonadal differentiation that is sensitive to a variety of exogenous conditions. During this window, endocrine active chemicals, aromatase inhibitors in particular, have the potential to alter gonad development and sex differentiation. This AOP is referred to as AOP 346 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: Aromatase, Endocrine effects, Fish, Sex ratio Creation-Date: 2023-12-12 Number: 34 Handle: RePEc:oec:envaad:34-EN Template-type: ReDIF-Paper 1.0 Author-Name: Kelvin J. Santana Rodriguez Author-Name: Daniel L. Villeneuve Author-Name: Kathleen M. Jensen Author-Name: Gerald T. Ankley Author-Name: David H. Miller Title: Adverse Outcome Pathway on Androgen receptor agonism leading to male-biased sex ratio Abstract: This adverse outcome pathway links androgen receptor agonism in teleost fish during gonadogenesis to male-biased sexual differentiation and consequently, reduced population growth rate. Sex determination in teleost fishes is highly plastic; it can be genetically or environmentally influenced. Species with environmentally-based sex determination in particular can be very sensitive to exogenous chemicals during the period of differentiation. Exogenous hormones are of ecological concern because they have the potential to alter gonad development and sex differentiation. This AOP is referred to as AOP 376 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki). Keywords: androgen receptor, endocrine effects, fish, sex ratio Creation-Date: 2023-12-12 Number: 35 Handle: RePEc:oec:envaad:35-EN