DEDUCT | Database of Endocrine Disrupting chemicals and their Toxicity profiles

Bisphenol A

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	0.4	KE:1265	Increase, Fushi tarazu factor-1 gene expression
						KE:1266	Decrease, Circulating crustacean cardioactive peptide
						KE:1267	Decrease, Ecdysis motoneuron bursts
						KE:1264	Increase, Nuclear receptor E75b gene expression
AOP:10	Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain	Nervous system disease	WPHA/WNT Endorsed	Human, Mouse, Rat, Bobwhite quail, Zebrafish	0.33	KE:616	Occurrence, A paroxysmal depolarizing shift
AOP:10		Nervous system disease	WPHA/WNT Endorsed	Human, Mouse, Rat, Bobwhite quail, Zebrafish	0.33	KE:682	Generation, Amplified excitatory postsynaptic potential (EPSP)
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:23	Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)	Unclassified	WPHA/WNT Endorsed	Pimephales promelas	0.4	KE:274	Reduction, Testosterone synthesis by ovarian theca cells
						KE:285	Reduction, Vitellogenin synthesis in liver
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:37	PPARα activation leading to hepatocellular adenomas and carcinomas in rodents	Cancer; Gastrointestinal system disease	Under Development	Mouse, Rat	0.2	KE:716	Increase, cell proliferation (hepatocytes)
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:40	Covalent Protein binding leading to Skin Sensitisation	Integumentary system disease	WPHA/WNT Endorsed	Mouse, Human	0.4	KE:826	Activation, Keratinocytes
AOP:73	Xenobiotic Inhibition of Dopamine-beta-Hydroxylase and subsequent reduced fecundity	Unclassified	-		0.46	KE:528	Decreased, Synthesis of NE
						KE:531	Decreased, LH Surge
						KE:10059	Decreased LH surge for 24 hours
						KE:529	Decreased, GnRH cfos activity
						KE:533	Decreased, Cortical granule release/distribution upon fertilization
						KE:530	Decreased, GnRH pulsatility/release
AOP:77	Nicotinic acetylcholine receptor activation contributes to abnormal foraging and leads to colony death/failure 1	Unclassified	-	Honey bee	0.29	KE:177	Mitochondrial dysfunction
AOP:77		Unclassified	-	Honey bee	0.29	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	0.38	KE:386	Decrease of neuronal network function
						KE:177	Mitochondrial dysfunction
						KE:341	Impairment, Learning and memory
AOP:79	Nicotinic acetylcholine receptor activation contributes to impaired hive thermoregulation and leads to colony loss/failure	Unclassified	-		0.2	KE:177	Mitochondrial dysfunction
AOP:80	Nicotinic acetylcholine receptor activation contributes to accumulation of damaged mitochondrial DNA and leads to colony loss/failure	Unclassified	-	Honey bee	0.25	KE:664	Overwhelmed, Mitochondrial DNA repair mechanisms
AOP:80		Unclassified	-	Honey bee	0.25	KE:177	Mitochondrial dysfunction
AOP:87	Nicotinic acetylcholine receptor activation contributes to abnormal foraging and leads to colony loss/failure	Unclassified	-	Honey bee	0.25	KE:177	Mitochondrial dysfunction
AOP:87		Unclassified	-	Honey bee	0.25	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	0.25	KE:386	Decrease of neuronal network function
AOP:90		Unclassified	-	Honey bee	0.25	KE:341	Impairment, Learning and memory
AOP:93	sodium channel inhibition leading to increased predation	Unclassified	-		0.25	KE:585	Decreased, Sodium conductance 1
AOP:94	Sodium channel inhibition leading to congenital malformations	Unclassified	-	Human, Rat, Mouse	0.33	KE:585	Decreased, Sodium conductance 1
AOP:94		Unclassified	-	Human, Rat, Mouse	0.33	KE:444	Increased, Atrioventricular block and bradycardia
AOP:96	Axonal sodium channel modulation leading to acute mortality	Unclassified	-	Insects, Fish	0.17	KE:599	prolonged, Depolarization of neuronal membrane
AOP:97	5-hydroxytryptamine transporter (5-HTT; SERT) inhibition leading to population decline	Unclassified	-	Mytilus galloprovincialis, Tritonea diomedea, Lymnaea stagnalis, Melibe leonine, Helix lucorum, Lampsilis fasciola	0.1	KE:626	Increased, serotonin (5-HT)
AOP:98	5-hydroxytryptamine transporter (5-HTT; SERT) inhibition leading to decreased shelter seeking and increased predation	Unclassified	-	Pimephales promelas, Echinogammarus marinus	0.2	KE:626	Increased, serotonin (5-HT)
AOP:104	Altered ion channel activity leading impaired heart function	Unclassified	-		0.5	KE:699	Increased, cardiac arrthymia
AOP:104		Unclassified	-		0.5	KE:698	Altered, Action Potential
AOP:105	Alpha2u-microglobulin cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)	Cancer; Urinary system disease	-	Rattus norvegicus	0.17	KE:710	Increase, Regenerative cell proliferation (tubular epithelial cells)
AOP:106	Chemical binding to tubulin in oocytes leading to aneuploid offspring	Chromosomal disease	Under Review	Mus musculus, Homo sapiens, Hamster	0.17	KE:721	Disorganization, Meiotic Spindle
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:1214	Altered gene expression specific to CAR activation, Hepatocytes
AOP:107		Cancer; Gastrointestinal system disease	Under Review	Rattus norvegicus, Mus musculus	0.4	KE:716	Increase, cell proliferation (hepatocytes)
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	0.33	KE:768	Increase, Cytotoxicity
AOP:108		Cancer; Gastrointestinal system disease	-	Mus musculus, Rattus norvegicus	0.33	KE:769	Increase, Oxidative metabolism
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	0.57	KE:1023	Increased, Thyroid-stimulating hormone (TSH)
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						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:116	Cytotoxicity leading to renal tubular adenomas and carcinomas (in male rat)	Cancer; Urinary system disease	-	Rattus norvegicus	0.25	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	0.25	KE:716	Increase, cell proliferation (hepatocytes)
AOP:120	Inhibition of 5α-reductase leading to Leydig cell tumors (in rat)	Cancer; Reproductive system disease	-	Rattus norvegicus, Mus musculus	0.4	KE:791	Increased, Leutinizing hormone (LH)
AOP:120		Cancer; Reproductive system disease	-	Rattus norvegicus, Mus musculus	0.4	KE:1690	Decrease, circulating testosterone levels
AOP:122	Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation	Unclassified	-	Pimephales promelas	0.4	KE:799	Increased, HIF-1 heterodimer
						KE:285	Reduction, Vitellogenin synthesis in liver
						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	0.45	KE:802	Increased, HIF-1 alpha transcription
						KE:285	Reduction, Vitellogenin synthesis in liver
						KE:799	Increased, HIF-1 heterodimer
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:126	Alpha-noradrenergic antagonism leads to reduced fecundity via delayed ovulation	Unclassified	-		0.46	KE:848	Decreased, Binding of NE to NE receptors on GnRH neurons
						KE:531	Decreased, LH Surge
						KE:10059	Decreased LH surge for 24 hours
						KE:529	Decreased, GnRH cfos activity
						KE:533	Decreased, Cortical granule release/distribution upon fertilization
						KE:530	Decreased, GnRH pulsatility/release
AOP:130	Phospholipase A2 (LPLA2) inhibitors leading to hepatotoxicity	Gastrointestinal system disease	Under Development	Sprague-Dawley, Homo sapiens	0.09	KE:177	Mitochondrial dysfunction
AOP:131	Aryl hydrocarbon receptor activation leading to uroporphyria	Inherited metabolic disorder	WPHA/WNT Endorsed	Mouse, Rat, Human, Japanese quail, Chicken, Herring gull, Common Starling	0.17	KE:850	Induction, CYP1A2/CYP1A5
AOP:136	Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors	Benign neoplasm; Respiratory system disease	Under Review		0.43	KE:868	Increase, Tissue Degeneration, Necrosis & Atrophy
						KE:768	Increase, Cytotoxicity
						KE:870	Increase, Cell Proliferation
AOP:144	Endocytic lysosomal uptake leading to liver fibrosis	Gastrointestinal system disease	Under Review	Human, Mouse, Rat	0.33	KE:1493	Increased Pro-inflammatory mediators
						KE:68	Accumulation, Collagen
						KE:177	Mitochondrial dysfunction
AOP:155	Deiodinase 2 inhibition leading to increased mortality via reduced posterior swim bladder inflation	Unclassified	WPHA/WNT Endorsed	Fathead minnow, Zebrafish	0.17	KE:1003	Decreased, Triiodothyronine (T3)
AOP:156	Deiodinase 2 inhibition leading to increased mortality via reduced anterior swim bladder inflation	Unclassified	WPHA/WNT Endorsed	Zebrafish, Fathead minnow	0.17	KE:1003	Decreased, Triiodothyronine (T3)
AOP:157	Deiodinase 1 inhibition leading to increased mortality via reduced posterior swim bladder inflation	Unclassified	WPHA/WNT Endorsed	Zebrafish, Fathead minnow	0.17	KE:1003	Decreased, Triiodothyronine (T3)
AOP:158	Deiodinase 1 inhibition leading to increased mortality via reduced anterior swim bladder inflation	Unclassified	WPHA/WNT Endorsed	Zebrafish, Fathead minnow	0.17	KE:1003	Decreased, Triiodothyronine (T3)
AOP:176	Sodium Iodide Symporter (NIS) Inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.6	KE:425	Decrease of Thyroidal iodide
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
AOP:188	Iodotyrosine deiodinase (IYD) inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.6	KE:425	Decrease of Thyroidal iodide
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
AOP:189	Type I iodothyronine deiodinase (DIO1) inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.5	KE:1116	Decreased, Triiodothyronine (T3) in tissues
AOP:189		Unclassified	-	African clawed frog	0.5	KE:1003	Decreased, Triiodothyronine (T3)
AOP:190	Type II iodothyronine deiodinase (DIO2) inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.67	KE:1116	Decreased, Triiodothyronine (T3) in tissues
						KE:1829	Altered, Thyroid hormone-dependent gene expression
						KE:1828	Increased, Thyroxine (T4) in serum
						KE:1023	Increased, Thyroid-stimulating hormone (TSH)
AOP:191	Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.25	KE:1829	Altered, Thyroid hormone-dependent gene expression
AOP:192	Pendrin inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.5	KE:277	Thyroid hormone synthesis, Decreased
AOP:192		Unclassified	-	African clawed frog	0.5	KE:281	Thyroxine (T4) in serum, Decreased
AOP:193	Dual oxidase (DUOX) inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.5	KE:277	Thyroid hormone synthesis, Decreased
AOP:193		Unclassified	-	African clawed frog	0.5	KE:281	Thyroxine (T4) in serum, Decreased
AOP:194	Hepatic nuclear receptor activation leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.33	KE:961	Increased, Clearance of thyroxine from serum
AOP:194		Unclassified	-	African clawed frog	0.33	KE:281	Thyroxine (T4) in serum, Decreased
AOP:195	5-hydroxytryptamine transporter (5-HTT) inhibition leading to population increase	Unclassified	-	Argopecten irradians, Mercenaria mercenaria, Arctica islandica, Spisula solidissima, Anodonta cygnea, Dreissena polymorpha	0.25	KE:626	Increased, serotonin (5-HT)
AOP:195		Unclassified	-		0.25	KE:1163	Increased, Reproductive Success
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:218	Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity	Unclassified	-	Japanese quail, Cynops pyrrhogaster	0.33	KE:1141	Decreased, Reproductive Success
AOP:218		Unclassified	-	Japanese quail, Cynops pyrrhogaster	0.33	KE:1389	Locomotor activity, decreased
AOP:219	Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior	Unclassified	-	Japanese quail, Cynops pyrrhogaster	0.33	KE:1390	Sexual behavior, decreased
AOP:219		Unclassified	-	Japanese quail, Cynops pyrrhogaster	0.33	KE:1141	Decreased, Reproductive Success
AOP:232	NFE2/Nrf2 repression to steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.12	KE:1422	Reduced, PPARalpha
AOP:238	Deposition of energy leading to population decline via DNA strand breaks and oocyte apoptosis	Unclassified	-	Mice, Daphnia magna	0.17	KE:1775	Increase, Oocyte apoptosis
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:1532	Decrease, Cardiac contractility
AOP:275	Histone deacetylase inhibition leads to neural tube defects	Neural tube defect	-		0.6	KE:1560	Altered differentiation
						KE:1239	Altered, Gene Expression
						KE:1503	Histone acetylation, increase
AOP:280	α-diketone-induced bronchiolitis obliterans	Musculoskeletal system disease; Respiratory system disease	-		0.14	KE:149	Increase, Inflammation
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	0.38	KE:1614	Decrease, androgen receptor activation
						KE:1613	Decrease, dihydrotestosterone (DHT) level
						KE:1690	Decrease, circulating testosterone levels
AOP:289	Inhibition of 5α-reductase leading to impaired fecundity in female fish	Unclassified	Under Development	Fish	0.33	KE:1613	Decrease, dihydrotestosterone (DHT) level
AOP:289		Unclassified	Under Development	Fish	0.33	KE:219	Reduction, Plasma 17beta-estradiol concentrations
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:305	5α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspring	Unclassified	Under Development	Rat, Human, Mouse	0.6	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:1614	Decrease, androgen receptor activation
						KE:1613	Decrease, dihydrotestosterone (DHT) level
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	0.25	KE:285	Reduction, Vitellogenin synthesis in liver
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						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	0.29	KE:1775	Increase, Oocyte apoptosis
AOP:311		Unclassified	-	Daphnia magna, Fish	0.29	KE:1115	Increase, Reactive oxygen species
AOP:315	Inhibition of JAK3 leading to impairment of T-Cell Dependent Antibody Response	Immune system disease	Under Development	Homo sapiens, Mus musculus	0.2	KE:1716	Blockade of STAT5 phosphorylation
AOP:318	Glucocorticoid Receptor activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.4	KE:860	Decreased, Mitochondrial Fatty Acid Beta Oxidation
AOP:318			-		0.4	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	0.33	KE:1738	SARS-CoV-2 cell entry
						KE:1496	Increased, secretion of proinflammatory mediators
						KE:1750	Increased inflammatory immune responses
AOP:321	Reduced environmental pH leading to thinner shells in Mytilus edulis	Unclassified	-		0.55	KE:10037	Downregulation of tyrosinase and hexokinase genes
						KE:10041	Altered metabolic rate
						KE:10039	Higher antioxidant enzyme activities and lipid peroxidation
						KE:592	Reduced, survival
						KE:10040	Reduced calcification rate
						KE:10042	Abnormal development
AOP:334	Glucocorticoid Receptor Agonism Leading to Impaired Fin Regeneration	Unclassified	-	Teleost fish	0.33	KE:2245	Altered Cell Differentiation Signaling
AOP:334		Unclassified	-	Teleost fish	0.33	KE:2089	Altered Bone Cell Homeostasis
AOP:336	DNA methyltransferase inhibition leading to population decline (1)	Unclassified	-	Daphnia magna	0.14	KE:1775	Increase, Oocyte apoptosis
AOP:337	DNA methyltransferase inhibition leading to population decline (2)	Unclassified	-	Daphnia magna	0.12	KE:1776	Increase, Ovarian somatic cell apoptosis
AOP:338	DNA methyltransferase inhibition leading to population decline (3)	Unclassified	-		0.14	KE:1775	Increase, Oocyte apoptosis
AOP:339	DNA methyltransferase inhibition leading to population decline (4)	Unclassified	-		0.12	KE:1776	Increase, Ovarian somatic cell apoptosis
AOP:341	DNA methyltransferase inhibition leading to transgenerational effects (2)	Physical disorder	-	Daphnia magna	0.11	KE:1783	Increase, Ovarian somatic cell apoptosis (F3)
AOP:348	Inhibition of 11β-Hydroxysteroid Dehydrogenase leading to decreased population trajectory	Unclassified	Under Development	Fish	0.6	KE:1756	Decreased, plasma 11-ketotestosterone level
						KE:1758	Impaired, Spermatogenesis
						KE:406	decreased, Fertility
AOP:349	Inhibition of 11β-hydroxylase leading to decresed population trajectory	Unclassified	Under Development	Fish	0.62	KE:1798	Decreased spermatogenesis
						KE:1835	Cortisol and 11β-(OH) testosterone decreased
						KE:1756	Decreased, plasma 11-ketotestosterone level
						KE:406	decreased, Fertility
						KE:1836	Decreased plasma Cortisol level
AOP:362	Immune mediated hepatitis	Gastrointestinal system disease; Immune system disease	-	Homo sapiens, Rat	0.5	KE:1818	Immune cell activation
						KE:1817	Apoptotic cell death
						KE:1633	Increase in inflammation
						KE:177	Mitochondrial dysfunction
AOP:366	Competitive binding to thyroid hormone carrier protein transthyretin (TTR) leading to altered amphibian metamorphosis	Unclassified	-		0.43	KE:281	Thyroxine (T4) in serum, Decreased
						KE:961	Increased, Clearance of thyroxine from serum
						KE:959	Increased, Free serum thyroxine (T4)
AOP:367	Competitive binding to thyroid hormone carrier protein thyroid binding globulin (TBG) leading to altered amphibian metamorphosis	Unclassified	-		0.43	KE:281	Thyroxine (T4) in serum, Decreased
						KE:961	Increased, Clearance of thyroxine from serum
						KE:959	Increased, Free serum thyroxine (T4)
AOP:368	Cytochrome oxidase inhibition leading to increased nasal lesions	Unclassified	-	Rodents, Human	0.33	KE:1825	Increase, Cell death
AOP:374	Binding of Sars-CoV-2 spike protein to ACE 2 receptors expressed on brain cells (neuronal and non-neuronal) leads to neuroinflammation resulting in encephalitis	Nervous system disease	Under Development	Human	0.5	KE:188	Neuroinflammation
AOP:374		Nervous system disease	Under Development	Human	0.5	KE:352	N/A, Neurodegeneration
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: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	0.38	KE:1770	Decrease, Mitochondrial membrane potential
						KE:1115	Increase, Reactive oxygen species
						KE:40	Decrease, Mitochondrial ATP production
AOP:388	Deposition of ionising energy leading to population decline via programmed cell death	Reproductive system disease	-	Lemna minor	0.2	KE:1864	Increase, Programmed cell death
AOP:394	SARS-CoV-2 infection of olfactory epithelium leading to impaired olfactory function (short-term anosmia)	Endocrine system disease	Under Development		0.14	KE:1738	SARS-CoV-2 cell entry
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	0.12	KE:1821	Decrease, Cell proliferation
AOP:410	GSK3beta inactivation leading to increased mortality via defects in developing inner ear	Unclassified	-	Zebrafish	0.1	KE:1825	Increase, Cell death
AOP:432	Deposition of Energy by Ionizing Radiation leading to Acute Myeloid Leukemia	Hematopoietic system disease; Cancer	-	Homo sapiens, Mus musculus	0.36	KE:1493	Increased Pro-inflammatory mediators
						KE:155	Inadequate DNA repair
						KE:870	Increase, Cell Proliferation
						KE:403	Suppression, Immune system
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:444	Ionizing radiation leads to reduced reproduction in Eisenia fetida via reduced spermatogenesis and cocoon hatchability	Unclassified	-		0.33	KE:1392	Oxidative Stress
						KE:1365	Increase, Apoptosis
						KE:1798	Decreased spermatogenesis
AOP:452	Adverse outcome pathway of PM-induced respiratory toxicity	Respiratory system disease	-		0.27	KE:1392	Oxidative Stress
						KE:2013	Airway remodeling
						KE:1262	Apoptosis
AOP:460	Antagonism of Smoothened receptor leading to orofacial clefting	Unclassified	Under Development	Mouse	0.33	KE:1821	Decrease, Cell proliferation
						KE:2040	Decrease, GLI1/2 target gene expression
						KE:1262	Apoptosis
AOP:464	Calcium overload in dopaminergic neurons of the substantia nigra leading to parkinsonian motor deficits	Nervous system disease	-		0.21	KE:1392	Oxidative Stress
						KE:1825	Increase, Cell death
						KE:177	Mitochondrial dysfunction
						KE:389	Increased, Intracellular Calcium overload
AOP:465	Alcohol dehydrogenase leading to reproductive dysfunction	Unclassified	-		0.25	KE:748	Increased, Estrogen receptor (ER) activity
AOP:465	Alcohol dehydrogenase leading to reproductive dysfunction	Unclassified	-		0.25	KE:2050	Increase, developmental abnormalities
AOP:467	Knickkopf leading to mortality	Unclassified	-		0.11	KE:2050	Increase, developmental abnormalities
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	0.4	KE:1392	Oxidative Stress
						KE:155	Inadequate DNA repair
						KE:870	Increase, Cell Proliferation
						KE:1636	Increase, Chromosomal aberrations
AOP:479	Mitochondrial complexes inhibition leading to left ventricular function decrease via increased myocardial oxidative stress	Cardiovascular system disease; Thoracic disease	Under Development		0.43	KE:1392	Oxidative Stress
						KE:1532	Decrease, Cardiac contractility
						KE:177	Mitochondrial dysfunction
AOP:480	Mitochondrial complexes inhibition leading to heart failure via decreased ATP production	Cardiovascular system disease; Thoracic disease	Under Development		0.6	KE:1532	Decrease, Cardiac contractility
						KE:177	Mitochondrial dysfunction
						KE:40	Decrease, Mitochondrial ATP production
AOP:482	Deposition of energy leading to occurrence of bone loss	Musculoskeletal system disease	Under Review	Human, Mouse, Rat, Rhesus monkeys	0.57	KE:1392	Oxidative Stress
						KE:1825	Increase, Cell death
						KE:2245	Altered Cell Differentiation Signaling
						KE:2089	Altered Bone Cell Homeostasis
AOP:496	Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）	Unclassified	-	Zebrafish	0.3	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:1690	Decrease, circulating testosterone levels
AOP:507	Nrf2 inhibition leading to vascular disrupting effects via inflammation pathway	Cardiovascular system disease	-	Mouse, Zebrafish, Human	0.33	KE:1392	Oxidative Stress
AOP:507		Cardiovascular system disease	-	Mouse, Zebrafish, Human	0.33	KE:2181	Angiogenesis dysfunction
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:2181	Angiogenesis dysfunction
AOP:509	Nrf2 inhibition leading to vascular disrupting effects through activating apoptosis signal pathway and mitochondrial dysfunction	Cardiovascular system disease	-		0.57	KE:1392	Oxidative Stress
						KE:2181	Angiogenesis dysfunction
						KE:1365	Increase, Apoptosis
						KE:177	Mitochondrial dysfunction
AOP:510	Demethylation of PPAR promotor leading to vascular disrupting effects	Cardiovascular system disease	-	Human, Mouse, Zebrafish	0.2	KE:1392	Oxidative Stress
AOP:510		Cardiovascular system disease	-	Human, Mouse, Zebrafish	0.2	KE:2181	Angiogenesis dysfunction
AOP:518	Liver X Receptor (LXR) activation leads to liver steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-	Vertebrates	0.4	KE:291	Accumulation, Triglyceride
AOP:518	Liver X Receptor (LXR) activation leads to liver steatosis		-	Vertebrates	0.4	KE:89	Synthesis, De Novo Fatty Acid (FA)
AOP:524	Gluten-driven immune activation leading to celiac disease in genetically predisposed individuals	Immune system disease; Gastrointestinal system disease	-	Human	0.22	KE:2255	Innate immune response, activation
AOP:524		Immune system disease; Gastrointestinal system disease	-	Human	0.22	KE:1931	Intestinal barrier, disruption
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	0.5	KE:2224	Dysregulation of transcriptional expression within PPAR signaling network
						KE:2225	Disrupted Lipid Storage
						KE:291	Accumulation, Triglyceride
						KE:179	Decreased, Mitochondrial fatty acid beta-oxidation
AOP:539	Decreased Sodium/Potassium ATPase activity leads to Heart failure	Cardiovascular system disease	-	Fish	0.14	KE:2261	Decreased, blood plasma volume
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:550	Increased LMNA gene mutation leading to heart failure	Cardiovascular system disease	-	Human, Mouse, Rat	0.2	KE:2066	Altered Signaling Pathways
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:698	Altered, Action Potential
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:1532	Decrease, Cardiac contractility
AOP:553		Cardiovascular system disease	-	Human, Rodents, Dogs, Pigs, Insects, Fish	0.5	KE:698	Altered, Action Potential
AOP:556	Decreased Na/K ATPase activity leading to heart failure	Cardiovascular system disease	-		0.33	KE:1532	Decrease, Cardiac contractility
AOP:556	Decreased Na/K ATPase activity leading to heart failure	Cardiovascular system disease	-		0.33	KE:389	Increased, Intracellular Calcium overload
AOP:558	Phosphodiesterase inhibition leading to heart failure	Cardiovascular system disease	-	Human and other cells in culture, Rodents, Dog, Pig, Zebrafish	0.33	KE:1532	Decrease, Cardiac contractility
AOP:558	Phosphodiesterase inhibition leading to heart failure	Cardiovascular system disease	-		0.33	KE:389	Increased, Intracellular Calcium overload
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:564	DBDPE-induced inhibition of mitochondrial complex Ⅰ leading to population decline via neurotoxicity and metabotoxicity.	Unclassified	-	Zebrafish	0.27	KE:2151	Disruption, neurotransmitter release
						KE:2301	Abnormal, Behavior
						KE:40	Decrease, Mitochondrial ATP production
AOP:568	Inhibition, 5-hydroxytryptamine transporter (5-HTT; SERT) leads to Inhibition, Feeding	Unclassified	-	Fish	0.25	KE:1320	Increased, extracellular serotonin
AOP:574	Inhibition, cytochrome oxidase leads to Loss of olfactory function	Unclassified	-	Rodents, Humans	0.33	KE:1825	Increase, Cell death

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: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	0.6	KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
						KE:406	decreased, Fertility
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	0.62	KE:352	N/A, Neurodegeneration
						KE:381	Reduced levels of BDNF
						KE:341	Impairment, Learning and memory
						KE:188	Neuroinflammation
						KE:52	Decreased, Calcium influx
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	0.5	KE:381	Reduced levels of BDNF
						KE:341	Impairment, Learning and memory
						KE:385	Decrease of synaptogenesis
						KE:386	Decrease of neuronal network function
						KE:52	Decreased, Calcium influx
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	0.5	KE:1493	Increased Pro-inflammatory mediators
						KE:1392	Oxidative Stress
						KE:341	Impairment, Learning and memory
						KE:188	Neuroinflammation
						KE:386	Decrease of neuronal network function
AOP:18	PPARα activation in utero leading to impaired fertility in males	Reproductive system disease	Under Review	Human, Rat, Mouse	0.75	KE:413	Reduction, Testosterone synthesis in Leydig cells
						KE:1690	Decrease, circulating testosterone levels
						KE:266	Decrease, Steroidogenic acute regulatory protein (STAR)
						KE:447	Reduction, Cholesterol transport in mitochondria
						KE:289	Decrease, Translocator protein (TSPO)
						KE:406	decreased, Fertility
AOP:21	Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2	Unclassified	WPHA/WNT Endorsed	Zebrafish, Medaka, Gallus gallus	0.6	KE:317	Altered, Cardiovascular development/function
						KE:1269	Increase, COX-2 expression
						KE:947	Increase, Early Life Stage Mortality
AOP:28	Cyclooxygenase inhibition leading reproductive failure	Reproductive system disease	-		0.33	KE:253	N/A, Reproductive failure
AOP:28	Cyclooxygenase inhibition leading reproductive failure	Reproductive system disease	-		0.33	KE:49	Reduction, Ca and HCO3 transport to shell gland
AOP:34	LXR activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.54	KE:177	Mitochondrial dysfunction
						KE:345	N/A, Liver Steatosis
						KE:115	Increase, FA Influx
						KE:291	Accumulation, Triglyceride
						KE:54	Up Regulation, CD36
						KE:89	Synthesis, De Novo Fatty Acid (FA)
						KE:258	Activation, SCD-1
AOP:39	Covalent Binding, Protein, leading to Increase, Allergic Respiratory Hypersensitivity Response	Respiratory system disease	Under Development	Human, Mouse	0.6	KE:272	Activation/Proliferation, T-cells
						KE:313	Increase, Allergic Respiratory Hypersensitivity Response
						KE:1496	Increased, secretion of proinflammatory mediators
AOP:43	Disruption of VEGFR Signaling Leading to Developmental Defects	Unclassified	WPHA/WNT Endorsed	Mouse, Zebrafish, Rats, Human	0.4	KE:1001	Increased, Developmental Defects
AOP:43		Unclassified	WPHA/WNT Endorsed	Mouse, Zebrafish, Rats, Human	0.4	KE:28	Reduction, Angiogenesis
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	0.67	KE:389	Increased, Intracellular Calcium overload
						KE:177	Mitochondrial dysfunction
						KE:352	N/A, Neurodegeneration
						KE:341	Impairment, Learning and memory
						KE:188	Neuroinflammation
						KE:618	Decreased, Neuronal network function in adult brain
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.	0.8	KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:425	Decrease of Thyroidal iodide
						KE:280	Thyroxine (T4) in neuronal tissue, Decreased
						KE:381	Reduced levels of BDNF
						KE:341	Impairment, Learning and memory
						KE:385	Decrease of synaptogenesis
						KE:386	Decrease of neuronal network function
AOP:63	Cyclooxygenase inhibition leading to reproductive dysfunction	Reproductive system disease	-	Goldfish, Human, Mouse, Rat	0.4	KE:675	Reduced, Reproductive Success
AOP:63		Reproductive system disease	-	Goldfish, Human, Mouse, Rat	0.4	KE:488	Decrease, Ovulation
AOP:64	Glucocorticoid Receptor (GR) Mediated Adult Leydig Cell Dysfunction Leading to Decreased Male Fertility	Reproductive system disease	-	Rattus norvegicus	0.86	KE:413	Reduction, Testosterone synthesis in Leydig cells
						KE:1690	Decrease, circulating testosterone levels
						KE:495	Repressed expression of steroidogenic enzymes
						KE:406	decreased, Fertility
						KE:520	Decreased sperm quantity or quality in the adult, Decreased fertility
						KE:496	Increased apoptosis, decreased fetal/adult Leydig Cells
AOP:91	Sodium channel inhibition leading to reduced survival	Unclassified	-	Medaka, Gammarus pulex, Hydra	0.33	KE:585	Decreased, Sodium conductance 1
AOP:91	Sodium channel inhibition leading to reduced survival	Unclassified	-	Medaka, Gammarus pulex, Hydra	0.33	KE:592	Reduced, survival
AOP:95	Ether-a-go-go (ERG) voltage-gated potassium channel inhibition leading to reduced survival	Unclassified	-		0.33	KE:585	Decreased, Sodium conductance 1
AOP:95		Unclassified	-		0.33	KE:592	Reduced, survival
AOP:99	Histamine (H2) receptor antagonism leading to reduced survival	Unclassified	-	Zebrafish	0.43	KE:636	Decreased, survival
						KE:635	Decreased, locomotion
						KE:341	Impairment, Learning and memory
AOP:100	Cyclooxygenase inhibition leading to reproductive dysfunction via inhibition of female spawning behavior	Reproductive system disease	-	Goldfish	0.29	KE:675	Reduced, Reproductive Success
AOP:100		Reproductive system disease	-	Goldfish	0.29	KE:672	Reduced, Prostaglandin F2alpha synthesis, ovary
AOP:101	Cyclooxygenase inhibition leading to reproductive dysfunction via inhibition of pheromone release	Reproductive system disease	-	Goldfish	0.29	KE:675	Reduced, Reproductive Success
AOP:101		Reproductive system disease	-	Goldfish	0.29	KE:681	Decreased, Prostaglandin F2alpha synthesis, ovary
AOP:102	Cyclooxygenase inhibition leading to reproductive dysfunction via interference with meiotic prophase I /metaphase I transition	Reproductive system disease	-	Goldfish, Human, Rat, Mouse	0.2	KE:690	Reduced, Luteinizing hormone (LH), plasma
AOP:102		Reproductive system disease	-	Goldfish, Human, Rat, Mouse	0.2	KE:675	Reduced, Reproductive Success
AOP:103	Cyclooxygenase inhibition leading to reproductive dysfunction via interference with spindle assembly checkpoint	Reproductive system disease	-	Goldfish, Human, Rat, Mouse	0.2	KE:690	Reduced, Luteinizing hormone (LH), plasma
AOP:103		Reproductive system disease	-	Goldfish, Human, Rat, Mouse	0.2	KE:675	Reduced, Reproductive Success
AOP:124	HMG-CoA reductase inhibition leading to decreased fertility	Reproductive system disease	-	Rattus rattus	0.5	KE:807	Decreased, cholesterol
						KE:1690	Decrease, circulating testosterone levels
						KE:330	Decrease, Fertility
AOP:134	Sodium Iodide Symporter (NIS) Inhibition and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	-	Rat, Homo sapiens	0.78	KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:425	Decrease of Thyroidal iodide
						KE:402	Cognitive function, decreased
						KE:280	Thyroxine (T4) in neuronal tissue, Decreased
						KE:757	Hippocampal anatomy, Altered
						KE:756	Hippocampal gene expression, Altered
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:148	EGFR Activation Leading to Decreased Lung Function	Respiratory system disease	Under Development	Human, Mouse, Rat	0.5	KE:1250	Decrease, Lung function
AOP:148	EGFR Activation Leading to Decreased Lung Function	Respiratory system disease	Under Development	Human, Mouse, Rat	0.5	KE:962	Increase, Mucin production
AOP:149	Peptide Oxidation Leading to Hypertension	Cardiovascular system disease	Under Development	Human, Mouse, Rat, Cow	0.4	KE:952	Hypertension
						KE:927	KE1 : S-Glutathionylation, eNOS
						KE:933	KE6 : Depletion, Nitric Oxide
						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	0.43	KE:317	Altered, Cardiovascular development/function
						KE:948	reduced production, VEGF
						KE:947	Increase, Early Life Stage Mortality
AOP:151	AhR activation leading to preeclampsia	Cardiovascular system disease	Under Development	Homo sapiens, Mus musculus	0.57	KE:1892	increase, placental insufficiency
						KE:1893	increase, Preeclampsia
						KE:1891	abnormal, placental labyrinth vasculature morphology
						KE:948	reduced production, VEGF
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	0.5	KE:68	Accumulation, Collagen
						KE:1497	Increased, recruitment of inflammatory cells
						KE:1496	Increased, secretion of proinflammatory mediators
						KE:1458	Pulmonary fibrosis
AOP:196	Volatile Organic Chemicals Activate TRPA1 Receptor to Induce Sensory Pulmonary Irritation	Respiratory system disease	-		0.22	KE:1218	Opening of calcium channel, Calcium influx
AOP:196		Respiratory system disease	-		0.22	KE:1226	Increased Respiratory irritability and Chronic Cough,
AOP:203	5-hydroxytryptamine transporter inhibition leading to decreased reproductive success and population decline	Reproductive system disease	-		0.25	KE:626	Increased, serotonin (5-HT)
AOP:203		Reproductive system disease	-		0.25	KE:1141	Decreased, Reproductive Success
AOP:204	5-hydroxytryptamine transporter inhibition leading to increased reproductive success and population increase	Unclassified	-		0.25	KE:626	Increased, serotonin (5-HT)
AOP:204		Unclassified	-		0.25	KE:1163	Increased, Reproductive Success
AOP:206	Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis	Musculoskeletal system disease; Respiratory system disease	Under Development	Homo sapiens	0.33	KE:149	Increase, Inflammation
AOP:206		Musculoskeletal system disease; Respiratory system disease	Under Development	Homo sapiens	0.33	KE:1276	Lung fibrosis
AOP:212	Histone deacetylase inhibition leading to testicular atrophy	Reproductive system disease	WPHA/WNT Endorsed	Rat, Human, Mouse	0.83	KE:1503	Histone acetylation, increase
						KE:1515	Spermatocyte depletion
						KE:1505	Cell cycle, disrupted
						KE:1506	Testicular atrophy
						KE:1262	Apoptosis
AOP:220	Cyp2E1 Activation Leading to Liver Cancer	Cancer; Gastrointestinal system disease	WPHA/WNT Endorsed	Rodents, Homo sapiens	0.8	KE:1395	Liver Cancer
						KE:1393	Hepatocytotoxicity
						KE:1392	Oxidative Stress
						KE:1394	Induction, persistent proliferation/sustained proliferation
AOP:237	Substance interaction with lung resident cell membrane components leading to atherosclerosis	Cardiovascular system disease	Under Development	Human, Mouse	0.4	KE:1443	Atherosclerosis
AOP:237		Cardiovascular system disease	Under Development	Human, Mouse	0.4	KE:1496	Increased, secretion of proinflammatory mediators
AOP:241	Latent Transforming Growth Factor beta1 activation leads to pulmonary fibrosis	Musculoskeletal system disease; Respiratory system disease	-		0.33	KE:68	Accumulation, Collagen
AOP:241		Musculoskeletal system disease; Respiratory system disease	-		0.33	KE:1458	Pulmonary fibrosis
AOP:242	Inhibition of lysyl oxidase leading to enhanced chronic fish toxicity	Unclassified	-	Fish	0.25	KE:636	Decreased, survival
AOP:242		Unclassified	-	Fish	0.25	KE:1467	Growth, reduction
AOP:245	Reduction in photophosphorylation leading to growth inhibition in aquatic plants	Unclassified	-	Lemna minor, Lemna gibba	0.18	KE:1521	Decrease, Growth
AOP:245		Unclassified	-	Lemna minor, Lemna gibba	0.18	KE:40	Decrease, Mitochondrial ATP production
AOP:256	Inhibition of mitochondrial DNA polymerase gamma leading to kidney toxicity	Urinary system disease	Under Development	Human, Rat, Mouse	0.4	KE:814	Occurrence, Kidney toxicity
AOP:256		Urinary system disease	Under Development	Human, Rat, Mouse	0.4	KE:177	Mitochondrial dysfunction
AOP:257	Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity	Urinary system disease	Under Development	Human, Rat, Mouse, Dog, Monkey	0.2	KE:814	Occurrence, Kidney toxicity
AOP:260	CYP2E1 activation and formation of protein adducts leading to neurodegeneration	Nervous system disease	-	Human	0.43	KE:1392	Oxidative Stress
						KE:1514	Neurodegeneration
						KE:1513	General Apoptosis
AOP:269	Elevated ATP demand for detoxification and repair mechanisms leading to impaired growth and development	Unclassified	-		0.17	KE:10013	Impaired growth and development
AOP:270	Elevated ATP demand for detoxification and repair mechanisms leading to impaired locomotor activity	Unclassified	-		0.12	KE:10016	Impaired locomotor activity
AOP:272	Deposition of energy leading to lung cancer	Cancer	WPHA/WNT Endorsed	Human, Rat, Mouse	0.57	KE:155	Inadequate DNA repair
						KE:870	Increase, Cell Proliferation
						KE:1636	Increase, Chromosomal aberrations
						KE:1556	Increase, lung cancer
AOP:274	Histone deacetylase inhibition leads to impeded craniofacial development	Musculoskeletal system disease	-		0.5	KE:1559	Facial cartilage structures are reduced in size and morphologically distorted
AOP:274		Musculoskeletal system disease	-		0.5	KE:1558	Collagen production, reduced
AOP:278	IKK complex inhibition leading to liver injury	Unclassified	-		0.12	KE:1549	Liver Injury
AOP:286	Mitochondrial complex III antagonism leading to growth inhibition (1)	Unclassified	-	Lemna minor, Daphnia magna, Danio rerio	0.75	KE:1821	Decrease, Cell proliferation
						KE:1521	Decrease, Growth
						KE:1771	Decrease, Adenosine triphosphate pool
AOP:287	Mitochondrial complex III antagonism leading to growth inhibition (2)	Unclassified	-	Lemna minor, Daphnia magna, Danio rerio	0.75	KE:1825	Increase, Cell death
						KE:1521	Decrease, Growth
						KE:1771	Decrease, Adenosine triphosphate pool
AOP:290	Mitochondrial ATP synthase antagonism leading to growth inhibition (1)	Unclassified	-	Daphnia magna	0.75	KE:1821	Decrease, Cell proliferation
						KE:1521	Decrease, Growth
						KE:1771	Decrease, Adenosine triphosphate pool
AOP:291	Mitochondrial ATP synthase antagonism leading to growth inhibition (2)	Unclassified	-	Daphnia magna	0.75	KE:1825	Increase, Cell death
						KE:1521	Decrease, Growth
						KE:1771	Decrease, Adenosine triphosphate pool
AOP:293	Increased DNA damage leading to increased risk of breast cancer	Genetic disease; Thoracic disease; Cancer	Under Development	Rattus rattus, Mus musculus	0.33	KE:1493	Increased Pro-inflammatory mediators
						KE:1193	N/A, Breast Cancer
						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		0.33	KE:1493	Increased Pro-inflammatory mediators
						KE:1193	N/A, Breast Cancer
						KE:1182	Increase, Cell Proliferation (Epithelial Cells)
AOP:296	Oxidative DNA damage leading to chromosomal aberrations and mutations	Genetic disease; Chromosomal disease	WPHA/WNT Endorsed	Human, Mice, Rat, Fish	0.4	KE:155	Inadequate DNA repair
AOP:296		Genetic disease; Chromosomal disease	WPHA/WNT Endorsed	Human, Mice, Rat, Fish	0.4	KE:1636	Increase, Chromosomal aberrations
AOP:300	Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	Under Development	Human, Mouse	0.6	KE:757	Hippocampal anatomy, Altered
						KE:402	Cognitive function, decreased
						KE:756	Hippocampal gene expression, Altered
AOP:302	Lung surfactant function inhibition leading to decreased lung function	Respiratory system disease	Under Development	Human, Mouse, Rat	0.2	KE:1250	Decrease, Lung function
AOP:304	TBX1 inhibition leading to congenital cardiac conotruncal anomalies	Cardiovascular system disease	-		0.17	KE:1685	Anomalies, Congenital cardiac conotruncal
AOP:322	Alkylation of DNA leading to reduced sperm count	Reproductive system disease	-		0.6	KE:155	Inadequate DNA repair
						KE:1365	Increase, Apoptosis
						KE:1757	Reduce, Sperm count
AOP:323	PPARalpha Agonism Leading to Decreased Viable Offspring via Decreased 11-Ketotestosterone	Unclassified	-	Teleost fish	0.67	KE:2147	Decreased, Viable Offspring
						KE:1756	Decreased, plasma 11-ketotestosterone level
						KE:1758	Impaired, Spermatogenesis
						KE:807	Decreased, cholesterol
AOP:347	Toll-like receptor 4 activation and peroxisome proliferator-activated receptor gamma inactivation leading to pulmonary fibrosis	Musculoskeletal system disease; Respiratory system disease	-		0.33	KE:1283	Activation, TGF-beta pathway
						KE:1458	Pulmonary fibrosis
						KE:1292	Activation, JNK
AOP:379	Binding to ACE2 leading to thrombosis and disseminated intravascular coagulation	Cardiovascular system disease	Under Development	Homo sapiens	0.43	KE:1738	SARS-CoV-2 cell entry
						KE:1869	Diminished protective oxidative stress response
						KE:1846	Thrombosis and Disseminated Intravascular Coagulation
AOP:382	Angiotensin II type 1 receptor (AT1R) agonism leading to lung fibrosis	Musculoskeletal system disease; Respiratory system disease	Under Development		0.83	KE:68	Accumulation, Collagen
						KE:1115	Increase, Reactive oxygen species
						KE:1172	Increased activation, Nuclear factor kappa B (NF-kB)
						KE:1276	Lung fibrosis
						KE:1496	Increased, secretion of proinflammatory mediators
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:406	SARS-CoV-2 infection leading to hyperinflammation	Unclassified	-		0.5	KE:1738	SARS-CoV-2 cell entry
						KE:1869	Diminished protective oxidative stress response
						KE:1868	Hyperinflammation
AOP:414	Aryl hydrocarbon receptor activation leading to lung fibrosis through TGF-β dependent fibrosis toxicity pathway	Musculoskeletal system disease; Respiratory system disease	-		0.4	KE:1920	Altered gene expression, TGF-β dependent fibrosis pathway
AOP:414		Musculoskeletal system disease; Respiratory system disease	-		0.4	KE:1276	Lung fibrosis
AOP:415	Aryl hydrocarbon receptor activation leading to lung fibrosis through IL-6 toxicity pathway	Musculoskeletal system disease; Respiratory system disease	-		0.2	KE:1276	Lung fibrosis
AOP:416	Aryl hydrocarbon receptor activation leading to lung cancer through IL-6 toxicity pathway	Cancer	-		0.5	KE:1669	Increased, DNA damage and mutation
						KE:1115	Increase, Reactive oxygen species
						KE:1670	Lung cancer
AOP:417	Aryl hydrocarbon receptor activation leading to lung cancer through AHR-ARNT toxicity pathway	Cancer	-		0.4	KE:1669	Increased, DNA damage and mutation
AOP:417		Cancer	-		0.4	KE:1670	Lung cancer
AOP:418	Aryl hydrocarbon receptor activation leading to impaired lung function through AHR-ARNT toxicity pathway	Respiratory system disease	-		0.6	KE:1825	Increase, Cell death
						KE:1250	Decrease, Lung function
						KE:1115	Increase, Reactive oxygen species
AOP:419	Aryl hydrocarbon receptor activation leading to impaired lung function through P53 toxicity pathway	Respiratory system disease	-		0.5	KE:1250	Decrease, Lung function
AOP:419		Respiratory system disease	-		0.5	KE:1262	Apoptosis
AOP:420	Aryl hydrocarbon receptor activation leading to lung cancer through sustained NRF2 toxicity pathway	Cancer	-		0.5	KE:870	Increase, Cell Proliferation
AOP:420		Cancer	-		0.5	KE:1670	Lung cancer
AOP:422	Binding of SARS-CoV-2 to ACE2 in enterocytes leads to intestinal barrier disruption	Gastrointestinal system disease	Under Development		0.4	KE:1738	SARS-CoV-2 cell entry
AOP:422		Gastrointestinal system disease	Under Development		0.4	KE:1931	Intestinal barrier, disruption
AOP:430	Binding of SARS-CoV-2 to ACE2 leads to viral infection proliferation	Viral infectious disease	Under Development	Mink, Ferret, Cat, Dog, Syrian golden hamster, Rhesus macaque, Lowland gorilla, Crab eating macaque, African green monkeys, Humans, Hippopotamus amphibius, Bank vole, Lynx canadensis, Puma concolor, Panthera tigris jacksoni, Panthera uncia, Prionailurus viverrinus, Crocuta crocuta, Arctictis binturong, Odocoileus virginianus, American mink, Nasua nasua, Panthera leo, Sus scrofa, European rabbit, Castor fiber, Aonyx cinereus, Vulpes vulpes, Nyctereutes procyonoides, Tupaia belangeri, Bos taurus, Odocoileus hemionus, Peromyscus maniculatus bairdii, Cynopterus brachyotis, Common marmoset, Baboon	0.4	KE:1738	SARS-CoV-2 cell entry
AOP:430		Viral infectious disease	Under Development		0.4	KE:1939	Viral infection and host-to-host transmission, proliferated
AOP:431	Increased tumor necrosis factor (TNF) leading to increased risk of gestational diabetes mellitus (GDM)	Inherited metabolic disorder	-	Human	0.4	KE:1953	Gestational diabetes mellitus
AOP:431		Inherited metabolic disorder	-	Human	0.4	KE:1952	Abnormal, Glucose homeostasis
AOP:437	Inhibition of mitochondrial electron transport chain (ETC) complexes leading to kidney toxicity	Urinary system disease	Under Development		0.6	KE:1392	Oxidative Stress
						KE:814	Occurrence, Kidney toxicity
						KE:177	Mitochondrial dysfunction
AOP:439	Activation of the AhR leading to metastatic breast cancer	Thoracic disease; Cancer	Under Development	Humans, Mice	0.56	KE:1982	metastatic breast cancer
						KE:1971	Increased, tumor growth
						KE:149	Increase, Inflammation
						KE:1241	Increased, Motility
						KE:1262	Apoptosis
AOP:442	Binding to voltage gate sodium channels during development leads to cognitive impairment	Cognitive disorder	Under Review	Rattus norvegicus, Mouse, Humans	0.43	KE:757	Hippocampal anatomy, Altered
						KE:1983	Disruption, action potential generation
						KE:402	Cognitive function, decreased
AOP:451	Interaction with lung resident cell membrane components leads to lung cancer	Cancer	-	Human	0.67	KE:1115	Increase, Reactive oxygen species
						KE:870	Increase, Cell Proliferation
						KE:1669	Increased, DNA damage and mutation
						KE:1670	Lung cancer
						KE:1496	Increased, secretion of proinflammatory mediators
						KE:1497	Increased, recruitment of inflammatory cells
AOP:455	Aryl hydrocarbon receptor activation leading to early life stage mortality via sox9 repression induced impeded craniofacial development	Musculoskeletal system disease	Under Review	Zebrafish, Mouse, Human, Sebastiscus marmoratus, Salmo salar, Chicken	0.67	KE:2020	Decrease, sox9 expression
						KE:1559	Facial cartilage structures are reduced in size and morphologically distorted
						KE:947	Increase, Early Life Stage Mortality
						KE:2021	Increase, slincR expression
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	0.67	KE:317	Altered, Cardiovascular development/function
						KE:2020	Decrease, sox9 expression
						KE:947	Increase, Early Life Stage Mortality
						KE:2021	Increase, slincR expression
AOP:458	AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	-	Rat, Mouse, Monkey, Human	0.62	KE:402	Cognitive function, decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:280	Thyroxine (T4) in neuronal tissue, Decreased
						KE:961	Increased, Clearance of thyroxine from serum
						KE:756	Hippocampal gene expression, Altered
AOP:459	AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	-	Human, Mouse, Rat	0.78	KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:850	Induction, CYP1A2/CYP1A5
						KE:1392	Oxidative Stress
						KE:402	Cognitive function, decreased
						KE:280	Thyroxine (T4) in neuronal tissue, Decreased
						KE:756	Hippocampal gene expression, Altered
AOP:468	Binding of SARS-CoV-2 to ACE2 leads to hyperinflammation (via cell death)	Unclassified	-		0.62	KE:1825	Increase, Cell death
						KE:1496	Increased, secretion of proinflammatory mediators
						KE:1738	SARS-CoV-2 cell entry
						KE:1497	Increased, recruitment of inflammatory cells
						KE:1868	Hyperinflammation
AOP:470	Deposition of energy leads to abnormal vascular remodeling	Cardiovascular system disease	Under Review	Human, Rat, Mouse, Rabbit	0.5	KE:1493	Increased Pro-inflammatory mediators
						KE:1392	Oxidative Stress
						KE:2069	Occurrence, Abnormal Vascular Remodeling
						KE:2244	Altered Stress Response Signaling
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	0.38	KE:386	Decrease of neuronal network function
						KE:389	Increased, Intracellular Calcium overload
						KE:341	Impairment, Learning and memory
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	0.38	KE:1392	Oxidative Stress
						KE:2244	Altered Stress Response Signaling
						KE:341	Impairment, Learning and memory
AOP:485	Thyroid hormone antagonism leading to impaired oligodendrocyte maturation during development and subsequent decreased cognition	Cognitive disorder	-	Human	0.29	KE:2107	Hypomyelination
AOP:485		Cognitive disorder	-	Human	0.29	KE:402	Cognitive function, decreased
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	-		0.27	KE:188	Neuroinflammation
						KE:2121	decreased, Intellectual Quotient
						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:495	Androgen receptor activation leading to prostate cancer	Reproductive system disease; Cancer	-		0.56	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:854	Alterations, Cellular proliferation / hyperplasia
						KE:2135	Prostate cancer
						KE:2136	prostatic intraepithelial neoplasia
						KE:1183	Decreased, Apoptosis (Epithelial Cells)
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	0.75	KE:1339	Increase, intracellular calcium
						KE:2151	Disruption, neurotransmitter release
						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	0.86	KE:1115	Increase, Reactive oxygen species
						KE:177	Mitochondrial dysfunction
						KE:352	N/A, Neurodegeneration
						KE:341	Impairment, Learning and memory
						KE:1262	Apoptosis
						KE:1339	Increase, intracellular calcium
AOP:501	Excessive iron accumulation leading to neurological disorders	Nervous system disease	-	Homo sapiens	0.75	KE:1392	Oxidative Stress
						KE:2150	Neurological disorder
						KE:386	Decrease of neuronal network function
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:519	Cardiac ion channels blockade leading to increased incidence of cardiovascular morbidity and mortality	Cardiovascular system disease	-	Human and other cells in culture, Guinea pig, Rabbit	0.25	KE:1929	Increased incidence of cardiovascular morbidity and mortality in the general population
AOP:521	Essential element imbalance leads to reproductive failure via oxidative stress	Unclassified	-	Murinae gen. sp.	0.71	KE:2206	Increased, histomorphological alteration of testis
						KE:1115	Increase, Reactive oxygen species
						KE:1392	Oxidative Stress
						KE:1758	Impaired, Spermatogenesis
						KE:2147	Decreased, Viable Offspring
AOP:530	Endocytotic lysosomal uptake leads to intestinal barrier disruption	Gastrointestinal system disease	-		0.4	KE:177	Mitochondrial dysfunction
AOP:530		Gastrointestinal system disease	-		0.4	KE:1931	Intestinal barrier, disruption
AOP:551	Increased Muscarinic M2 Receptor leading to Arrhythmia	Symptom	-	Human, Mouse, Rat	0.4	KE:1983	Disruption, action potential generation
AOP:551	Increased Muscarinic M2 Receptor leading to Arrhythmia	Symptom	-	Human, Mouse, Rat	0.4	KE:1106	Occurrence, cardiac arrhythmia
AOP:560	Inhibition of Funny current (If) leading to Arrhythmias	Symptom	-	Human and other cells in culture, Rodents, Dogs, Zebrafish	0.25	KE:1106	Occurrence, cardiac arrhythmia
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
AOP:562	HCN Channel Inhibition leading to Arrhythmias	Symptom	-	Human and other cells in culture, Dogs, Zebrafish, Rodents, Pigs	0.2	KE:1106	Occurrence, cardiac arrhythmia
AOP:569	Decreased DNA methylation of FAM50B/PTCHD3 leading to IQ loss of children via PI3K-Akt pathway	Developmental disorder of mental health	-		0.5	KE:1115	Increase, Reactive oxygen species
						KE:2121	decreased, Intellectual Quotient
						KE:2195	Increase, CNS Neural cell death
AOP:573	Inhibition, cytochrome oxidase leads to Increased, pulmonary edema	Respiratory system disease	-	Rodents, Humans	0.67	KE:2316	Increased, pulmonary edema
AOP:573		Respiratory system disease	-	Rodents, Humans	0.67	KE:1825	Increase, Cell death

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:3	Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits	Nervous system disease	WPHA/WNT Endorsed	Human, Rat	0.57	KE:188	Neuroinflammation
						KE:888	Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I)
						KE:887	Inhibition, NADH-ubiquinone oxidoreductase (complex I)
						KE:177	Mitochondrial dysfunction
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	0.67	KE:239	Activation, Pregnane-X receptor, NR1l2
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:280	Thyroxine (T4) in neuronal tissue, Decreased
						KE:757	Hippocampal anatomy, Altered
						KE:961	Increased, Clearance of thyroxine from serum
						KE:756	Hippocampal gene expression, Altered
AOP:16	Acetylcholinesterase inhibition leading to acute mortality	Unclassified	Under Development		0.29	KE:12	Acetylcholinesterase (AchE) Inhibition
AOP:16	Acetylcholinesterase inhibition leading to acute mortality	Unclassified	Under Development		0.29	KE:1703	Dysregulation of heart rate and vascular tone
AOP:25	Aromatase inhibition leading to reproductive dysfunction	Unclassified	WPHA/WNT Endorsed	Fathead minnow, Medaka, Zebrafish	0.5	KE:36	Inhibition, Aromatase
						KE:285	Reduction, Vitellogenin synthesis in liver
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:27	Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)	Gastrointestinal system disease	Under Development	Humans	0.5	KE:149	Increase, Inflammation
						KE:41	Inhibition, Bile Salt Export Pump (ABCB11)
						KE:1115	Increase, Reactive oxygen species
						KE:288	Activation of specific nuclear receptors, Transcriptional change
AOP:30	Estrogen receptor antagonism leading to reproductive dysfunction	Unclassified	Under Review	Zebra danio, Fathead minnow, Medaka	0.33	KE:112	Antagonism, Estrogen receptor
AOP:30		Unclassified	Under Review	Zebra danio, Fathead minnow, Medaka	0.33	KE:285	Reduction, Vitellogenin synthesis in liver
AOP:36	Peroxisomal Fatty Acid Beta-Oxidation Inhibition Leading to Steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.38	KE:140	Decreased, HSD17B10 expression
						KE:231	Decreased, PPAR-alpha activation
						KE:179	Decreased, Mitochondrial fatty acid beta-oxidation
AOP:38	Protein Alkylation leading to Liver Fibrosis	Gastrointestinal system disease	WPHA/WNT Endorsed	Human, Rat	0.43	KE:244	Alkylation, Protein
						KE:1493	Increased Pro-inflammatory mediators
						KE:68	Accumulation, Collagen
AOP:41	Sustained AhR Activation leading to Rodent Liver Tumours	Cancer; Gastrointestinal system disease	Under Review	Rattus sp. ABTC 42503, Mus sp. 2000082	0.8	KE:854	Alterations, Cellular proliferation / hyperplasia
						KE:165	Activation, Long term AHR receptor driven direct and indirect gene expression changes
						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	0.56	KE:456	Suppression, Constitutive androstane receptor, NR1l3
						KE:454	Increased, Triglyceride formation
						KE:463	Up Regulation, FAS
						KE:465	Increased, FA Influx
						KE:462	Up Regulation, SCD-1
						KE:468	Inhibition, PPAR alpha
						KE:54	Up Regulation, CD36
						KE:451	Inhibition, Mitochondrial fatty acid beta-oxidation
						KE:458	Increased, De Novo FA synthesis
AOP:60	NR1I2 (Pregnane X Receptor, PXR) activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.75	KE:472	Down Regulation, CPT1A
						KE:454	Increased, Triglyceride formation
						KE:474	Down Regulation, HMGCS2
						KE:465	Increased, FA Influx
						KE:462	Up Regulation, SCD-1
						KE:54	Up Regulation, CD36
						KE:471	Inhibition, FoxA2
						KE:245	Activation, PXR/SXR
						KE:179	Decreased, Mitochondrial fatty acid beta-oxidation
AOP:62	AKT2 activation leading to hepatic steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-		0.5	KE:486	systemic inflammation leading to hepatic steatosis
AOP:62	AKT2 activation leading to hepatic steatosis		-		0.5	KE:484	Activation, AKT2
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:112	Increased dopaminergic activity leading to endometrial adenocarcinomas (in Wistar rat)	Reproductive system disease; Cancer	-	Rattus norvegicus	0.83	KE:111	Agonism, Estrogen receptor
						KE:749	Decreased, Progesterone from corpus luteum
						KE:747	Decreased, Prolactin
						KE:746	Increase, Dopaminergic activity
						KE:772	Increase, Hyperplasia (glandular epithelial cells of endometrium)
AOP:118	Chronic cytotoxicity leading to hepatocellular adenomas and carcinomas (in mouse and rat)	Cancer; Gastrointestinal system disease	-	Mus musculus, Rattus norvegicus	0.5	KE:786	Increase, Cytotoxicity (hepatocytes)
AOP:118		Cancer; Gastrointestinal system disease	-	Mus musculus, Rattus norvegicus	0.5	KE:787	Increase, Regenerative cell proliferation (hepatocytes)
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	0.71	KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:1023	Increased, Thyroid-stimulating hormone (TSH)
						KE:279	Thyroperoxidase, Inhibition
						KE:739	Increase, Hypertrophy and proliferation (follicular cell)
AOP:121	Urinary bladder calculi leading to urothelial papillomas and carcinomas (in mouse and rat)	Cancer; Urinary system disease	-	Mus musculus, Rattus norvegicus	0.6	KE:795	Increase, Regenerative cell proliferation (urothelial cells)
						KE:793	Increase, Urinary bladder calculi
						KE:796	Increase, Hyperplasia (urothelial)
AOP:159	Thyroperoxidase inhibition leading to increased mortality via reduced anterior swim bladder inflation	Unclassified	WPHA/WNT Endorsed	Zebrafish, Fathead minnow	0.5	KE:279	Thyroperoxidase, Inhibition
						KE:1003	Decreased, Triiodothyronine (T3)
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
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	0.33	KE:1038	Activation, beta-2 adrenergic receptor
AOP:164		Cancer; Reproductive system disease	-	CD-1 mouse, SD rat	0.33	KE:1042	Proliferation/Clonal Expansion, smooth muscle
AOP:167	Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.	Reproductive system disease; Cancer	-	Mouse, Homo sapiens	0.71	KE:1069	Increased, Hyperplasia (glandular epithelial cells of endometrium)
						KE:1067	Proliferation/Clonal Expansion, aberrant basal cells
						KE:1065	Activation, estrogen receptor alpha
						KE:1066	Promotion, SIX-1 postive basal-type progenitor cells
						KE:1064	prepubertal increase, Estrogen receptor (ER) activity
AOP:175	Thyroperoxidase inhibition leading to altered amphibian metamorphosis	Unclassified	-	African clawed frog	0.75	KE:279	Thyroperoxidase, Inhibition
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
AOP:201	Juvenile hormone receptor agonism leading to male offspring induction associated population decline	Unclassified	-	Daphnia magna, Daphnia pulex	0.33	KE:1205	Activation, Juvenile hormone receptor
AOP:201		Unclassified	-	Daphnia magna, Daphnia pulex	0.33	KE:1206	Induction, Doublesex1 gene
AOP:207	NADPH oxidase and P38 MAPK activation leading to reproductive failure in Caenorhabditis elegans	Reproductive system disease	-	Caenorhabditis elegans	0.75	KE:1115	Increase, Reactive oxygen species
						KE:177	Mitochondrial dysfunction
						KE:1262	Apoptosis
						KE:1279	Increase, Oxidative Stress / Activation, PMK-1 P38 MAPK
						KE:1174	Activation, NADPH Oxidase
						KE:1281	Increased, DNA Damage-Repair
AOP:209	Perturbation of cholesterol and glutathione homeostasis leading to hepatotoxicity: Integrated multi-OMICS approach for building AOP	Gastrointestinal system disease	-		0.62	KE:1285	Up Regulation, Unsaturated fatty acid
						KE:1286	Down Regulation, GSS and GSTs gene
						KE:1289	Perturbation of cholesterol
						KE:1287	Glutathione synthesis
						KE:1284	Up Regulation, SREBF2
AOP:233	Mu Opioid Receptor Agonism leading to Analgesia via K Channel Opening	Developmental disorder of mental health	-		0.2	KE:1425	Mu Opioid Receptor Agonism
AOP:234	Mu Opioid Receptor Agonism leading to Analgesia via Ca Channel Inhibition	Developmental disorder of mental health	-		0.2	KE:1425	Mu Opioid Receptor Agonism
AOP:271	Inhibition of thyroid peroxidase leading to impaired fertility in fish	Unclassified	Under Development	Fish	0.6	KE:279	Thyroperoxidase, Inhibition
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
						KE:277	Thyroid hormone synthesis, Decreased
AOP:276	Inhibition of complex I of the electron transport chain leading to chemical induced Fanconi syndrome	Urinary system disease	-		0.33	KE:888	Binding of inhibitor, NADH-ubiquinone oxidoreductase (complex I)
AOP:276		Urinary system disease	-		0.33	KE:887	Inhibition, NADH-ubiquinone oxidoreductase (complex I)
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	0.5	KE:1753	Chronic reactive oxygen species
						KE:1754	Porcupine-induced Wnt secretion and Wnt signaling activation
						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	0.75	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:1614	Decrease, androgen receptor activation
						KE:26	Antagonism, Androgen receptor
AOP:312	Acetylcholinesterase Inhibition leading to Acute Mortality via Impaired Coordination & Movement	Unclassified	-		0.17	KE:12	Acetylcholinesterase (AchE) Inhibition
AOP:327	Excessive reactive oxygen species production leading to mortality (1)	Unclassified	-	Daphnia magna	0.4	KE:1115	Increase, Reactive oxygen species
AOP:327		Unclassified	-	Daphnia magna	0.4	KE:1769	Increase, Body fluid overload
AOP:328	Excessive reactive oxygen species production leading to mortality (2)	Unclassified	-	Daphnia magna	0.6	KE:1771	Decrease, Adenosine triphosphate pool
						KE:1770	Decrease, Mitochondrial membrane potential
						KE:1115	Increase, Reactive oxygen species
AOP:329	Excessive reactive oxygen species production leading to mortality (3)	Unclassified	-	Daphnia magna, Paracyclopina nana	0.6	KE:1771	Decrease, Adenosine triphosphate pool
						KE:1115	Increase, Reactive oxygen species
						KE:1772	Decrease, Triglyceride
AOP:330	Excessive reactive oxygen species production leading to mortality (4)	Unclassified	-	Daphnia magna	0.4	KE:1365	Increase, Apoptosis
AOP:330		Unclassified	-	Daphnia magna	0.4	KE:1115	Increase, Reactive oxygen species
AOP:335	AOP for urothelial carcinogenesis due to chemical cytotoxicity by mitochondrial impairment	Cancer; Urinary system disease	-	Rat	0.6	KE:795	Increase, Regenerative cell proliferation (urothelial cells)
						KE:796	Increase, Hyperplasia (urothelial)
						KE:177	Mitochondrial dysfunction
AOP:344	Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspring	Unclassified	Under Development		0.75	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:1614	Decrease, androgen receptor activation
						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:363	Thyroperoxidase inhibition leading to altered visual function via altered retinal layer structure	Unclassified	Under Review	Zebrafish	0.5	KE:279	Thyroperoxidase, Inhibition
						KE:1003	Decreased, Triiodothyronine (T3)
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
AOP:364	Thyroperoxidase inhibition leading to altered visual function via decreased eye size	Unclassified	Under Development		0.5	KE:279	Thyroperoxidase, Inhibition
						KE:1003	Decreased, Triiodothyronine (T3)
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
AOP:365	Thyroperoxidase inhibition leading to altered visual function via altered photoreceptor patterning	Unclassified	Under Development		0.5	KE:279	Thyroperoxidase, Inhibition
						KE:1003	Decreased, Triiodothyronine (T3)
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
AOP:372	Androgen receptor antagonism leading to testicular cancer	Endocrine system disease; Reproductive system disease; Cancer	-		0.6	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:1614	Decrease, androgen receptor activation
						KE:26	Antagonism, Androgen receptor
AOP:409	Frustrated phagocytosis leads to malignant mesothelioma	Cancer	-		0.88	KE:1115	Increase, Reactive oxygen species
						KE:870	Increase, Cell Proliferation
						KE:1669	Increased, DNA damage and mutation
						KE:1496	Increased, secretion of proinflammatory mediators
						KE:1896	Genomic instability
						KE:1497	Increased, recruitment of inflammatory cells
						KE:1668	Frustrated phagocytosis
AOP:413	Oxidation and antagonism of reduced glutathione leading to mortality via acute renal failure	Unclassified	-	Fish, Mice	0.5	KE:1607	Increase, Necrosis
						KE:1115	Increase, Reactive oxygen species
						KE:926	Oxidation, Glutathione (To be considered with MIE)
AOP:446	PM-related Adverse outcome pathway frameworks on various systems	Respiratory system disease	-		0.7	KE:1115	Increase, Reactive oxygen species
						KE:165	Activation, Long term AHR receptor driven direct and indirect gene expression changes
						KE:1458	Pulmonary fibrosis
						KE:1993	Increase, Pneumonia
						KE:1392	Oxidative Stress
						KE:1250	Decrease, Lung function
						KE:1994	Increase, Ferroptosis
						KE:1496	Increased, secretion of proinflammatory mediators
						KE:1738	SARS-CoV-2 cell entry
						KE:1198	Activation, Macrophages
						KE:1239	Altered, Gene Expression
						KE:1497	Increased, recruitment of inflammatory cells
						KE:149	Increase, Inflammation
						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	-		0.58	KE:1097	Occurrence, renal proximal tubular necrosis
						KE:177	Mitochondrial dysfunction
						KE:1392	Oxidative Stress
						KE:814	Occurrence, Kidney toxicity
						KE:1365	Increase, Apoptosis
						KE:1633	Increase in inflammation
						KE:1770	Decrease, Mitochondrial membrane potential
AOP:450	Inhibition of AChE and activation of CYP2E1 leading to sensory axonal peripheral neuropathy and mortality	Nervous system disease	-	Rattus norvegicus, Mus musculus, Homo sapiens	0.57	KE:1392	Oxidative Stress
						KE:12	Acetylcholinesterase (AchE) Inhibition
						KE:352	N/A, Neurodegeneration
						KE:618	Decreased, Neuronal network function in adult brain
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	-		0.46	KE:2016	Hepatocyte cell apoptosis
						KE:1115	Increase, Reactive oxygen species
						KE:1931	Intestinal barrier, disruption
						KE:1392	Oxidative Stress
						KE:1995	Abnormal lipid metabolism
						KE:1198	Activation, Macrophages
AOP:469	Reactive oxygen speicies overproduction leading to increased digestive morbidity and mortality in generation population	Gastrointestinal system disease	-		0.46	KE:2016	Hepatocyte cell apoptosis
						KE:1115	Increase, Reactive oxygen species
						KE:1931	Intestinal barrier, disruption
						KE:1392	Oxidative Stress
						KE:1995	Abnormal lipid metabolism
						KE:1198	Activation, Macrophages
AOP:472	DNA adduct formation leading to kidney failure	Urinary system disease	-		0.67	KE:1097	Occurrence, renal proximal tubular necrosis
						KE:1825	Increase, Cell death
						KE:1115	Increase, Reactive oxygen species
						KE:1392	Oxidative Stress
						KE:149	Increase, Inflammation
						KE:1816	Mitochondrial dysfunction EMPTY
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:491	Decrease, GLI1/2 target gene expression leads to orofacial clefting	Unclassified	Under Development	Mouse	0.5	KE:1821	Decrease, Cell proliferation
						KE:2040	Decrease, GLI1/2 target gene expression
						KE:1262	Apoptosis
AOP:511	The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects	Cardiovascular system disease	-	Human, Mouse, Zebrafish	0.25	KE:1392	Oxidative Stress
						KE:2181	Angiogenesis dysfunction
						KE:1115	Increase, Reactive oxygen species
						KE:177	Mitochondrial dysfunction
AOP:517	Pregnane X Receptor (PXR) activation leads to liver steatosis	Gastrointestinal system disease; Inherited metabolic disorder	-	Vertebrates	0.8	KE:115	Increase, FA Influx
						KE:239	Activation, Pregnane-X receptor, NR1l2
						KE:291	Accumulation, Triglyceride
						KE:54	Up Regulation, CD36
AOP:523	Retinoic acid receptor agonism during neurodevelopment leading to microcephaly	Congenital nervous system abnormality; Nervous system disease	-		0.2	KE:2201	Agonism, Retinoic acid receptor
AOP:536	Estrogen receptor agonism leading to reduced survival and population growth due to renal failure	Unclassified	-		0.33	KE:307	Increase, Vitellogenin synthesis in liver
AOP:536		Unclassified	-		0.33	KE:111	Agonism, Estrogen receptor
AOP:537	Estrogen receptor agonism leads to reduced fecundity via increased vitellogenin in the liver	Unclassified	-		0.6	KE:307	Increase, Vitellogenin synthesis in liver
						KE:111	Agonism, Estrogen receptor
						KE:364	Impaired development of, Reproductive organs
AOP:540	Oxidative Stress in the Fish Ovary Leads to Reproductive Impairment via Reduced Vitellogenin Production	Unclassified	-		0.56	KE:1115	Increase, Reactive oxygen species
						KE:1392	Oxidative Stress
						KE:285	Reduction, Vitellogenin synthesis in liver
						KE:1262	Apoptosis
						KE:3	Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AOP:541	Excessive ROS generation leading to increased incidence of vascular calcification by VSMC phenotype switching	Cardiovascular system disease	-		0.38	KE:1493	Increased Pro-inflammatory mediators
						KE:1115	Increase, Reactive oxygen species
						KE:1392	Oxidative Stress
						KE:1198	Activation, Macrophages
						KE:1816	Mitochondrial dysfunction EMPTY

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:6	Antagonist binding to PPARα leading to body-weight loss	Symptom	WPHA/WNT Endorsed	Mus musculus, Homo sapiens, Pimephales promelas, Colinus virginianus, Rattus norvegicus	0.38	KE:1528	Fatty Acid Beta Oxidation, Decreased
						KE:864	Decreased, Body Weight
						KE:998	Binding of antagonist, PPAR alpha
AOP:19	Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)	Reproductive system disease	-		0.8	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:26	Antagonism, Androgen receptor
						KE:337	N/A, Impairment of reproductive capacity
						KE:240	Feminisation or incomplete development, Primary and accessory male sex organs
AOP:42	Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals	Cognitive disorder	WPHA/WNT Endorsed	Human, Rat, Mouse	0.88	KE:402	Cognitive function, decreased
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:280	Thyroxine (T4) in neuronal tissue, Decreased
						KE:279	Thyroperoxidase, Inhibition
						KE:757	Hippocampal anatomy, Altered
						KE:756	Hippocampal gene expression, Altered
AOP:69	Modulation of Adult Leydig Cell Function Subsequent to Decreased Cholesterol Synthesis or Transport in the Adult Leydig Cell	Reproductive system disease	-	Rattus norvegicus, Homo sapiens	0.6	KE:646	Decreased Cholesterol, Decreased sperm quantity and/or quality in the adult testis
						KE:645	Decreased Cholesterol, Decreased Testosterone Production by Adult Leydig Cells
						KE:642	Decreased Cholesterol, Decreased De Novo Biosynthesis of Choleseterol
AOP:128	Kidney dysfunction by decreased thyroid hormone	Urinary system disease	Under Development	Sprague-Dawley, Homo sapiens	0.36	KE:821	Decreased, Sodium reabsorption
						KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:814	Occurrence, Kidney toxicity
AOP:205	AOP from chemical insult to cell death	Unclassified	-	Vertebrates	0.67	KE:1258	Decompartmentalization
						KE:1263	Necrosis
						KE:177	Mitochondrial dysfunction
						KE:1262	Apoptosis
AOP:258	Renal protein alkylation leading to kidney toxicity	Urinary system disease	Under Development	Human, Rat, Mouse	0.8	KE:244	Alkylation, Protein
						KE:814	Occurrence, Kidney toxicity
						KE:177	Mitochondrial dysfunction
						KE:40	Decrease, Mitochondrial ATP production
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	1.0	KE:1771	Decrease, Adenosine triphosphate pool
						KE:1446	Decrease, Coupling of oxidative phosphorylation
						KE:1521	Decrease, Growth
						KE:1821	Decrease, Cell proliferation
AOP:264	Uncoupling of oxidative phosphorylation leading to growth inhibition via ATP depletion associated cell death	Unclassified	Under Development		0.75	KE:1771	Decrease, Adenosine triphosphate pool
						KE:1521	Decrease, Growth
						KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:265	Uncoupling of oxidative phosphorylation leading to growth inhibition via increased cytosolic calcium	Unclassified	Under Development		0.75	KE:1521	Decrease, Growth
						KE:2064	Increase, Cytosolic calcium
						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		0.5	KE:1771	Decrease, Adenosine triphosphate pool
						KE:1521	Decrease, Growth
						KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:267	Uncoupling of oxidative phosphorylation leading to growth inhibition via glucose depletion	Unclassified	Under Development		0.8	KE:1821	Decrease, Cell proliferation
						KE:1521	Decrease, Growth
						KE:1446	Decrease, Coupling of oxidative phosphorylation
						KE:2071	Decrease, Glucose pool
AOP:268	Uncoupling of oxidative phosphorylation leading to growth inhibition via mitochondrial swelling	Unclassified	Under Development		0.5	KE:1521	Decrease, Growth
AOP:268		Unclassified	Under Development		0.5	KE:1446	Decrease, Coupling of oxidative phosphorylation
AOP:281	Acetylcholinesterase Inhibition Leading to Neurodegeneration	Nervous system disease	-		0.3	KE:12	Acetylcholinesterase (AchE) Inhibition
						KE:389	Increased, Intracellular Calcium overload
						KE:352	N/A, Neurodegeneration
AOP:303	Frustrated phagocytosis-induced lung cancer	Cancer	Under Development	Mammals	0.86	KE:1115	Increase, Reactive oxygen species
						KE:870	Increase, Cell Proliferation
						KE:1670	Lung cancer
						KE:1669	Increased, DNA damage and mutation
						KE:1497	Increased, recruitment of inflammatory cells
						KE:1668	Frustrated phagocytosis
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	1.0	KE:1713	Increase of anti-DNA antibody from autoreactive B cell
						KE:1710	Binding to estrogen receptor (ER)-α in immune cells
						KE:1712	Increase of Th2 cells producing IL-4
						KE:1714	Exacerbation of systemic lupus erythematosus (SLE)
						KE:1711	Induction of GATA3 expression
AOP:324	Excessive reactive oxygen species leading to growth inhibition via oxidative DNA damage and cell death	Unclassified	-	Fish	0.5	KE:1521	Decrease, Growth
AOP:324		Unclassified	-	Fish	0.5	KE:1115	Increase, Reactive oxygen species
AOP:325	Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and cell death	Unclassified	-	Fish	0.5	KE:1521	Decrease, Growth
AOP:325		Unclassified	-	Fish	0.5	KE:1115	Increase, Reactive oxygen species
AOP:326	Excessive reactive oxygen species leading to growth inhibition via protein oxidation and cell death	Unclassified	-	Fish	0.5	KE:1521	Decrease, Growth
AOP:326		Unclassified	-	Fish	0.5	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	0.67	KE:1821	Decrease, Cell proliferation
						KE:1505	Cell cycle, disrupted
						KE:1521	Decrease, Growth
						KE:1115	Increase, Reactive oxygen species
AOP:332	Excessive reactive oxygen species leading to growth inhibition via lipid peroxidation and reduced cell proliferation	Unclassified	-		0.8	KE:1821	Decrease, Cell proliferation
						KE:1505	Cell cycle, disrupted
						KE:1521	Decrease, Growth
						KE:1115	Increase, Reactive oxygen species
AOP:333	Excessive reactive oxygen species leading to growth inhibition via uncoupling of oxidative phosphorylation	Unclassified	-		1.0	KE:1821	Decrease, Cell proliferation
						KE:1115	Increase, Reactive oxygen species
						KE:1446	Decrease, Coupling of oxidative phosphorylation
						KE:1771	Decrease, Adenosine triphosphate pool
						KE:1521	Decrease, Growth
AOP:345	Androgen receptor (AR) antagonism leading to decreased fertility in females	Endocrine system disease; Reproductive system disease; Reproductive system disease	Under Development	Mammals	0.67	KE:286	Altered, Transcription of genes by the androgen receptor
						KE:1614	Decrease, androgen receptor activation
						KE:26	Antagonism, Androgen receptor
						KE:406	decreased, Fertility
AOP:392	Decreased fibrinolysis and activated bradykinin system leading to hyperinflammation	Unclassified	Under Development	Humans	1.0	KE:1867	Bradykinin system, hyperactivated
						KE:1496	Increased, secretion of proinflammatory mediators
						KE:1866	Fibrinolysis, decreased
						KE:1868	Hyperinflammation
						KE:1497	Increased, recruitment of inflammatory cells
AOP:405	Organo-Phosphate Chemicals induced inhibition of AChE leading to impaired cognitive function	Cognitive disorder	-	Rattus norvegicus, Mus musculus, Homo sapiens	0.6	KE:12	Acetylcholinesterase (AchE) Inhibition
						KE:402	Cognitive function, decreased
						KE:386	Decrease of neuronal network function
AOP:411	Oxidative stress Leading to Decreased Lung Function	Respiratory system disease	-	Homo sapiens	0.5	KE:1392	Oxidative Stress
AOP:411	Oxidative stress Leading to Decreased Lung Function	Respiratory system disease	-	Homo sapiens	0.5	KE:1250	Decrease, Lung function
AOP:423	Toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway	Unclassified	-		0.5	KE:1817	Apoptotic cell death
						KE:1115	Increase, Reactive oxygen species
						KE:177	Mitochondrial dysfunction
AOP:424	Oxidative stress Leading to Decreased Lung Function via CFTR dysfunction	Respiratory system disease	-	Human	0.33	KE:1392	Oxidative Stress
AOP:424		Respiratory system disease	-	Human	0.33	KE:1250	Decrease, Lung function
AOP:425	Oxidative Stress Leading to Decreased Lung Function via Decreased FOXJ1	Respiratory system disease	-	Human	0.33	KE:1392	Oxidative Stress
AOP:425		Respiratory system disease	-	Human	0.33	KE:1250	Decrease, Lung function
AOP:438	reactive oxygen species generation leading to increased cardiovascular morbidity and mortality	Cardiovascular system disease	-		0.42	KE:1929	Increased incidence of cardiovascular morbidity and mortality in the general population
						KE:1115	Increase, Reactive oxygen species
						KE:177	Mitochondrial dysfunction
						KE:1919	Increased, Cardiac Dysregulation
						KE:1392	Oxidative Stress
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	0.78	KE:1047	Increased, secretion of GnRH from hypothalamus
						KE:1046	Suppression, Estrogen receptor (ER) activity
						KE:1973	Increased, estrogens
						KE:1052	Hyperplasia, ovarian epithelium
						KE:1076	Increased, circulating estrogen levels
						KE:2092	Promotion, Ovarian Cancer
						KE:1050	Increased, secretion of LH from anterior pituitary
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	0.6	KE:155	Inadequate DNA repair
						KE:1172	Increased activation, Nuclear factor kappa B (NF-kB)
						KE:1669	Increased, DNA damage and mutation
						KE:1982	metastatic breast cancer
						KE:112	Antagonism, Estrogen receptor
						KE:1554	Increase Chromosomal Aberrations
AOP:445	Estrogen Receptor Alpha Agonism leads to Impaired Reproduction	Reproductive system disease	-		0.5	KE:1991	Impaired, Reproduction
						KE:1065	Activation, estrogen receptor alpha
						KE:1987	Decreased, Androgen and Progestin
						KE:1989	Impaired, Oocyte maturation and ovulation
AOP:448	ROS, inflammation, and activation of nAChR lead to increased incidence of cardiovascular morbidity and mortality	Cardiovascular system disease	-		0.47	KE:2004	Increased, secretion of catecholamine
						KE:1929	Increased incidence of cardiovascular morbidity and mortality in the general population
						KE:1115	Increase, Reactive oxygen species
						KE:1392	Oxidative Stress
						KE:2001	Cardiac hypertrophy
						KE:2003	Vascular remodeling
						KE:1198	Activation, Macrophages
						KE:1443	Atherosclerosis
AOP:457	Succinate dehydrogenase inhibition leading to increased insulin resistance through reduction in circulating thyroxine	Inherited metabolic disorder	-	Human	1.0	KE:277	Thyroid hormone synthesis, Decreased
						KE:281	Thyroxine (T4) in serum, Decreased
						KE:1392	Oxidative Stress
						KE:2118	Succinate dehydrogenase, inhibited
						KE:2120	Superoxide generation, increased
						KE:2119	Insulin resistance, increased
AOP:463	The AOP framwork on silica nanopariticles induced hepatoxicity	Gastrointestinal system disease	-		0.55	KE:1115	Increase, Reactive oxygen species
						KE:177	Mitochondrial dysfunction
						KE:1392	Oxidative Stress
						KE:2034	liver dysfunction
						KE:149	Increase, Inflammation
						KE:1262	Apoptosis
AOP:474	Succinate dehydrogenase inactivation leads to cancer by promoting EMT	Cancer	Under Development	Human and other cells in culture	0.4	KE:885	Increase, Cancer
AOP:474		Cancer	Under Development	Human and other cells in culture	0.4	KE:2118	Succinate dehydrogenase, inhibited
AOP:488	Increased reactive oxygen species production leading to decreased cognitive function	Cognitive disorder	-	Human	0.71	KE:1115	Increase, Reactive oxygen species
						KE:402	Cognitive function, decreased
						KE:1392	Oxidative Stress
						KE:1869	Diminished protective oxidative stress response
						KE:2107	Hypomyelination
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	0.8	KE:2126	Estrogen receptor alpha inactivation
						KE:1633	Increase in inflammation
						KE:2127	Increased adipocyte size
						KE:2125	Increased fat mass
						KE:1497	Increased, recruitment of inflammatory cells
						KE:2119	Insulin resistance, increased
						KE:2129	Metabolically unhealthy Obesity
						KE:2128	Increased adipocyte numbers
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	-		1.0	KE:2126	Estrogen receptor alpha inactivation
						KE:1115	Increase, Reactive oxygen species
						KE:177	Mitochondrial dysfunction
						KE:1392	Oxidative Stress
						KE:2144	Impaired insulin signaling
						KE:2145	Metabolic syndrome
						KE:2119	Insulin resistance, increased
						KE:179	Decreased, Mitochondrial fatty acid beta-oxidation
AOP:503	Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation	Reproductive system disease; Cancer	Under Review	Human, Mouse	0.83	KE:2152	Epigenetic modification process
						KE:2154	Uterine adenocarcinoma (endometrioid adenocarcinoma Type I)
						KE:1065	Activation, estrogen receptor alpha
						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	1.0	KE:1513	General Apoptosis
						KE:1115	Increase, Reactive oxygen species
						KE:1392	Oxidative Stress
						KE:885	Increase, Cancer
						KE:149	Increase, Inflammation
AOP:513	Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway	Cancer	-	Human, Mouse, Rat	0.8	KE:1513	General Apoptosis
						KE:885	Increase, Cancer
						KE:1115	Increase, Reactive oxygen species
						KE:1060	Alteration, lipid metabolism
AOP:520	Retinoic acid receptor agonism during neurodevelopment leading to impaired learning and memory	Developmental disorder of mental health	-	Mouse, Rat, Human	0.6	KE:2201	Agonism, Retinoic acid receptor
						KE:2204	Altered brain morphology
						KE:341	Impairment, Learning and memory
AOP:525	Reduced oligodendrocyte differentiation during neurodevelopment leading to impaired learning and memory	Developmental disorder of mental health	-		0.46	KE:2216	Binding of antagonist to thyroid hormone receptor
						KE:2115	Altered, cholesterol metabolism
						KE:341	Impairment, Learning and memory
						KE:2220	Antagonism, Glucocorticoid hormone receptor
						KE:2217	Binding of antagonist to glucocorticoid hormone receptor
						KE:2107	Hypomyelination
AOP:532	Retinoic acid receptor agonism during cerebellar development leading to impaired locomotor function	Unclassified	-		0.8	KE:2229	Cerebellar neuronal differentiation. Decreased
						KE:2201	Agonism, Retinoic acid receptor
						KE:2230	Cerebellar hypoplasia
						KE:2231	Locomotor function. Impaired
AOP:533	Retinoic acid receptor antagonism during neurodevelopment leading to impaired learning and memory	Developmental disorder of mental health	-		0.83	KE:341	Impairment, Learning and memory
						KE:1239	Altered, Gene Expression
						KE:385	Decrease of synaptogenesis
						KE:386	Decrease of neuronal network function
						KE:2232	Antagonism, Retinoic acid receptors
AOP:534	Succinate dehydrogenase (SDH) inhibition leads to cancer through oxidative stress	Cancer	-	Vertebrates	0.83	KE:1115	Increase, Reactive oxygen species
						KE:1392	Oxidative Stress
						KE:1446	Decrease, Coupling of oxidative phosphorylation
						KE:885	Increase, Cancer
						KE:2118	Succinate dehydrogenase, inhibited
AOP:535	Binding and activation of GPER leading to learning and memory impairments	Developmental disorder of mental health	-	Mouse, Human	1.0	KE:389	Increased, Intracellular Calcium overload
						KE:1392	Oxidative Stress
						KE:2151	Disruption, neurotransmitter release
						KE:2233	Decreased, ERαβ heterodimers
						KE:341	Impairment, Learning and memory
						KE:188	Neuroinflammation
						KE:2029	protein-coupled estrogen receptor 1 (GPER) activation
						KE:2208	Aberrant, synaptic formation and plasticity
						KE:1262	Apoptosis
AOP:545	Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased cholesterol synthesis	Unclassified	-	Mammals	0.4	KE:2271	Increased, plasma low-density lipoprotein (LDL) cholesterol
AOP:545		Unclassified	-	Mammals	0.4	KE:239	Activation, Pregnane-X receptor, NR1l2
AOP:546	Succinate dehydrogenase inactivation leads to cancer through hypoxic-like mechanisms	Cancer	-	Human and other cells in culture	0.4	KE:885	Increase, Cancer
AOP:546		Cancer	-	Human and other cells in culture	0.4	KE:2118	Succinate dehydrogenase, inhibited
AOP:548	Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased PCSK9 protein expression	Unclassified	-	Mammals	0.4	KE:2271	Increased, plasma low-density lipoprotein (LDL) cholesterol
AOP:548		Unclassified	-	Mammals	0.4	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	-		0.38	KE:36	Inhibition, Aromatase
						KE:1467	Growth, reduction
						KE:219	Reduction, Plasma 17beta-estradiol concentrations
AOP:554	β-adrenergic receptor agonists leading to arrhythmias.	Symptom	-	Human and other cells in culture, Rodents, Macaca mulatta, Zebrafish, Gallus gallus	1.0	KE:1038	Activation, beta-2 adrenergic receptor
						KE:2285	Increased the delayed and early afterdepolarizations
						KE:2284	Increased Intracellular cAMP Levels
						KE:1106	Occurrence, cardiac arrhythmia
AOP:559	Inhibition of acetylcholinesterase (AChE) leading to arrhythmias	Symptom	-	Human and other cells in culture, Rattus norvegicus, Dogs, Sus scrofa, Zebrafish, Insecta sp. BOLD:AAN5199	0.6	KE:12	Acetylcholinesterase (AchE) Inhibition
						KE:1106	Occurrence, cardiac arrhythmia
						KE:698	Altered, Action Potential

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