Clomiphene citrate


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:18PPARα activation in utero leading to impaired fertility in malesReproductive system diseaseUnder ReviewHuman, Rat, Mouse0.12KE:289Decrease, Translocator protein (TSPO)
AOP:27Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)Gastrointestinal system diseaseUnder DevelopmentHumans0.12KE:288Activation of specific nuclear receptors, Transcriptional change
AOP:58NR1I3 (CAR) suppression leading to hepatic steatosisGastrointestinal system disease; Inherited metabolic disorder-Human, Mouse, Rat0.06KE:457Activation, SREBF1
AOP:62AKT2 activation leading to hepatic steatosisGastrointestinal system disease; Inherited metabolic disorder-0.25KE:457Activation, SREBF1
AOP:112Increased dopaminergic activity leading to endometrial adenocarcinomas (in Wistar rat)Reproductive system disease; Cancer-Rattus norvegicus0.17KE:111Agonism, Estrogen receptor
AOP:122Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formationUnclassified-Pimephales promelas0.1KE:800Decreased, Aromatase (Cyp19a1) mRNA
AOP:123Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcriptionUnclassified-Pimephales promelas0.09KE:800Decreased, Aromatase (Cyp19a1) mRNA
AOP:167Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.Reproductive system disease; Cancer-Mouse, Homo sapiens0.14KE:1065Activation, estrogen receptor alpha
AOP:190Type II iodothyronine deiodinase (DIO2) inhibition leading to altered amphibian metamorphosisUnclassified-African clawed frog0.17KE:1829Altered, Thyroid hormone-dependent gene expression
AOP:191Type III iodotyrosine deiodinase (DIO3) inhibition leading to altered amphibian metamorphosisUnclassified-African clawed frog0.5KE:1154Increased, Triiodothyronine (T3) in tissues
KE:1829Altered, Thyroid hormone-dependent gene expression
AOP:209Perturbation of cholesterol and glutathione homeostasis leading to hepatotoxicity: Integrated multi-OMICS approach for building AOPGastrointestinal system disease-0.12KE:1289Perturbation of cholesterol
AOP:3055α-reductase inhibition leading to short anogenital distance (AGD) in male (mammalian) offspringUnclassifiedUnder DevelopmentRat, Human, Mouse0.4KE:286Altered, Transcription of genes by the androgen receptor
KE:1614Decrease, androgen receptor activation
AOP:414Aryl hydrocarbon receptor activation leading to lung fibrosis through TGF-β dependent fibrosis toxicity pathwayMusculoskeletal system disease; Respiratory system disease-0.2KE:1920Altered gene expression, TGF-β dependent fibrosis pathway
AOP:420Aryl hydrocarbon receptor activation leading to lung cancer through sustained NRF2 toxicity pathwayCancer-0.25KE:1917Altered gene expression, NRF2 dependent antioxidant pathway
AOP:443DNA damage and mutations leading to Metastatic Breast CancerThoracic disease; CancerUnder DevelopmentHuman and other cells in culture, Human, Mice, Rat, Canine heartworm nematode, Yeast0.1KE:112Antagonism, Estrogen receptor
AOP:449Ceramide synthase inhibition leading to neural tube defectsNeural tube defect-0.14KE:1502Histone deacetylase inhibition
AOP:465Alcohol dehydrogenase leading to reproductive dysfunctionUnclassified-0.12KE:748Increased, Estrogen receptor (ER) activity
AOP:495Androgen receptor activation leading to prostate cancerReproductive system disease; Cancer-0.11KE:286Altered, Transcription of genes by the androgen receptor
AOP:496Androgen receptor agonism leading to reproduction dysfunction （in zebrafish）Unclassified-Zebrafish0.1KE:286Altered, Transcription of genes by the androgen receptor
AOP:521Essential element imbalance leads to reproductive failure via oxidative stressUnclassified-Murinae gen. sp.0.14KE:2206Increased, histomorphological alteration of testis

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:504SULT1E1 inhibition leading to uterine adenocarcinoma via increased estrogen availability at target organ levelUnclassified-Mammals0.33KE:1065Activation, estrogen receptor alpha
AOP:561Aromatase induction leading to estrogen receptor alpha activation via increased estradiolUnclassified-Vertebrates0.4KE:1065Activation, estrogen receptor alpha
KE:1076Increased, circulating estrogen levels

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:7Aromatase (Cyp19a1) reduction leading to impaired fertility in adult femaleReproductive system disease; Endocrine system disease; Reproductive system diseaseUnder ReviewRat, Mouse, Human0.2KE:408reduction in ovarian granulosa cells, Aromatase (Cyp19a1)
AOP:8Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in MammalsNervous system diseaseUnder DevelopmentRat0.11KE:239Activation, Pregnane-X receptor, NR1l2
AOP:19Androgen receptor antagonism leading to adverse effects in the male foetus (mammals)Reproductive system disease-0.4KE:286Altered, Transcription of genes by the androgen receptor
KE:26Antagonism, Androgen receptor
AOP:25Aromatase inhibition leading to reproductive dysfunctionUnclassifiedWPHA/WNT EndorsedFathead minnow, Medaka, Zebrafish0.12KE:36Inhibition, Aromatase
AOP:30Estrogen receptor antagonism leading to reproductive dysfunctionUnclassifiedUnder ReviewZebra danio, Fathead minnow, Medaka0.17KE:112Antagonism, Estrogen receptor
AOP:60NR1I2 (Pregnane X Receptor, PXR) activation leading to hepatic steatosisGastrointestinal system disease; Inherited metabolic disorder-0.08KE:245Activation, PXR/SXR
AOP:91Sodium channel inhibition leading to reduced survivalUnclassified-Medaka, Gammarus pulex, Hydra0.17KE:584Inhibition, sodium channel
AOP:93sodium channel inhibition leading to increased predationUnclassified-0.25KE:584Inhibition, sodium channel
AOP:94Sodium channel inhibition leading to congenital malformationsUnclassified-Human, Rat, Mouse0.17KE:584Inhibition, sodium channel
AOP:111Decrease in androgen receptor activity leading to Leydig cell tumors (in rat)Cancer; Reproductive system disease-Rattus norvegicus0.2KE:1614Decrease, androgen receptor activation
AOP:232NFE2/Nrf2 repression to steatosisGastrointestinal system disease; Inherited metabolic disorder-0.12KE:1417NFE2/Nrf2 repression
AOP:233Mu Opioid Receptor Agonism leading to Analgesia via K Channel OpeningDevelopmental disorder of mental health-0.2KE:1425Mu Opioid Receptor Agonism
AOP:234Mu Opioid Receptor Agonism leading to Analgesia via Ca Channel InhibitionDevelopmental disorder of mental health-0.2KE:1425Mu Opioid Receptor Agonism
AOP:274Histone deacetylase inhibition leads to impeded craniofacial developmentMusculoskeletal system disease-0.25KE:1502Histone deacetylase inhibition
AOP:275Histone deacetylase inhibition leads to neural tube defectsNeural tube defect-0.2KE:1502Histone deacetylase inhibition
AOP:288Inhibition of 17α-hydrolase/C 10,20-lyase (Cyp17A1) activity leads to birth reproductive defects (cryptorchidism) in male (mammals)Endocrine system disease-Human, Rat0.25KE:1609Inhibition, Cytochrome P450 enzyme (CYP17A1) activity
KE:1614Decrease, androgen receptor activation
AOP:300Thyroid Receptor Antagonism and Subsequent Adverse Neurodevelopmental Outcomes in MammalsCognitive disorderUnder DevelopmentHuman, Mouse0.2KE:1656Antagonism, Thyroid Receptor
AOP:306Androgen receptor (AR) antagonism leading to short anogenital distance (AGD) in male (mammalian) offspringUnclassifiedUnder DevelopmentRat, Human, Mouse0.75KE:286Altered, Transcription of genes by the androgen receptor
KE:1614Decrease, androgen receptor activation
KE:26Antagonism, Androgen receptor
AOP:314Binding to estrogen receptor (ER)-α in immune cells leading to exacerbation of systemic lupus erythematosus (SLE)Immune system disease; Musculoskeletal system diseaseUnder DevelopmentHomo sapiens0.2KE:1710Binding to estrogen receptor (ER)-α in immune cells
AOP:344Androgen receptor (AR) antagonism leading to nipple retention (NR) in male (mammalian) offspringUnclassifiedUnder Development0.75KE:286Altered, Transcription of genes by the androgen receptor
KE:1614Decrease, androgen receptor activation
KE:26Antagonism, Androgen receptor
AOP:345Androgen receptor (AR) antagonism leading to decreased fertility in femalesEndocrine system disease; Reproductive system disease; Reproductive system diseaseUnder DevelopmentMammals0.5KE:286Altered, Transcription of genes by the androgen receptor
KE:1614Decrease, androgen receptor activation
KE:26Antagonism, Androgen receptor
AOP:346Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiationUnclassifiedWPHA/WNT EndorsedZebrafish, Oreochromis niloticus, Chinook salmon, Fathead minnow, European sea bass0.2KE:36Inhibition, Aromatase
AOP:372Androgen receptor antagonism leading to testicular cancerEndocrine system disease; Reproductive system disease; Cancer-0.6KE:286Altered, Transcription of genes by the androgen receptor
KE:1614Decrease, androgen receptor activation
KE:26Antagonism, Androgen receptor
AOP:392Decreased fibrinolysis and activated bradykinin system leading to hyperinflammationUnclassifiedUnder DevelopmentHumans0.2KE:1866Fibrinolysis, decreased
AOP:445Estrogen Receptor Alpha Agonism leads to Impaired ReproductionReproductive system disease-0.25KE:1065Activation, estrogen receptor alpha
KE:1987Decreased, Androgen and Progestin
AOP:447Kidney failure induced by inhibition of mitochondrial electron transfer chain through apoptosis, inflammation and oxidative stress pathwaysUrinary system disease-0.08KE:1917Altered gene expression, NRF2 dependent antioxidant pathway
AOP:477Androgen receptor (AR) antagonism leading to hypospadias in male (mammalian) offspringPhysical disorder-0.67KE:1614Decrease, androgen receptor activation
KE:26Antagonism, Androgen receptor
AOP:485Thyroid hormone antagonism leading to impaired oligodendrocyte maturation during development and subsequent decreased cognitionCognitive disorder-Human0.14KE:1656Antagonism, Thyroid Receptor
AOP:493ERa inactivation alters AT expansion and functions and leads to insulin resistance and metabolically unhealthy obesityAcquired metabolic disease-Mus musculus, Homo sapiens0.1KE:2126Estrogen receptor alpha inactivation
AOP:497ERa inactivation alters mitochondrial functions and insulin signalling in skeletal muscle and leads to insulin resistance and metabolic syndromeInherited metabolic disorder; Disease of metabolism-0.12KE:2126Estrogen receptor alpha inactivation
AOP:503Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulationReproductive system disease; CancerUnder ReviewHuman, Mouse0.17KE:1065Activation, estrogen receptor alpha
AOP:507Nrf2 inhibition leading to vascular disrupting effects via inflammation pathwayCardiovascular system disease-Mouse, Zebrafish, Human0.17KE:1417NFE2/Nrf2 repression
AOP:508Nrf2 inhibition leading to vascular disrupting effects through activating HIF1α, Semaphorin 6A, and Dll4-Notch pathwayCardiovascular system disease-Mouse, Zebrafish, Human0.14KE:1417NFE2/Nrf2 repression
AOP:509Nrf2 inhibition leading to vascular disrupting effects through activating apoptosis signal pathway and mitochondrial dysfunctionCardiovascular system disease-0.14KE:1417NFE2/Nrf2 repression
AOP:517Pregnane X Receptor (PXR) activation leads to liver steatosisGastrointestinal system disease; Inherited metabolic disorder-Vertebrates0.2KE:239Activation, Pregnane-X receptor, NR1l2
AOP:525Reduced oligodendrocyte differentiation during neurodevelopment leading to impaired learning and memoryDevelopmental disorder of mental health-0.31KE:2217Binding of antagonist to glucocorticoid hormone receptor
KE:1656Antagonism, Thyroid Receptor
KE:2115Altered, cholesterol metabolism
KE:2220Antagonism, Glucocorticoid hormone receptor
AOP:536Estrogen receptor agonism leading to reduced survival and population growth due to renal failureUnclassified-0.17KE:111Agonism, Estrogen receptor
AOP:537Estrogen receptor agonism leads to reduced fecundity via increased vitellogenin in the liverUnclassified-0.2KE:111Agonism, Estrogen receptor
AOP:545Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased cholesterol synthesisUnclassified-Mammals0.2KE:239Activation, Pregnane-X receptor, NR1l2
AOP:548Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased PCSK9 protein expressionUnclassified-Mammals0.2KE:239Activation, Pregnane-X receptor, NR1l2
AOP:549Aromatase inhibition leads to reproductive toxicity (including growth and developmental toxicity) in adult female zebrafishUnclassified-0.12KE:36Inhibition, Aromatase
AOP:553Inhibition of Voltage-gated sodium channels (Na⁺ channels) leading to heart failureCardiovascular system disease-Human, Rodents, Dogs, Pigs, Insects, Fish0.25KE:584Inhibition, sodium channel

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:212Histone deacetylase inhibition leading to testicular atrophyReproductive system diseaseWPHA/WNT EndorsedRat, Human, Mouse0.33KE:1506Testicular atrophy
KE:1502Histone deacetylase inhibition
AOP:440Hypothalamus estrogen receptors activity suppression leading to ovarian cancer via ovarian epithelial cell hyperplasiaBenign neoplasm; Endocrine system disease; Reproductive system disease; Reproductive system disease; Cancer; Endocrine system diseaseUnder DevelopmentHuman, Rat, Mice1.0KE:1047Increased, secretion of GnRH from hypothalamus
KE:1046Suppression, Estrogen receptor (ER) activity
KE:1972Increased, Steroidogenic acute regulatory protein (StAR)
KE:1973Increased, estrogens
KE:1052Hyperplasia, ovarian epithelium
KE:1076Increased, circulating estrogen levels
KE:1053Promotion, ovarian adenomas
KE:2092Promotion, Ovarian Cancer
KE:1050Increased, secretion of LH from anterior pituitary
DISCLAIMER

We have built a comprehensive resource which compiles potential endocrine disrupting chemicals (EDCs) based on the observed adverse effects or endocrine-mediated endpoints in published experiments on humans or rodents to support basic research. We are not responsible for any errors or omissions in the published research articles or supporting literature on potential EDCs compiled in this resource. Users are advised to exercise their own judgement on the weight of evidence for potential EDCs compiled in this resource. Importantly, our sole goal to build this resource on potential EDCs is to enable future basic research towards better understanding of the systems-level perturbations upon chemical exposure rather than influencing regulatory advice on chemical use.