DEDUCT | Database of Endocrine Disrupting chemicals and their Toxicity profiles

Tamoxifen

Associated AOPs with Level of Relevance - 1 AOPs with at least 1 KE associated with chemical, where the KE(s) are neither MIE nor AO

AOP Identifier	AOP Title	AO Classification	OECD Status	Taxonomic applicability	Coverage Score ⓘ The fraction of KEs within the AOP, that are mapped to the chemical-associated toxicological endpoints.	KE Identifier	KE Name
AOP:4	Ecdysone receptor agonism leading to incomplete ecdysis associated mortality	Unclassified	-	Insects, Crustaceans	0.1	KE:993	Decrease, Abdominal muscle contraction
AOP:15	Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations	Genetic disease	WPHA/WNT Endorsed	Mus musculus, Drosophila melanogaster, Oryzias latipes, Syrian golden hamster	0.25	KE:155	Inadequate DNA repair
AOP:16	Acetylcholinesterase inhibition leading to acute mortality	Unclassified	Under Development		0.14	KE:1703	Dysregulation of heart rate and vascular tone
AOP:21	Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2	Unclassified	WPHA/WNT Endorsed	Zebrafish, Medaka, Gallus gallus	0.2	KE:317	Altered, Cardiovascular development/function
AOP:23	Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)	Unclassified	WPHA/WNT Endorsed	Pimephales promelas	0.2	KE:219	Reduction, Plasma 17beta-estradiol concentrations
AOP:23		Unclassified	WPHA/WNT Endorsed	Pimephales promelas	0.2	KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:39	Covalent Binding, Protein, leading to Increase, Allergic Respiratory Hypersensitivity Response	Respiratory system disease	Under Development	Human, Mouse	0.2	KE:272	Activation/Proliferation, T-cells
AOP:41	Sustained AhR Activation leading to Rodent Liver Tumours	Cancer; Gastrointestinal system disease	Under Review	Rattus sp. ABTC 42503, Mus sp. 2000082	0.6	KE:854	Alterations, Cellular proliferation / hyperplasia
						KE:853	Changes/Inhibition, Cellular Homeostasis and Apoptosis
						KE:139	N/A, Hepatotoxicity, Hepatopathy, including a constellation of observable effects
AOP:58	NR1I3 (CAR) suppression leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-	Human, Mouse, Rat	0.06	KE:454	Increased, Triglyceride formation
AOP:63	Cyclooxygenase inhibition leading to reproductive dysfunction	Reproductive system disease	-	Goldfish, Human, Mouse, Rat	0.2	KE:488	Decrease, Ovulation
AOP:77	Nicotinic acetylcholine receptor activation contributes to abnormal foraging and leads to colony death/failure 1	Unclassified	-	Honey bee	0.14	KE:341	Impairment, Learning and memory
AOP:78	Nicotinic acetylcholine receptor activation contributes to abnormal role change within the worker bee caste leading to colony death failure 1	Unclassified	-	Honey bee	0.12	KE:341	Impairment, Learning and memory
AOP:80	Nicotinic acetylcholine receptor activation contributes to accumulation of damaged mitochondrial DNA and leads to colony loss/failure	Unclassified	-	Honey bee	0.12	KE:664	Overwhelmed, Mitochondrial DNA repair mechanisms
AOP:87	Nicotinic acetylcholine receptor activation contributes to abnormal foraging and leads to colony loss/failure	Unclassified	-	Honey bee	0.12	KE:341	Impairment, Learning and memory
AOP:88	Nicotinic acetylcholine receptor activation contributes to abnormal foraging and leads to colony loss/failure via abnormal role change within caste	Unclassified	-	Honey bee	0.14	KE:341	Impairment, Learning and memory
AOP:89	Nicotinic acetylcholine receptor activation followed by desensitization contributes to abnormal foraging and directly leads to colony loss/failure	Unclassified	-	Honey bee	0.12	KE:341	Impairment, Learning and memory
AOP:90	Nicotinic acetylcholine receptor activation contributes to abnormal roll change within the worker bee caste leading to colony loss/failure 2	Unclassified	-	Honey bee	0.12	KE:341	Impairment, Learning and memory
AOP:96	Axonal sodium channel modulation leading to acute mortality	Unclassified	-	Insects, Fish	0.17	KE:601	Overactivation, muscle contraction
AOP:99	Histamine (H2) receptor antagonism leading to reduced survival	Unclassified	-	Zebrafish	0.14	KE:341	Impairment, Learning and memory
AOP:109	Cytotoxicity leading to bronchioloalveolar adenomas and carcinomas (in mouse)	Cancer; Respiratory system disease	-	Mus musculus	0.2	KE:734	Increase, Regenerative cell proliferation (terminal bronchiolar epithelial cells)
AOP:110	Inhibition of iodide pump activity leading to follicular cell adenomas and carcinomas (in rat and mouse)	Cancer; Endocrine system disease	-	Rattus norvegicus, Mus musculus	0.29	KE:1023	Increased, Thyroid-stimulating hormone (TSH)
AOP:110		Cancer; Endocrine system disease	-	Rattus norvegicus, Mus musculus	0.29	KE:739	Increase, Hypertrophy and proliferation (follicular cell)
AOP:114	HPPD inhibition leading to corneal papillomas and carcinomas (in rat)	Cancer	-	Rattus norvegicus	0.33	KE:778	Increase, Regenerative cell proliferation (corneal cells)
AOP:114		Cancer	-	Rattus norvegicus	0.33	KE:777	Increase, Inflammation (corneal cells)
AOP:115	Epithelial cytotoxicity leading to forestomach tumors (in mouse and rat)	Cancer	-	Mus musculus, Rattus norvegicus	0.4	KE:149	Increase, Inflammation
AOP:115		Cancer	-	Mus musculus, Rattus norvegicus	0.4	KE:781	Increase, Regenerative cell proliferation (forestomach epithelial cells)
AOP:119	Inhibition of thyroid peroxidase leading to follicular cell adenomas and carcinomas (in rat and mouse)	Cancer; Endocrine system disease	-	Rattus norvegicus, Mus musculus	0.29	KE:1023	Increased, Thyroid-stimulating hormone (TSH)
AOP:119		Cancer; Endocrine system disease	-	Rattus norvegicus, Mus musculus	0.29	KE:739	Increase, Hypertrophy and proliferation (follicular cell)
AOP:120	Inhibition of 5α-reductase leading to Leydig cell tumors (in rat)	Cancer; Reproductive system disease	-	Rattus norvegicus, Mus musculus	0.2	KE:791	Increased, Leutinizing hormone (LH)
AOP:121	Urinary bladder calculi leading to urothelial papillomas and carcinomas (in mouse and rat)	Cancer; Urinary system disease	-	Mus musculus, Rattus norvegicus	0.2	KE:795	Increase, Regenerative cell proliferation (urothelial cells)
AOP:122	Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation	Unclassified	-	Pimephales promelas	0.3	KE:800	Decreased, Aromatase (Cyp19a1) mRNA
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:123	Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription	Unclassified	-	Pimephales promelas	0.27	KE:800	Decreased, Aromatase (Cyp19a1) mRNA
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:136	Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors	Benign neoplasm; Respiratory system disease	Under Review		0.29	KE:868	Increase, Tissue Degeneration, Necrosis & Atrophy
AOP:136		Benign neoplasm; Respiratory system disease	Under Review		0.29	KE:870	Increase, Cell Proliferation
AOP:149	Peptide Oxidation Leading to Hypertension	Cardiovascular system disease	Under Development	Human, Mouse, Rat, Cow	0.2	KE:933	KE6 : Depletion, Nitric Oxide
AOP:149	Peptide Oxidation Leading to Hypertension	Cardiovascular system disease	Under Development	Human, Mouse, Rat, Cow	0.2	KE:937	KE7 : Impaired, Vasodilation
AOP:150	Aryl hydrocarbon receptor activation leading to early life stage mortality, via reduced VEGF	Unclassified	WPHA/WNT Endorsed	Chicken, Zebrafish, Mouse, Rattus norvegicus	0.14	KE:317	Altered, Cardiovascular development/function
AOP:164	Beta-2 adrenergic agonist activity leading to mesovarian leiomyomas in the rat and mouse	Cancer; Reproductive system disease	-	CD-1 mouse, SD rat	0.17	KE:1042	Proliferation/Clonal Expansion, smooth muscle
AOP:173	Substance interaction with the pulmonary resident cell membrane components leading to pulmonary fibrosis	Musculoskeletal system disease; Respiratory system disease	WPHA/WNT Endorsed	Human, Mouse, Rat	0.12	KE:1497	Increased, recruitment of inflammatory cells
AOP:190	Type II iodothyronine deiodinase (DIO2) inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.33	KE:1023	Increased, Thyroid-stimulating hormone (TSH)
AOP:190		Unclassified	-	African clawed frog	0.33	KE:1829	Altered, Thyroid hormone-dependent gene expression
AOP:191	Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.5	KE:1154	Increased, Triiodothyronine (T3) in tissues
AOP:191		Unclassified	-	African clawed frog	0.5	KE:1829	Altered, Thyroid hormone-dependent gene expression
AOP:206	Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis	Musculoskeletal system disease; Respiratory system disease	Under Development	Homo sapiens	0.17	KE:149	Increase, Inflammation
AOP:207	NADPH oxidase and P38 MAPK activation leading to reproductive failure in Caenorhabditis elegans	Reproductive system disease	-	Caenorhabditis elegans	0.38	KE:1115	Increase, Reactive oxygen species
						KE:1281	Increased, DNA Damage-Repair
						KE:1262	Apoptosis
AOP:212	Histone deacetylase inhibition leading to testicular atrophy	Reproductive system disease	WPHA/WNT Endorsed	Rat, Human, Mouse	0.17	KE:1262	Apoptosis
AOP:213	Inhibition of fatty acid beta oxidation leading to nonalcoholic steatohepatitis (NASH)	Gastrointestinal system disease; Inherited metabolic disorder	-	Vertebrates	0.17	KE:1115	Increase, Reactive oxygen species
AOP:219	Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior	Unclassified	-	Japanese quail, Cynops pyrrhogaster	0.17	KE:1390	Sexual behavior, decreased
AOP:227	NSAID induced PTGS1 inactivation to gastric ulcer	Gastrointestinal system disease	-		0.14	KE:1403	Reduced, platelet aggregation
AOP:271	Inhibition of thyroid peroxidase leading to impaired fertility in fish	Unclassified	Under Development	Fish	0.2	KE:219	Reduction, Plasma 17beta-estradiol concentrations
AOP:272	Deposition of energy leading to lung cancer	Cancer	WPHA/WNT Endorsed	Human, Rat, Mouse	0.29	KE:155	Inadequate DNA repair
AOP:272	Deposition of energy leading to lung cancer	Cancer	WPHA/WNT Endorsed	Human, Rat, Mouse	0.29	KE:870	Increase, Cell Proliferation
AOP:274	Histone deacetylase inhibition leads to impeded craniofacial development	Musculoskeletal system disease	-		0.25	KE:1558	Collagen production, reduced
AOP:280	α-diketone-induced bronchiolitis obliterans	Musculoskeletal system disease; Respiratory system disease	-		0.14	KE:149	Increase, Inflammation
AOP:281	Acetylcholinesterase Inhibition Leading to Neurodegeneration	Nervous system disease	-		0.1	KE:389	Increased, Intracellular Calcium overload
AOP:286	Mitochondrial complex III antagonism leading to growth inhibition (1)	Unclassified	-	Lemna minor, Daphnia magna, Danio rerio	0.25	KE:1821	Decrease, Cell proliferation
AOP:289	Inhibition of 5α-reductase leading to impaired fecundity in female fish	Unclassified	Under Development	Fish	0.17	KE:219	Reduction, Plasma 17beta-estradiol concentrations
AOP:290	Mitochondrial ATP synthase antagonism leading to growth inhibition (1)	Unclassified	-	Daphnia magna	0.25	KE:1821	Decrease, Cell proliferation
AOP:296	Oxidative DNA damage leading to chromosomal aberrations and mutations	Genetic disease; Chromosomal disease	WPHA/WNT Endorsed	Human, Mice, Rat, Fish	0.2	KE:155	Inadequate DNA repair
AOP:297	Inhibition of retinaldehyde dehydrogenase leads to population decline	Unclassified	Under Development	Fish	0.17	KE:1643	Altered, Visual function
AOP:299	Deposition of energy leading to population decline via DNA oxidation and follicular atresia	Unclassified	-		0.14	KE:1115	Increase, Reactive oxygen species
AOP:303	Frustrated phagocytosis-induced lung cancer	Cancer	Under Development	Mammals	0.43	KE:870	Increase, Cell Proliferation
						KE:1115	Increase, Reactive oxygen species
						KE:1497	Increased, recruitment of inflammatory cells
AOP:305	5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring	Unclassified	Under Development	Rat, Human, Mouse	0.2	KE:1614	Decrease, androgen receptor activation
AOP:309	Luteinizing hormone receptor antagonism leading to reproductive dysfunction	Unclassified	-	Fish	0.43	KE:1693	Reduction, Plasma progesterone concentration
						KE:1692	Reduction, Progesterone synthesis
						KE:1695	Impaired ovulation
AOP:310	Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR	Unclassified	-	Zebrafish	0.17	KE:219	Reduction, Plasma 17beta-estradiol concentrations
AOP:310		Unclassified	-	Zebrafish	0.17	KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:311	Deposition of energy leading to population decline via DNA oxidation and oocyte apoptosis	Unclassified	-	Daphnia magna, Fish	0.14	KE:1115	Increase, Reactive oxygen species
AOP:318	Glucocorticoid Receptor activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.2	KE:291	Accumulation, Triglyceride
AOP:320	Binding of SARS-CoV-2 to ACE2 receptor leading to acute respiratory distress associated mortality	Unclassified	Under Development	Homo sapiens	0.11	KE:1750	Increased inflammatory immune responses
AOP:321	Reduced environmental pH leading to thinner shells in Mytilus edulis	Unclassified	-		0.09	KE:10042	Abnormal development
AOP:322	Alkylation of DNA leading to reduced sperm count	Reproductive system disease	-		0.2	KE:155	Inadequate DNA repair
AOP:323	PPARalpha Agonism Leading to Decreased Viable Offspring via Decreased 11-Ketotestosterone	Unclassified	-	Teleost fish	0.17	KE:1758	Impaired, Spermatogenesis
AOP:334	Glucocorticoid Receptor Agonism Leading to Impaired Fin Regeneration	Unclassified	-	Teleost fish	0.17	KE:2089	Altered Bone Cell Homeostasis
AOP:335	AOP for urothelial carcinogenesis due to chemical cytotoxicity by mitochondrial impairment	Cancer; Urinary system disease	-	Rat	0.2	KE:795	Increase, Regenerative cell proliferation (urothelial cells)
AOP:348	Inhibition of 11β-Hydroxysteroid Dehydrogenase leading to decreased population trajectory	Unclassified	Under Development	Fish	0.4	KE:1758	Impaired, Spermatogenesis
AOP:348		Unclassified	Under Development	Fish	0.4	KE:406	decreased, Fertility
AOP:349	Inhibition of 11β-hydroxylase leading to decresed population trajectory	Unclassified	Under Development	Fish	0.25	KE:1798	Decreased spermatogenesis
AOP:349		Unclassified	Under Development	Fish	0.25	KE:406	decreased, Fertility
AOP:363	Thyroperoxidase inhibition leading to altered visual function via altered retinal layer structure	Unclassified	Under Review	Zebrafish	0.12	KE:1643	Altered, Visual function
AOP:364	Thyroperoxidase inhibition leading to altered visual function via decreased eye size	Unclassified	Under Development		0.12	KE:1643	Altered, Visual function
AOP:365	Thyroperoxidase inhibition leading to altered visual function via altered photoreceptor patterning	Unclassified	Under Development		0.12	KE:1643	Altered, Visual function
AOP:376	Androgen receptor agonism leading to male-biased sex ratio	Unclassified	WPHA/WNT Endorsed	Zebrafish, Medaka, Fathead minnow, Channel catfish, Oreochromis niloticus, Chinook salmon	0.25	KE:1790	Increased, Differentiation to Testis
AOP:382	Angiotensin II type 1 receptor (AT1R) agonism leading to lung fibrosis	Musculoskeletal system disease; Respiratory system disease	Under Development		0.17	KE:1115	Increase, Reactive oxygen species
AOP:383	Inhibition of Angiotensin-converting enzyme 2 leading to liver fibrosis	Gastrointestinal system disease	Under Development		0.17	KE:1115	Increase, Reactive oxygen species
AOP:386	Deposition of ionizing energy leading to population decline via inhibition of photosynthesis	Reproductive system disease	-	Lemna minor, Chlamydomonas reinhardtii	0.12	KE:1115	Increase, Reactive oxygen species
AOP:387	Deposition of ionising energy leading to population decline via mitochondrial dysfunction	Reproductive system disease	-	Lemna minor	0.12	KE:1115	Increase, Reactive oxygen species
AOP:397	Bulky DNA adducts leading to mutations	Genetic disease	Under Development		0.33	KE:155	Inadequate DNA repair
AOP:399	Inhibition of Fyna leading to increased mortality via decreased eye size (Microphthalmos)	Unclassified	-	Zebrafish	0.25	KE:1821	Decrease, Cell proliferation
AOP:399		Unclassified	-	Zebrafish	0.25	KE:1643	Altered, Visual function
AOP:406	SARS-CoV-2 infection leading to hyperinflammation	Unclassified	-		0.17	KE:1869	Diminished protective oxidative stress response
AOP:409	Frustrated phagocytosis leads to malignant mesothelioma	Cancer	-		0.5	KE:870	Increase, Cell Proliferation
						KE:1115	Increase, Reactive oxygen species
						KE:1497	Increased, recruitment of inflammatory cells
						KE:1896	Genomic instability
AOP:413	Oxidation and antagonism of reduced glutathione leading to mortality via acute renal failure	Unclassified	-	Fish, Mice	0.33	KE:1607	Increase, Necrosis
AOP:413		Unclassified	-	Fish, Mice	0.33	KE:1115	Increase, Reactive oxygen species
AOP:414	Aryl hydrocarbon receptor activation leading to lung fibrosis through TGF-β dependent fibrosis toxicity pathway	Musculoskeletal system disease; Respiratory system disease	-		0.2	KE:1920	Altered gene expression, TGF-β dependent fibrosis pathway
AOP:416	Aryl hydrocarbon receptor activation leading to lung cancer through IL-6 toxicity pathway	Cancer	-		0.17	KE:1115	Increase, Reactive oxygen species
AOP:418	Aryl hydrocarbon receptor activation leading to impaired lung function through AHR-ARNT toxicity pathway	Respiratory system disease	-		0.2	KE:1115	Increase, Reactive oxygen species
AOP:419	Aryl hydrocarbon receptor activation leading to impaired lung function through P53 toxicity pathway	Respiratory system disease	-		0.25	KE:1262	Apoptosis
AOP:420	Aryl hydrocarbon receptor activation leading to lung cancer through sustained NRF2 toxicity pathway	Cancer	-		0.5	KE:1917	Altered gene expression, NRF2 dependent antioxidant pathway
AOP:420		Cancer	-		0.5	KE:870	Increase, Cell Proliferation
AOP:432	Deposition of Energy by Ionizing Radiation leading to Acute Myeloid Leukemia	Hematopoietic system disease; Cancer	-	Homo sapiens, Mus musculus	0.18	KE:155	Inadequate DNA repair
AOP:432		Hematopoietic system disease; Cancer	-	Homo sapiens, Mus musculus	0.18	KE:870	Increase, Cell Proliferation
AOP:439	Activation of the AhR leading to metastatic breast cancer	Thoracic disease; Cancer	Under Development	Humans, Mice	0.33	KE:1971	Increased, tumor growth
						KE:149	Increase, Inflammation
						KE:1262	Apoptosis
AOP:441	Ionizing radiation-induced DNA damage leads to microcephaly via apoptosis and premature cell differentiation	Congenital nervous system abnormality; Nervous system disease	-	Homo sapiens, Mus musculus musculus, Rattus norvegicus	0.14	KE:1262	Apoptosis
AOP:443	DNA damage and mutations leading to Metastatic Breast Cancer	Thoracic disease; Cancer	Under Development	Human and other cells in culture, Human, Mice, Rat, Canine heartworm nematode, Yeast	0.2	KE:155	Inadequate DNA repair
AOP:443		Thoracic disease; Cancer	Under Development		0.2	KE:112	Antagonism, Estrogen receptor
AOP:444	Ionizing radiation leads to reduced reproduction in Eisenia fetida via reduced spermatogenesis and cocoon hatchability	Unclassified	-		0.11	KE:1798	Decreased spermatogenesis
AOP:451	Interaction with lung resident cell membrane components leads to lung cancer	Cancer	-	Human	0.33	KE:870	Increase, Cell Proliferation
						KE:1115	Increase, Reactive oxygen species
						KE:1497	Increased, recruitment of inflammatory cells
AOP:452	Adverse outcome pathway of PM-induced respiratory toxicity	Respiratory system disease	-		0.18	KE:2013	Airway remodeling
AOP:452	Adverse outcome pathway of PM-induced respiratory toxicity	Respiratory system disease	-		0.18	KE:1262	Apoptosis
AOP:456	Aryl hydrocarbon receptor activation leading to early life stage mortality via sox9 repression induced cardiovascular toxicity	Unclassified	Under Review	Zebrafish, Mouse, Human, Chicken	0.17	KE:317	Altered, Cardiovascular development/function
AOP:460	Antagonism of Smoothened receptor leading to orofacial clefting	Unclassified	Under Development	Mouse	0.22	KE:1821	Decrease, Cell proliferation
AOP:460		Unclassified	Under Development	Mouse	0.22	KE:1262	Apoptosis
AOP:464	Calcium overload in dopaminergic neurons of the substantia nigra leading to parkinsonian motor deficits	Nervous system disease	-		0.05	KE:389	Increased, Intracellular Calcium overload
AOP:465	Alcohol dehydrogenase leading to reproductive dysfunction	Unclassified	-		0.12	KE:748	Increased, Estrogen receptor (ER) activity
AOP:468	Binding of SARS-CoV-2 to ACE2 leads to hyperinflammation (via cell death)	Unclassified	-		0.12	KE:1497	Increased, recruitment of inflammatory cells
AOP:482	Deposition of energy leading to occurrence of bone loss	Musculoskeletal system disease	Under Review	Human, Mouse, Rat, Rhesus monkeys	0.14	KE:2089	Altered Bone Cell Homeostasis
AOP:491	Decrease, GLI1/2 target gene expression leads to orofacial clefting	Unclassified	Under Development	Mouse	0.33	KE:1821	Decrease, Cell proliferation
AOP:491		Unclassified	Under Development	Mouse	0.33	KE:1262	Apoptosis
AOP:495	Androgen receptor activation leading to prostate cancer	Reproductive system disease; Cancer	-		0.22	KE:854	Alterations, Cellular proliferation / hyperplasia
AOP:495	Androgen receptor activation leading to prostate cancer	Reproductive system disease; Cancer	-		0.22	KE:1183	Decreased, Apoptosis (Epithelial Cells)
AOP:496	Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）	Unclassified	-	Zebrafish	0.1	KE:219	Reduction, Plasma 17beta-estradiol concentrations
AOP:518	Liver X Receptor (LXR) activation leads to liver steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-	Vertebrates	0.2	KE:291	Accumulation, Triglyceride
AOP:521	Essential element imbalance leads to reproductive failure via oxidative stress	Unclassified	-	Murinae gen. sp.	0.29	KE:1758	Impaired, Spermatogenesis
AOP:521		Unclassified	-	Murinae gen. sp.	0.29	KE:1115	Increase, Reactive oxygen species
AOP:529	Perfluorooctanesulfonic acid (PFOS) binding to peroxisome proliferator-activated receptors (PPARs) causes dysregulation of lipid metabolism and subsequent liver steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-	Vertebrates, Mouse, Rat, Zebrafish	0.12	KE:291	Accumulation, Triglyceride
AOP:544	Inhibition of neuropathy target esterase leading to delayed neuropathy via increased inflammation	Nervous system disease	-	Homo sapiens, Mus musculus	0.17	KE:149	Increase, Inflammation
AOP:563	Aryl hydrocarbon Receptor (AHR) activation causes Premature Ovarian Insufficiency via Bax mediated apoptosis	Reproductive system disease; Endocrine system disease	-	Rat, Mouse, Zebra fish, Human	0.17	KE:1262	Apoptosis
AOP:569	Decreased DNA methylation of FAM50B/PTCHD3 leading to IQ loss of children via PI3K-Akt pathway	Developmental disorder of mental health	-		0.17	KE:1115	Increase, Reactive oxygen species

Associated AOPs with Level of Relevance - 2 AOPs with at least 1 AO associated with chemical, and no associated MIE

AOP Identifier	AOP Title	AO Classification	OECD Status	Taxonomic applicability	Coverage Score ⓘ The fraction of KEs within the AOP, that are mapped to the chemical-associated toxicological endpoints.	KE Identifier	KE Name
AOP:6	Antagonist binding to PPARα leading to body-weight loss	Symptom	WPHA/WNT Endorsed	Mus musculus, Homo sapiens, Pimephales promelas, Colinus virginianus, Rattus norvegicus	0.12	KE:864	Decreased, Body Weight
AOP:12	Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging	Nervous system disease; Developmental disorder of mental health	WPHA/WNT Endorsed	Monkey, Rat, Human, Mouse, Zebrafish	0.12	KE:341	Impairment, Learning and memory
AOP:13	Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities	Developmental disorder of mental health	WPHA/WNT Endorsed	Human, Mouse, Monkey sp., Rat	0.1	KE:341	Impairment, Learning and memory
AOP:17	Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory	Developmental disorder of mental health	WPHA/WNT Endorsed	Rat, Mouse, Human	0.1	KE:341	Impairment, Learning and memory
AOP:18	PPARα activation in utero leading to impaired fertility in males	Reproductive system disease	Under Review	Human, Rat, Mouse	0.12	KE:406	decreased, Fertility
AOP:27	Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)	Gastrointestinal system disease	Under Development	Humans	0.5	KE:357	Cholestasis, Pathology
						KE:149	Increase, Inflammation
						KE:1115	Increase, Reactive oxygen species
						KE:288	Activation of specific nuclear receptors, Transcriptional change
AOP:34	LXR activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.15	KE:291	Accumulation, Triglyceride
AOP:34	LXR activation leading to hepatic steatosis		-		0.15	KE:345	N/A, Liver Steatosis
AOP:37	PPARα activation leading to hepatocellular adenomas and carcinomas in rodents	Cancer; Gastrointestinal system disease	Under Development	Mouse, Rat	0.4	KE:716	Increase, cell proliferation (hepatocytes)
AOP:37		Cancer; Gastrointestinal system disease	Under Development	Mouse, Rat	0.4	KE:719	Increase, hepatocellular adenomas and carcinomas
AOP:40	Covalent Protein binding leading to Skin Sensitisation	Integumentary system disease	WPHA/WNT Endorsed	Mouse, Human	0.4	KE:827	sensitisation, skin
AOP:40	Covalent Protein binding leading to Skin Sensitisation	Integumentary system disease	WPHA/WNT Endorsed	Mouse, Human	0.4	KE:272	Activation/Proliferation, T-cells
AOP:42	Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	WPHA/WNT Endorsed	Human, Rat, Mouse	0.12	KE:402	Cognitive function, decreased
AOP:43	Disruption of VEGFR Signaling Leading to Developmental Defects	Unclassified	WPHA/WNT Endorsed	Mouse, Zebrafish, Rats, Human	0.2	KE:1001	Increased, Developmental Defects
AOP:48	Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.	Developmental disorder of mental health	WPHA/WNT Endorsed	Human, Mouse, Rat	0.22	KE:389	Increased, Intracellular Calcium overload
AOP:48		Developmental disorder of mental health	WPHA/WNT Endorsed	Human, Mouse, Rat	0.22	KE:341	Impairment, Learning and memory
AOP:54	Inhibition of Na+/I- symporter (NIS) leads to learning and memory impairment	Developmental disorder of mental health	WPHA/WNT Endorsed	Homo sapiens, Rattus sp.	0.1	KE:341	Impairment, Learning and memory
AOP:64	Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility	Reproductive system disease	-	Rattus norvegicus	0.29	KE:496	Increased apoptosis, decreased fetal/adult Leydig Cells
AOP:64		Reproductive system disease	-	Rattus norvegicus	0.29	KE:406	decreased, Fertility
AOP:105	Alpha2u-microglobulin cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)	Cancer; Urinary system disease	-	Rattus norvegicus	0.33	KE:713	Increase, Adenomas/carcinomas (renal tubular)
AOP:105		Cancer; Urinary system disease	-	Rattus norvegicus	0.33	KE:710	Increase, Regenerative cell proliferation (tubular epithelial cells)
AOP:107	Constitutive androstane receptor activation leading to hepatocellular adenomas and carcinomas in the mouse and the rat	Cancer; Gastrointestinal system disease	Under Review	Rattus norvegicus, Mus musculus	0.4	KE:716	Increase, cell proliferation (hepatocytes)
AOP:107		Cancer; Gastrointestinal system disease	Under Review	Rattus norvegicus, Mus musculus	0.4	KE:719	Increase, hepatocellular adenomas and carcinomas
AOP:108	Inhibition of pyruvate dehydrogenase kinase leading to hepatocellular adenomas and carcinomas (in mouse and rat)	Cancer; Gastrointestinal system disease	-	Mus musculus, Rattus norvegicus	0.17	KE:719	Increase, hepatocellular adenomas and carcinomas
AOP:112	Increased dopaminergic activity leading to endometrial adenocarcinomas (in Wistar rat)	Reproductive system disease; Cancer	-	Rattus norvegicus	0.67	KE:111	Agonism, Estrogen receptor
						KE:772	Increase, Hyperplasia (glandular epithelial cells of endometrium)
						KE:749	Decreased, Progesterone from corpus luteum
						KE:773	Increase, Endometrial adenocarcinomas
AOP:116	Cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)	Cancer; Urinary system disease	-	Rattus norvegicus	0.5	KE:713	Increase, Adenomas/carcinomas (renal tubular)
AOP:116		Cancer; Urinary system disease	-	Rattus norvegicus	0.5	KE:710	Increase, Regenerative cell proliferation (tubular epithelial cells)
AOP:117	Androgen receptor activation leading to hepatocellular adenomas and carcinomas (in mouse and rat)	Cancer; Gastrointestinal system disease	Under Development	Mus musculus, Rattus norvegicus	0.5	KE:716	Increase, cell proliferation (hepatocytes)
AOP:117		Cancer; Gastrointestinal system disease	Under Development	Mus musculus, Rattus norvegicus	0.5	KE:719	Increase, hepatocellular adenomas and carcinomas
AOP:124	HMG-CoA reductase inhibition leading to decreased fertility	Reproductive system disease	-	Rattus rattus	0.17	KE:330	Decrease, Fertility
AOP:134	Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	-	Rat, Homo sapiens	0.11	KE:402	Cognitive function, decreased
AOP:139	Alkylation of DNA leading to cancer 1	Cancer	-	Homo sapiens, Mus musculus	0.5	KE:885	Increase, Cancer
AOP:139	Alkylation of DNA leading to cancer 1	Cancer	-	Homo sapiens, Mus musculus	0.5	KE:155	Inadequate DNA repair
AOP:167	Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.	Reproductive system disease; Cancer	-	Mouse, Homo sapiens	0.57	KE:1069	Increased, Hyperplasia (glandular epithelial cells of endometrium)
						KE:1067	Proliferation/Clonal Expansion, aberrant basal cells
						KE:1065	Activation, estrogen receptor alpha
						KE:1070	Increased, adenosquamous carcinomas of endometrium
AOP:196	Volatile Organic Chemicals Activate TRPA1 Receptor to Induce Sensory Pulmonary Irritation	Respiratory system disease	-		0.11	KE:1226	Increased Respiratory irritability and Chronic Cough,
AOP:205	AOP from chemical insult to cell death	Unclassified	-	Vertebrates	0.33	KE:1263	Necrosis
AOP:205	AOP from chemical insult to cell death	Unclassified	-	Vertebrates	0.33	KE:1262	Apoptosis
AOP:220	Cyp2E1 Activation Leading to Liver Cancer	Cancer; Gastrointestinal system disease	WPHA/WNT Endorsed	Rodents, Homo sapiens	0.6	KE:1395	Liver Cancer
						KE:1393	Hepatocytotoxicity
						KE:1394	Induction, persistent proliferation/sustained proliferation
AOP:261	L-type calcium channel blockade leading to heart failure via decrease in cardiac contractility	Cardiovascular system disease	Under Development	Vertebrates	0.12	KE:1535	Heart failure
AOP:288	Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)	Endocrine system disease	-	Human, Rat	0.25	KE:1614	Decrease, androgen receptor activation
AOP:288		Endocrine system disease	-	Human, Rat	0.25	KE:1616	Malformation, cryptorchidism - maldescended testis
AOP:293	Increased DNA damage leading to increased risk of breast cancer	Genetic disease; Thoracic disease; Cancer	Under Development	Rattus rattus, Mus musculus	0.22	KE:1193	N/A, Breast Cancer
AOP:293		Genetic disease; Thoracic disease; Cancer	Under Development	Rattus rattus, Mus musculus	0.22	KE:1182	Increase, Cell Proliferation (Epithelial Cells)
AOP:294	Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer	Genetic disease; Thoracic disease; Cancer	Under Development		0.22	KE:1193	N/A, Breast Cancer
AOP:294		Genetic disease; Thoracic disease; Cancer	Under Development		0.22	KE:1182	Increase, Cell Proliferation (Epithelial Cells)
AOP:379	Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation	Cardiovascular system disease	Under Development	Homo sapiens	0.29	KE:1846	Thrombosis and Disseminated Intravascular Coagulation
AOP:379		Cardiovascular system disease	Under Development	Homo sapiens	0.29	KE:1869	Diminished protective oxidative stress response
AOP:384	Hyperactivation of ACE/Ang-II/AT1R axis leading to chronic kidney disease	Urinary system disease	-		0.33	KE:1603	Chronic kidney disease
AOP:384		Urinary system disease	-		0.33	KE:1115	Increase, Reactive oxygen species
AOP:398	Decreased ALDH1A (RALDH) activity leading to decreased fertility via disrupted meiotic initiation of fetal oogonia	Reproductive system disease	Under Development	Mouse, Rat, Human	0.17	KE:406	decreased, Fertility
AOP:405	Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function	Cognitive disorder	-	Rattus norvegicus, Mus musculus, Homo sapiens	0.2	KE:402	Cognitive function, decreased
AOP:442	Binding to voltage gate sodium channels during development leads to cognitive impairment	Cognitive disorder	Under Review	Rattus norvegicus, Mouse, Humans	0.14	KE:402	Cognitive function, decreased
AOP:458	AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	-	Rat, Mouse, Monkey, Human	0.12	KE:402	Cognitive function, decreased
AOP:459	AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	-	Human, Mouse, Rat	0.11	KE:402	Cognitive function, decreased
AOP:474	Succinate dehydrogenase inactivation leads to cancer by promoting EMT	Cancer	Under Development	Human and other cells in culture	0.2	KE:885	Increase, Cancer
AOP:475	Binding of chemicals to ionotropic glutamate receptors leads to impairment of learning and memory via loss of drebrin from dendritic spines of neurons	Developmental disorder of mental health	Under Development	Mouse, Rat, Human, Caenorhabditis elegans	0.25	KE:389	Increased, Intracellular Calcium overload
AOP:475		Developmental disorder of mental health	Under Development	Mouse, Rat, Human, Caenorhabditis elegans	0.25	KE:341	Impairment, Learning and memory
AOP:478	Deposition of energy leading to occurrence of cataracts	Nervous system disease; Monogenic disease	Under Review	Human, Mouse, Rat, Rhesus monkeys, Rabbit, Guinea pig	0.3	KE:2083	Occurrence of Cataracts
						KE:155	Inadequate DNA repair
						KE:870	Increase, Cell Proliferation
AOP:483	Deposition of Energy Leading to Learning and Memory Impairment	Developmental disorder of mental health	Under Review	Mouse, Rat, Rabbit, Dog, Pigs, Cow, Human	0.12	KE:341	Impairment, Learning and memory
AOP:486	Binding to the extracellular protein laminin leading to decreased cognitive function	Cognitive disorder	-	Human	0.14	KE:402	Cognitive function, decreased
AOP:490	Co-activation of IP3R and RyR leads to reduced IQ through non-cholinergic mechanisms	Developmental disorder of mental health	-		0.09	KE:341	Impairment, Learning and memory
AOP:492	Glutathione conjugation leading to reproductive dysfunction via oxidative stress	Reproductive system disease	-	Mammals, Fish	0.4	KE:1115	Increase, Reactive oxygen species
AOP:492		Reproductive system disease	-	Mammals, Fish	0.4	KE:406	decreased, Fertility
AOP:498	Increased LCN2/iron complex leading to neurological disorders	Nervous system disease	-	Homo sapiens	0.5	KE:2150	Neurological disorder
AOP:498		Nervous system disease	-	Homo sapiens	0.5	KE:191	Neuronal dysfunction
AOP:499	Activation of MEK-ERK1/2 leads to deficits in learning and cognition via disrupted neurotransmitter release	Developmental disorder of mental health	-	Rattus norvegicus, Mus musculus, Homo sapiens	0.5	KE:1339	Increase, intracellular calcium
AOP:499		Developmental disorder of mental health	-	Rattus norvegicus, Mus musculus, Homo sapiens	0.5	KE:341	Impairment, Learning and memory
AOP:500	Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis	Developmental disorder of mental health	-	Rattus norvegicus, Mus musculus, Homo sapiens	0.57	KE:1339	Increase, intracellular calcium
						KE:1115	Increase, Reactive oxygen species
						KE:1262	Apoptosis
						KE:341	Impairment, Learning and memory
AOP:501	Excessive iron accumulation leading to neurological disorders	Nervous system disease	-	Homo sapiens	0.25	KE:2150	Neurological disorder
AOP:504	SULT1E1 inhibition leading to uterine adenocarcinoma via increased estrogen availability at target organ level	Unclassified	-	Mammals	0.67	KE:1065	Activation, estrogen receptor alpha
AOP:504		Unclassified	-	Mammals	0.67	KE:2251	Estradiol availability, increased
AOP:520	Retinoic acid receptor agonism during neurodevelopment leading to impaired learning and memory	Developmental disorder of mental health	-	Mouse, Rat, Human	0.2	KE:341	Impairment, Learning and memory
AOP:533	Retinoic acid receptor antagonism during neurodevelopment leading to impaired learning and memory	Developmental disorder of mental health	-		0.17	KE:341	Impairment, Learning and memory
AOP:534	Succinate dehydrogenase (SDH) inhibition leads to cancer through oxidative stress	Cancer	-	Vertebrates	0.5	KE:885	Increase, Cancer
						KE:1115	Increase, Reactive oxygen species
						KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:535	Binding and activation of GPER leading to learning and memory impairments	Developmental disorder of mental health	-	Mouse, Human	0.33	KE:389	Increased, Intracellular Calcium overload
						KE:1262	Apoptosis
						KE:341	Impairment, Learning and memory
AOP:539	Decreased Sodium/Potassium ATPase activity leads to Heart failure	Cardiovascular system disease	-	Fish	0.14	KE:1535	Heart failure
AOP:546	Succinate dehydrogenase inactivation leads to cancer through hypoxic-like mechanisms	Cancer	-	Human and other cells in culture	0.2	KE:885	Increase, Cancer
AOP:550	Increased LMNA gene mutation leading to heart failure	Cardiovascular system disease	-	Human, Mouse, Rat	0.2	KE:1535	Heart failure
AOP:552	Inhibiton of L-Type Calcium Channels leading to heart failure via QT interval prolongation and Torsades de Pointes (TdP)	Cardiovascular system disease	-	Human, Rat, Mouse	0.17	KE:1535	Heart failure
AOP:555	Inhibition, Ether-a-go-go (ERG) Voltage-Gated Potassium Channel leading to heart failure	Cardiovascular system disease	-	Human and other cells in culture, Dogs, Rat, Guinea pig, Rabbits, Zebrafish	0.2	KE:1535	Heart failure
AOP:556	Decreased Na/K ATPase activity leading to heart failure	Cardiovascular system disease	-		0.33	KE:389	Increased, Intracellular Calcium overload
AOP:556	Decreased Na/K ATPase activity leading to heart failure	Cardiovascular system disease	-		0.33	KE:1535	Heart failure
AOP:558	Phosphodiesterase inhibition leading to heart failure	Cardiovascular system disease	-	Human and other cells in culture, Rodents, Dog, Pig, Zebrafish	0.33	KE:389	Increased, Intracellular Calcium overload
AOP:558	Phosphodiesterase inhibition leading to heart failure	Cardiovascular system disease	-		0.33	KE:1535	Heart failure
AOP:561	Aromatase induction leading to estrogen receptor alpha activation via increased estradiol	Unclassified	-	Vertebrates	0.8	KE:2294	Plasma estradiol, increased
						KE:1065	Activation, estrogen receptor alpha
						KE:1076	Increased, circulating estrogen levels
						KE:2251	Estradiol availability, increased

Associated AOPs with Level of Relevance - 3 AOPs with at least 1 MIE associated with chemical, and no associated AO

AOP Identifier	AOP Title	AO Classification	OECD Status	Taxonomic applicability	Coverage Score ⓘ The fraction of KEs within the AOP, that are mapped to the chemical-associated toxicological endpoints.	KE Identifier	KE Name
AOP:8	Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Nervous system disease	Under Development	Rat	0.11	KE:239	Activation, Pregnane-X receptor, NR1l2
AOP:25	Aromatase inhibition leading to reproductive dysfunction	Unclassified	WPHA/WNT Endorsed	Fathead minnow, Medaka, Zebrafish	0.38	KE:36	Inhibition, Aromatase
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:30	Estrogen receptor antagonism leading to reproductive dysfunction	Unclassified	Under Review	Zebra danio, Fathead minnow, Medaka	0.17	KE:112	Antagonism, Estrogen receptor
AOP:60	NR1I2 (Pregnane X Receptor, PXR) activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.17	KE:454	Increased, Triglyceride formation
AOP:60			-		0.17	KE:245	Activation, PXR/SXR
AOP:62	AKT2 activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.25	KE:486	systemic inflammation leading to hepatic steatosis
AOP:91	Sodium channel inhibition leading to reduced survival	Unclassified	-	Medaka, Gammarus pulex, Hydra	0.17	KE:584	Inhibition, sodium channel
AOP:93	sodium channel inhibition leading to increased predation	Unclassified	-		0.25	KE:584	Inhibition, sodium channel
AOP:94	Sodium channel inhibition leading to congenital malformations	Unclassified	-	Human, Rat, Mouse	0.17	KE:584	Inhibition, sodium channel
AOP:111	Decrease in androgen receptor activity leading to Leydig cell tumors (in rat)	Cancer; Reproductive system disease	-	Rattus norvegicus	0.4	KE:754	Increased, Luteinizing hormone (LH)
AOP:111		Cancer; Reproductive system disease	-	Rattus norvegicus	0.4	KE:1614	Decrease, androgen receptor activation
AOP:209	Perturbation of cholesterol and glutathione homeostasis leading to hepatotoxicity: Integrated multi-OMICS approach for building AOP	Gastrointestinal system disease	-		0.25	KE:1289	Perturbation of cholesterol
AOP:209		Gastrointestinal system disease	-		0.25	KE:1286	Down Regulation, GSS and GSTs gene
AOP:232	NFE2/Nrf2 repression to steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.12	KE:1417	NFE2/Nrf2 repression
AOP:263	Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased cell proliferation	Unclassified	WPHA/WNT Endorsed	Zebrafish, Mouse, Rat, Lemna minor, Human, Caenorhabditis elegans	0.5	KE:1821	Decrease, Cell proliferation
AOP:263		Unclassified	WPHA/WNT Endorsed		0.5	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:264	Uncoupling of oxidative phosphorylation leading to growth inhibition via ATP depletion associated cell death	Unclassified	Under Development		0.25	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:265	Uncoupling of oxidative phosphorylation leading to growth inhibition via increased cytosolic calcium	Unclassified	Under Development		0.5	KE:2064	Increase, Cytosolic calcium
AOP:265		Unclassified	Under Development		0.5	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:266	Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased Na-K ATPase activity	Unclassified	Under Development		0.17	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:267	Uncoupling of oxidative phosphorylation leading to growth inhibition via glucose depletion	Unclassified	Under Development		0.4	KE:1821	Decrease, Cell proliferation
AOP:267		Unclassified	Under Development		0.4	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:268	Uncoupling of oxidative phosphorylation leading to growth inhibition via mitochondrial swelling	Unclassified	Under Development		0.25	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:270	Elevated ATP demand for detoxification and repair mechanisms leading to impaired locomotor activity	Unclassified	-		0.12	KE:10008	Increased transcription for detoxification and repair mechanism
AOP:282	Adverse outcome pathway on photochemical toxicity initiated by light exposure	Unclassified	Under Review	Human	0.25	KE:1115	Increase, Reactive oxygen species
AOP:298	Increase in reactive oxygen species (ROS) leading to human treatment-resistant gastric cancer via chronic ROS	Cancer; Gastrointestinal system disease	Under Review	Homo sapiens	0.33	KE:1753	Chronic reactive oxygen species
AOP:298		Cancer; Gastrointestinal system disease	Under Review	Homo sapiens	0.33	KE:1115	Increase, Reactive oxygen species
AOP:306	Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspring	Unclassified	Under Development	Rat, Human, Mouse	0.5	KE:1614	Decrease, androgen receptor activation
AOP:306		Unclassified	Under Development	Rat, Human, Mouse	0.5	KE:26	Antagonism, Androgen receptor
AOP:314	Binding to estrogen receptor (ER)-α in immune cells leading to exacerbation of systemic lupus erythematosus (SLE)	Immune system disease; Musculoskeletal system disease	Under Development	Homo sapiens	0.2	KE:1710	Binding to estrogen receptor (ER)-α in immune cells
AOP:324	Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and cell death	Unclassified	-	Fish	0.25	KE:1115	Increase, Reactive oxygen species
AOP:325	Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and cell death	Unclassified	-	Fish	0.25	KE:1115	Increase, Reactive oxygen species
AOP:326	Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell death	Unclassified	-	Fish	0.25	KE:1115	Increase, Reactive oxygen species
AOP:327	Excessive reactive oxygen species production leading to mortality (1)	Unclassified	-	Daphnia magna	0.2	KE:1115	Increase, Reactive oxygen species
AOP:328	Excessive reactive oxygen species production leading to mortality (2)	Unclassified	-	Daphnia magna	0.2	KE:1115	Increase, Reactive oxygen species
AOP:329	Excessive reactive oxygen species production leading to mortality (3)	Unclassified	-	Daphnia magna, Paracyclopina nana	0.2	KE:1115	Increase, Reactive oxygen species
AOP:330	Excessive reactive oxygen species production leading to mortality (4)	Unclassified	-	Daphnia magna	0.2	KE:1115	Increase, Reactive oxygen species
AOP:331	Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and reduced cell proliferation	Unclassified	-	Daphnia magna, Daphnia middendorffiana, Daphnia pulex, Daphnia pulicaria, Daphnia parvula	0.33	KE:1821	Decrease, Cell proliferation
AOP:331		Unclassified	-		0.33	KE:1115	Increase, Reactive oxygen species
AOP:332	Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell proliferation	Unclassified	-		0.4	KE:1821	Decrease, Cell proliferation
AOP:332		Unclassified	-		0.4	KE:1115	Increase, Reactive oxygen species
AOP:333	Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation	Unclassified	-		0.6	KE:1821	Decrease, Cell proliferation
						KE:1115	Increase, Reactive oxygen species
						KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:344	Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring	Unclassified	Under Development		0.5	KE:1614	Decrease, androgen receptor activation
AOP:344		Unclassified	Under Development		0.5	KE:26	Antagonism, Androgen receptor
AOP:346	Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiation	Unclassified	WPHA/WNT Endorsed	Zebrafish, Oreochromis niloticus, Chinook salmon, Fathead minnow, European sea bass	0.6	KE:1789	Reduction, 17beta-estradiol synthesis by the undifferentiated gonad
						KE:36	Inhibition, Aromatase
						KE:1790	Increased, Differentiation to Testis
AOP:372	Androgen receptor antagonism leading to testicular cancer	Endocrine system disease; Reproductive system disease; Cancer	-		0.6	KE:1614	Decrease, androgen receptor activation
						KE:26	Antagonism, Androgen receptor
						KE:1616	Malformation, cryptorchidism - maldescended testis
AOP:392	Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation	Unclassified	Under Development	Humans	0.6	KE:1866	Fibrinolysis, decreased
						KE:1867	Bradykinin system, hyperactivated
						KE:1497	Increased, recruitment of inflammatory cells
AOP:423	Toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway	Unclassified	-		0.17	KE:1115	Increase, Reactive oxygen species
AOP:438	reactive oxygen species generation leading to increased cardiovascular morbidity and mortality	Cardiovascular system disease	-		0.17	KE:1115	Increase, Reactive oxygen species
AOP:438		Cardiovascular system disease	-		0.17	KE:1919	Increased, Cardiac Dysregulation
AOP:445	Estrogen Receptor Alpha Agonism leads to Impaired Reproduction	Reproductive system disease	-		0.25	KE:1065	Activation, estrogen receptor alpha
AOP:445		Reproductive system disease	-		0.25	KE:1989	Impaired, Oocyte maturation and ovulation
AOP:446	PM-related Adverse outcome pathway frameworks on various systems	Respiratory system disease	-		0.2	KE:149	Increase, Inflammation
						KE:1115	Increase, Reactive oxygen species
						KE:1497	Increased, recruitment of inflammatory cells
						KE:1262	Apoptosis
AOP:447	Kidney failure induced by inhibition of mitochondrial electron transfer chain through apoptosis, inflammation and oxidative stress pathways	Urinary system disease	-		0.08	KE:1917	Altered gene expression, NRF2 dependent antioxidant pathway
AOP:448	ROS, inflammation, and activation of nAChR lead to increased incidence of cardiovascular morbidity and mortality	Cardiovascular system disease	-		0.06	KE:1115	Increase, Reactive oxygen species
AOP:453	Reactive oxygen species and subsequent oxidative stress lead to increased incidence of digestive morbidity and mortality in the general population	Gastrointestinal system disease	-		0.08	KE:1115	Increase, Reactive oxygen species
AOP:469	Reactive oxygen speicies overproduction leading to increased digestive morbidity and mortality in generation population	Gastrointestinal system disease	-		0.08	KE:1115	Increase, Reactive oxygen species
AOP:472	DNA adduct formation leading to kidney failure	Urinary system disease	-		0.22	KE:149	Increase, Inflammation
AOP:472	DNA adduct formation leading to kidney failure	Urinary system disease	-		0.22	KE:1115	Increase, Reactive oxygen species
AOP:477	Androgen receptor (AR) antagonism leading to hypospadias in male (mammalian) offspring	Physical disorder	-		0.67	KE:1614	Decrease, androgen receptor activation
AOP:477		Physical disorder	-		0.67	KE:26	Antagonism, Androgen receptor
AOP:493	ERa inactivation alters AT expansion and functions and leads to insulin resistance and metabolically unhealthy obesity	Acquired metabolic disease	-	Mus musculus, Homo sapiens	0.3	KE:2126	Estrogen receptor alpha inactivation
						KE:2125	Increased fat mass
						KE:1497	Increased, recruitment of inflammatory cells
AOP:507	Nrf2 inhibition leading to vascular disrupting effects via inflammation pathway	Cardiovascular system disease	-	Mouse, Zebrafish, Human	0.17	KE:1417	NFE2/Nrf2 repression
AOP:508	Nrf2 inhibition leading to vascular disrupting effects through activating HIF1α, Semaphorin 6A, and Dll4-Notch pathway	Cardiovascular system disease	-	Mouse, Zebrafish, Human	0.14	KE:1417	NFE2/Nrf2 repression
AOP:509	Nrf2 inhibition leading to vascular disrupting effects through activating apoptosis signal pathway and mitochondrial dysfunction	Cardiovascular system disease	-		0.14	KE:1417	NFE2/Nrf2 repression
AOP:511	The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects	Cardiovascular system disease	-	Human, Mouse, Zebrafish	0.06	KE:1115	Increase, Reactive oxygen species
AOP:517	Pregnane X Receptor (PXR) activation leads to liver steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-	Vertebrates	0.4	KE:291	Accumulation, Triglyceride
AOP:517			-	Vertebrates	0.4	KE:239	Activation, Pregnane-X receptor, NR1l2
AOP:536	Estrogen receptor agonism leading to reduced survival and population growth due to renal failure	Unclassified	-		0.17	KE:111	Agonism, Estrogen receptor
AOP:537	Estrogen receptor agonism leads to reduced fecundity via increased vitellogenin in the liver	Unclassified	-		0.2	KE:111	Agonism, Estrogen receptor
AOP:540	Oxidative Stress in the Fish Ovary Leads to Reproductive Impairment via Reduced Vitellogenin Production	Unclassified	-		0.33	KE:1115	Increase, Reactive oxygen species
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
						KE:1262	Apoptosis
AOP:541	Excessive ROS generation leading to increased incidence of vascular calcification by VSMC phenotype switching	Cardiovascular system disease	-		0.08	KE:1115	Increase, Reactive oxygen species
AOP:545	Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased cholesterol synthesis	Unclassified	-	Mammals	0.2	KE:239	Activation, Pregnane-X receptor, NR1l2
AOP:548	Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased PCSK9 protein expression	Unclassified	-	Mammals	0.2	KE:239	Activation, Pregnane-X receptor, NR1l2
AOP:549	Aromatase inhibition leads to reproductive toxicity (including growth and developmental toxicity) in adult female zebrafish	Unclassified	-		0.25	KE:36	Inhibition, Aromatase
AOP:549		Unclassified	-		0.25	KE:219	Reduction, Plasma 17beta-estradiol concentrations

Associated AOPs with Level of Relevance - 5 AOPs with at least 1 MIE and AO associated with chemical, and there exists a directed path between that MIE and AO

AOP Identifier	AOP Title	AO Classification	OECD Status	Taxonomic applicability	Coverage Score ⓘ The fraction of KEs within the AOP, that are mapped to the chemical-associated toxicological endpoints.	KE Identifier	KE Name
AOP:7	Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female	Reproductive system disease; Endocrine system disease; Reproductive system disease	Under Review	Rat, Mouse, Human	0.8	KE:408	reduction in ovarian granulosa cells, Aromatase (Cyp19a1)
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
						KE:406	decreased, Fertility
AOP:19	Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)	Reproductive system disease	-		0.4	KE:337	N/A, Impairment of reproductive capacity
AOP:19		Reproductive system disease	-		0.4	KE:26	Antagonism, Androgen receptor
AOP:118	Chronic cytotoxicity leading to hepatocellular adenomas and carcinomas (in mouse and rat)	Cancer; Gastrointestinal system disease	-	Mus musculus, Rattus norvegicus	0.75	KE:719	Increase, hepatocellular adenomas and carcinomas
						KE:786	Increase, Cytotoxicity (hepatocytes)
						KE:787	Increase, Regenerative cell proliferation (hepatocytes)
AOP:269	Elevated ATP demand for detoxification and repair mechanisms leading to impaired growth and development	Unclassified	-		0.33	KE:10008	Increased transcription for detoxification and repair mechanism
AOP:269		Unclassified	-		0.33	KE:10013	Impaired growth and development
AOP:300	Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	Under Development	Human, Mouse	0.4	KE:1656	Antagonism, Thyroid Receptor
AOP:300		Cognitive disorder	Under Development	Human, Mouse	0.4	KE:402	Cognitive function, decreased
AOP:345	Androgen receptor (AR) antagonism leading to decreased fertility in females	Endocrine system disease; Reproductive system disease; Reproductive system disease	Under Development	Mammals	0.5	KE:1614	Decrease, androgen receptor activation
						KE:26	Antagonism, Androgen receptor
						KE:406	decreased, Fertility
AOP:440	Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasia	Benign neoplasm; Endocrine system disease; Reproductive system disease; Reproductive system disease; Cancer; Endocrine system disease	Under Development	Human, Rat, Mice	1.0	KE:1047	Increased, secretion of GnRH from hypothalamus
						KE:1046	Suppression, Estrogen receptor (ER) activity
						KE:1972	Increased, Steroidogenic acute regulatory protein (StAR)
						KE:1973	Increased, estrogens
						KE:1052	Hyperplasia, ovarian epithelium
						KE:1076	Increased, circulating estrogen levels
						KE:1053	Promotion, ovarian adenomas
						KE:2092	Promotion, Ovarian Cancer
						KE:1050	Increased, secretion of LH from anterior pituitary
AOP:463	The AOP framwork on silica nanopariticles induced hepatoxicity	Gastrointestinal system disease	-		0.36	KE:2034	liver dysfunction
						KE:149	Increase, Inflammation
						KE:1115	Increase, Reactive oxygen species
						KE:1262	Apoptosis
AOP:485	Thyroid hormone antagonism leading to impaired oligodendrocyte maturation during development and subsequent decreased cognition	Cognitive disorder	-	Human	0.29	KE:1656	Antagonism, Thyroid Receptor
AOP:485		Cognitive disorder	-	Human	0.29	KE:402	Cognitive function, decreased
AOP:488	Increased reactive oxygen species production leading to decreased cognitive function	Cognitive disorder	-	Human	0.43	KE:1869	Diminished protective oxidative stress response
						KE:1115	Increase, Reactive oxygen species
						KE:402	Cognitive function, decreased
AOP:497	ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndrome	Inherited metabolic disorder; Disease of metabolism	-		0.38	KE:2145	Metabolic syndrome
						KE:2126	Estrogen receptor alpha inactivation
						KE:1115	Increase, Reactive oxygen species
AOP:503	Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation	Reproductive system disease; Cancer	Under Review	Human, Mouse	1.0	KE:2152	Epigenetic modification process
						KE:2154	Uterine adenocarcinoma (endometrioid adenocarcinoma Type I)
						KE:1065	Activation, estrogen receptor alpha
						KE:2153	Expression of factors ruling proliferation, modified
						KE:1896	Genomic instability
						KE:772	Increase, Hyperplasia (glandular epithelial cells of endometrium)
AOP:505	Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway	Cancer	-	Human, Mouse, Rat	0.6	KE:885	Increase, Cancer
						KE:149	Increase, Inflammation
						KE:1115	Increase, Reactive oxygen species
AOP:513	Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway	Cancer	-	Human, Mouse, Rat	0.6	KE:885	Increase, Cancer
						KE:1115	Increase, Reactive oxygen species
						KE:1060	Alteration, lipid metabolism
AOP:525	Reduced oligodendrocyte differentiation during neurodevelopment leading to impaired learning and memory	Developmental disorder of mental health	-		0.38	KE:1656	Antagonism, Thyroid Receptor
						KE:2115	Altered, cholesterol metabolism
						KE:2220	Antagonism, Glucocorticoid hormone receptor
						KE:341	Impairment, Learning and memory
						KE:2217	Binding of antagonist to glucocorticoid hormone receptor
AOP:553	Inhibition of Voltage-gated sodium channels (Na⁺ channels) leading to heart failure	Cardiovascular system disease	-	Human, Rodents, Dogs, Pigs, Insects, Fish	0.5	KE:584	Inhibition, sodium channel
AOP:553		Cardiovascular system disease	-	Human, Rodents, Dogs, Pigs, Insects, Fish	0.5	KE:1535	Heart failure

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