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Adverse Outcome Pathway on Cyp2E1 activation leading to liver cancer Cyp2E1激活导致肝癌的不良后果途径
OECD Series on Adverse Outcome Pathways Pub Date : 2021-10-15 DOI: 10.1787/56e9bbf0-en
Francina Webster, I. Lambert, C. Yauk
{"title":"Adverse Outcome Pathway on Cyp2E1 activation leading to liver cancer","authors":"Francina Webster, I. Lambert, C. Yauk","doi":"10.1787/56e9bbf0-en","DOIUrl":"https://doi.org/10.1787/56e9bbf0-en","url":null,"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. \u0000The 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).","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"38 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129966345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
Oxidative DNA damage leading to chromosomal aberrations and mutations 氧化性DNA损伤导致染色体畸变和突变
OECD Series on Adverse Outcome Pathways Pub Date : 2018-10-19 DOI: 10.1787/399d2c34-en
E. Cho, Ashley Allemang, M. Audebert, V. Chauhan, S. Dertinger, G. Hendriks, M. Luijten, F. Marchetti, L. Peel, S. Pfuhler, Daniel J. Roberts, K. Trenz, C. Yauk
{"title":"Oxidative DNA damage leading to chromosomal aberrations and mutations","authors":"E. Cho, Ashley Allemang, M. Audebert, V. Chauhan, S. Dertinger, G. Hendriks, M. Luijten, F. Marchetti, L. Peel, S. Pfuhler, Daniel J. Roberts, K. Trenz, C. Yauk","doi":"10.1787/399d2c34-en","DOIUrl":"https://doi.org/10.1787/399d2c34-en","url":null,"abstract":"","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"187 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132873937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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 在大脑发育过程中，拮抗剂与n -甲基- d -天冬氨酸受体的慢性结合导致神经退行性变，并在衰老过程中导致学习和记忆障碍
OECD Series on Adverse Outcome Pathways Pub Date : 2018-10-12 DOI: 10.1787/95F569AD-EN
F. Tschudi-Monnet, R. Fitzgerald
{"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","authors":"F. Tschudi-Monnet, R. Fitzgerald","doi":"10.1787/95F569AD-EN","DOIUrl":"https://doi.org/10.1787/95F569AD-EN","url":null,"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.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"59 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133853221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
Adverse Outcome Pathway on Inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits 抑制黑质纹状体神经元线粒体复合体I导致帕金森运动缺陷的不良后果途径
OECD Series on Adverse Outcome Pathways Pub Date : 2018-10-12 DOI: 10.1787/B46C3C00-EN
A. Bal-Price, M. Leist, S. Schildknecht, F. Tschudi-Monnet, A. Paini, A. Terron
{"title":"Adverse Outcome Pathway on Inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits","authors":"A. Bal-Price, M. Leist, S. Schildknecht, F. Tschudi-Monnet, A. Paini, A. Terron","doi":"10.1787/B46C3C00-EN","DOIUrl":"https://doi.org/10.1787/B46C3C00-EN","url":null,"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.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"22 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122815262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 15
Adverse Outcome Pathway on Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish) 雄激素受体激动作用导致生殖功能障碍的不良后果途径(在重复产卵的鱼类中)
OECD Series on Adverse Outcome Pathways Pub Date : 2018-10-12 DOI: 10.1787/B0C6838A-EN
D. Villeneuve
{"title":"Adverse Outcome Pathway on Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)","authors":"D. Villeneuve","doi":"10.1787/B0C6838A-EN","DOIUrl":"https://doi.org/10.1787/B0C6838A-EN","url":null,"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.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"4 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131284274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Adverse Outcome Pathway on Aryl hydrogen receptor activation leading to uroporphyria 芳基氢受体激活导致尿卟啉症的不良后果途径
OECD Series on Adverse Outcome Pathways Pub Date : 1900-01-01 DOI: 10.1787/FDE13D2C-EN
Amani Farhat, Gillian E Manning, J. O'Brien, S. Kennedy
{"title":"Adverse Outcome Pathway on Aryl hydrogen receptor activation leading to uroporphyria","authors":"Amani Farhat, Gillian E Manning, J. O'Brien, S. Kennedy","doi":"10.1787/FDE13D2C-EN","DOIUrl":"https://doi.org/10.1787/FDE13D2C-EN","url":null,"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).","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"73 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125516128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adverse Outcome Pathway on inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment Na+/I-同向转运蛋白(NIS)抑制通路导致学习和记忆障碍
OECD Series on Adverse Outcome Pathways Pub Date : 1900-01-01 DOI: 10.1787/7CA86A34-EN
A. Rolaki, F. Pistollato, S. Munn, A. Bal-Price
{"title":"Adverse Outcome Pathway on inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment","authors":"A. Rolaki, F. Pistollato, S. Munn, A. Bal-Price","doi":"10.1787/7CA86A34-EN","DOIUrl":"https://doi.org/10.1787/7CA86A34-EN","url":null,"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.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"47 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121213534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 7
Adverse Outcome Pathway on antagonist binding to PPARα leading to body-weight loss 拮抗剂与PPARα结合导致体重减轻的不良结局途径
OECD Series on Adverse Outcome Pathways Pub Date : 1900-01-01 DOI: 10.1787/29D4E08D-EN
K. Gust, Mitchell S. Wilbanks, Zachary A. Collier, L. Burgoon, E. Perkins
{"title":"Adverse Outcome Pathway on antagonist binding to PPARα leading to body-weight loss","authors":"K. Gust, Mitchell S. Wilbanks, Zachary A. Collier, L. Burgoon, E. Perkins","doi":"10.1787/29D4E08D-EN","DOIUrl":"https://doi.org/10.1787/29D4E08D-EN","url":null,"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.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"47 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116359709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Adverse Outcome Pathway on Aryl hydrogen receptor activation leading to early life stage mortality, via reduced VEGF 通过降低VEGF，芳基氢受体激活导致生命早期死亡的不良结局途径
OECD Series on Adverse Outcome Pathways Pub Date : 1900-01-01 DOI: 10.1787/063E1BF4-EN
Amani Farhat, S. Kennedy
{"title":"Adverse Outcome Pathway on Aryl hydrogen receptor activation leading to early life stage mortality, via reduced VEGF","authors":"Amani Farhat, S. Kennedy","doi":"10.1787/063E1BF4-EN","DOIUrl":"https://doi.org/10.1787/063E1BF4-EN","url":null,"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.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134437270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 7
Adverse Outcome Pathway on aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2 通过增加COX-2，芳烃受体激活导致生命早期死亡的不良结局途径
OECD Series on Adverse Outcome Pathways Pub Date : 1900-01-01 DOI: 10.1787/BD46B538-EN
Jon A. Doering, M. Hecker, D. Villeneuve, Xiaowei Zhang
{"title":"Adverse Outcome Pathway on aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2","authors":"Jon A. Doering, M. Hecker, D. Villeneuve, Xiaowei Zhang","doi":"10.1787/BD46B538-EN","DOIUrl":"https://doi.org/10.1787/BD46B538-EN","url":null,"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.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"53 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116805719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 9
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