Aromatase, induction

50471-44-8

FSCWZHGZWWDELK-UHFFFAOYNA-N

FSCWZHGZWWDELK-UHFFFAOYSA-N

Vinclozolin

2,4-Oxazolidinedione, 3-(3,5-dichlorophenyl)-5-ethenyl-5-methyl- (.+-.)-Vinclozolin BAS 352-04F N-3,5-Dichlorophenyl-5-methyl-5-vinyl-1,3-oxazolidine-2,4-dione N-3,5-Dichlorophenyl-5-methyl-5-vinyloxazolidine-2,4-dione N-3,5-Dichlorphenyl-5-methyl-5-vinyl-1,3-oxazolidin-2,4-dion N-3,5-diclorofenil-5-metil-5-vinil-1,3-oxazolidina-2,4-diona Ornalin Ranilan Ronilan Ronilan 50WP

DTXSID4022361

1912-24-9

MXWJVTOOROXGIU-UHFFFAOYSA-N

Atrazine

1,3,5-Triazine-2,4-diamine, 6-chloro-N-ethyl-N'-(1-methylethyl)- 1,3,5-Triazine-2,4-diamine, 6-chloro-N2-ethyl-N4-(1-methylethyl)- 1-Chloro-3-ethylamino-5-isopropylamino-2,4,6-triazine 2-Chloro-4-(ethylamino)-6-(2-propylamino)-s-triazine 2-Chloro-4-(ethylamino)-6-(isopropylamino)-s-triazine 2-Chloro-4-(ethylamino)-6-(isopropylamino)triazine 2-Chloro-4-ethylamineisopropylamine-s-triazine 2-Chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine 2-Chloro-4-ethylamino-6-isopropylamino-s-triazine 2-Ethylamino-4-isopropylamino-6-chloro-s-triazine 6-Chloro-4-(ethylamino)-2-(isopropylamino)-s-triazine 6-Chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine AAtrex Nine-O Akticon Aktikon Aktikon PK Aktinit A Aktinit PK Argezin Atragranz Atranex Atranex 80WP Atraphyt Atrataf Atrazin atrazina Azoprim Chromozin Farmozine Gesamprim Gesaprim Gesaprim 50 Gesaprim 500 Gesaprim L Herbatoxol Hungazin Hungazin PK NSC 163046 Nu-Trazine Oleogesaprim Oleogesaprim 200 Primatol A Primoleo Radazin Radazin T s-Triazine, 2-chloro-4-(ethylamino)-6-(isopropylamino)- Triazine A 1294 Zealin L Zeazine

DTXSID9020112

28822-58-4

APIXJSLKIYYUKG-UHFFFAOYSA-N

Isobutylmethylxanthine

methylisobutylxanthine 1H-Purine-2,6-dione, 3,7-dihydro-1-methyl-3-(2-methylpropyl)- 1H-Purine-2,6-dione, 3,9-dihydro-1-methyl-3-(2-methylpropyl)- 1-Methyl-3-isobutylxanthine 3,7-dihidro-3-isobutil-1-metil-1H-purina-2,6-diona 3,7-Dihydro-3-isobutyl-1-methyl-1H-purin-2,6-dion 3,7-dihydro-3-isobutyl-1-methyl-1H-purine-2,6-dione NSC 165960 Xanthine, 3-isobutyl-1-methyl- IBMX 3-Isobutyl-1-methylxanthine

DTXSID0040549

309-00-2

QBYJBZPUGVGKQQ-SJJAEHHWNA-N

QBYJBZPUGVGKQQ-SJJAEHHWSA-N

Aldrin

1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-, (1.alpha.,4.alpha.,4a.beta.,5.alpha.,8.alpha.,8a.beta.)-1,4:5,8-Dimethanonaphthalene 1,4:5,8-Dimethanonaphthalene, 1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-, (1R,4S,4aS,5S,8R,8aR)-rel- 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexachloro-1,4-endo-exo-5,8-dimethanonaphthalene 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-(1α,4α,4aβ,5α,8α,8aβ)1,4 ,5,8-dimethanonaphthalene 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-(1α,4α,4aβ,5β,8β,8aβ)-1,4,5,8-dimethanonaphthalene 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-1,4,5,8-endo, endodimethanonaphthalene 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-1,4-endo-exo-5,8-dimethanonaphthalene 1,2,3,4,10,10-Hexachloro-1,4,4a,5,8,8a-hexahydro-endo-1,4-exo-5,8-dimethanonaphthalene 1,4,5,8-Dimethanonaphthalene, 1,2,3,4,10,10-10-hexachloro-1,4,4a,5,8,8a-hexahydro-, (α,4α,4β,5α,8α,8aβ)- 1,4,5,8-Dimethanonaphthalene, 1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro (1α,4α,4aβ,5β,8β,8aβ)- 1,4,5,8-Dimethanonaphthalene,1,2,3,4,10,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-,(1α,4α,4aβ,5α,8α,8β)- 1,4:5,8-Dimethanonaphthalene, 1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-, (1α,4α,4aβ,5α,8α,8aβ)- 1,4:5,8-Dimethanonaphthalene, 1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro-, endo,exo- 1,4:5,8-Dimethanonaphthalene,1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a- hexahydro-(1α,4α,4aβ,5α,8α,8aβ)- Aldocit Aldrin[1,4,5,8-Dimethanonaphthalene, 1,2,3,4,10,10-hexachloro-1,4,4a,5,8,8a-hexahydro (1 α,4α,4aβ,5β,8β,8aβ)-] aldrine Kortofin Octalene Seedrin Tatuzinho

DTXSID8020040

12789-03-6

Technical chlordane

Termex Chlor Kil Chlordan Chlorotox Kypchlor Octachlor Octachlordane Ortho-Klor Starchlor Unexan-Koeder

DTXSID5023954

52315-07-8

KAATUXNTWXVJKI-UHFFFAOYNA-N

KAATUXNTWXVJKI-UHFFFAOYSA-N

Cypermethrin

3-(2,2-Dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, cyano (3-phenoxyphenyl)methyl ester Zeta-cypermethrin (ECL) Cyclopropanecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-, cyano(3-phenoxyphenyl)methyl ester (RS)-alpha-Cyano-3-phenoxybenzyl (1RS)-cis-trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (S)-α-Cyano-3-phenoxybenzyl(1RS,3RS;1RS,3SR)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-carboxylate 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate de α-cyano-3-phenoxybenzyle 3-(2,2-diclorovinil)-2,2-dimetilciclopropanocarboxilato de α-ciano-3-fenoxibencilo Agrometrin Agrothrin Almetrin Ambush C Ambush CY Antiborer 3767 Asymmethrin Barrage Barricade Barricade 10EC Basathrin Chinimix Chinmix Cilcord cis-Cypermethrin Creokhin Cyano(3-phenoxyphenyl)methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate Cymbush Cympa-Ti Cymperator Cyperco Cyperil Cyperkill Demon TC Ecofleece Sheep Dip (Non-OP) Ectomin Ectopor Flytick Hilcyperin Kreokhin Leptocide Luseweilei Neramethrin Neramethrin EC 50 Nurse Green Peststop B Peststop B 5SC Polytrin Prevail Prevail FT PYR-VU-TO 2 Ralothrin Ripcord Ronatak Summerin Supercypermethrin Supercypermethrin forte Supermethrin Supersect alpha-Cyan-3-phenoxybenzyl-3-(2,2-dichlorvinyl)-2,2-dimethylcyclopropancarboxylat alpha-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate alpha-Cyano-m-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate

DTXSID1023998

298-00-0

RLBIQVVOMOPOHC-UHFFFAOYSA-N

Methyl parathion

Parathion-methyl Phosphorothioic acid, O,O-dimethylO-(4-nitrophenyl) ester Azophos Bravik 600CE Demethylfenitrothion Dimethyl 4-nitrophenyl phosphorothioate Dimethyl parathion Dimethyl p-nitrophenyl phosphorothionate Dimethyl p-nitrophenyl thiophosphate Folidol 600 Folidol M Folidol M 40 Folidol M 50 Mentox 600CE Metacid Metacide Metaphos Methyl 1605 Methyl Bladan Methyl E 605 Methylthiophos Metil paration Morphos M-Parathion O,O-Dimethyl O-(4-nitrophenyl) phosphorothioate O,O-Dimethyl O-(4-nitrophenyl) thiophosphate O,O-Dimethyl O-(p-nitrophenyl) phosphorothioate O,O-Dimethyl O-(p-nitrophenyl) thiophosphate O,O-Dimethyl O-p-nitrophenyl phosphorothioate Oleovofotox Parataf Parathion M Parathion methyl homolog PARATHION, METHYL paration-metil Paratuf Penncap M Penncap MLS Phosphorothioic acid, O,O-dimethyl O-(4-nitrophenyl) ester Phosphorothioic acid, O,O-dimethyl O-(p-nitrophenyl) ester Probel MP 2 Quinophos Sinafid M 48 Thiophenit Vofatox Wofatox

DTXSID1020855

115-29-7

RDYMFSUJUZBWLH-UHFFFAOYNA-N

RDYMFSUJUZBWLH-UHFFFAOYSA-N

Endosulfan

6,9-Methano-2,4,3-benzodioxathiepin, 6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-, 3-oxide 1,2,3,4,7,7-Hexachlorobicyclo[2.2.1]-2-heptene-5,6-bisoxymethylene sulfite 1,4,5,6,7,7-Hexachloro-5-norbornene-2,3-dimethanol cyclic sulfite 5-Norbornene-2,3-dimethanol, 1,4,5,6,7,7-hexachloro-, cyclic sulfite 6,7,8,9,10,10-Hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3-benzodioxathiepin-3-oxide 6,7,8,9,10,10-Hexachloro-1,5,5α,6,9,9α-hexahydro-6,9-methano-2,4,3-benzodioxathiepin-3-oxide 6,9-Methano-2,4,3-benzodioxathiepin, 6,7,8,9,10,10-hexachloro-1,5, 5a,6,9,9a-hexahydro-, 3-oxide Benzoepin Chlorthiepin Endocel Endodhan Endosulfan 35EC Endosulphan Endotaf Ethiosulfan Madhusulphan Niagara 5462 Parrysulfan Thiodan Thiodan 35EC Thioflo Thionex α,β-1,2,3,4,7,7-Hexachlorobicyclo[2.2.1]-2-heptene-5,6-bisoxymethylene sulfite

DTXSID1020560

72-43-5

IAKOZHOLGAGEJT-UHFFFAOYSA-N

Methoxychlor

MXC Benzene, 1,1'-(2,2,2-trichloroethylidene)bis[4-methoxy- 1,1-(2,2,2-Trichloroethylidene)bis(4-methoxybenzene) 1,1'-(2,2,2-trichloroethylidene)bis[4-methoxybenzene] 1,1,1-Trichloro-2,2-bis(4-methoxyphenyl)ethane 1,1,1-Trichloro-2,2-di(4-methoxyphenyl)ethane 1,1-Bis(p-methoxyphenyl)-2,2,2-trichloroethane 2,2,2-Trichloro-1,1-bis(4-methoxyphenyl)ethane 2,2-Bis(4-methoxyphenyl)-1,1,1-trichloroethane 2,2-Bis(p-methoxyphenyl)-1,1,1-trichloroethane 2,2-Di-p-anisyl-1,1,1-trichloroethane 4,4'-(2,2,2-Trichloroethylidene)dianisole Di(p-methoxyphenyl)(trichloromethyl)methane Dimethoxy-DDT Ethane, 1,1,1-trichloro-2,2-bis(p-methoxyphenyl)- Marlate Mesox K Methoxcide Methoxychlor [Benzene, 1,1'-(2,2,2-trichloroethylidene)bis[4-methoxy-] Methoxychlore Methoxy-DDT Metox plynny metoxicloro Mezox K NSC 8945 p,p'-Dimethoxydiphenyltrichloroethane p,p'-DMDT p,p'-Methoxychlor 1,1,1-trichloro-2,2-bis(p-methoxyphenyl)ethane p,p'- Methoxychlor

DTXSID9020827

19666-30-9

CHNUNORXWHYHNE-UHFFFAOYSA-N

Oxadiazon

1,3,4-Oxadiazol-2(3H)-one, 3-[2,4-dichloro-5-(1-methylethoxy)phenyl]-5-(1,1-dimethylethyl)- 2-t-Butyl-4-(2, 4-dichloro-5-isopropoxyphenyl)-1,3,4-oxadiazolin-5-one 2-tert-Butyl-4-(2,4-dichloro-5-isopropoxyphenyl)-1,3,4-oxadiazolin-5-one 2-tert-Butyl-4-(2,4-dichloro-5-isopropoxyphenyl)-5-oxo-1,3,4-oxadiazoline 2-tert-Butyl-4-(2,4-dichloro-5-isopropyloxyphenyl)-5-oxo-1,3,4-oxadiazoline 3-[2,4-Dichlor-5-(1-methylethoxy)phenyl]-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-on 3-[2,4-dichloro-5-(1-methylethoxy)phenyl]-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one 3-[2,4-dichloro-5-(1-methylethoxy)phenyl]-5-(1,1-dimethylethyl)-1,3,4-oxadiazole-2(3H)-one 5-(1,1-dimetiletil)-3-[2,4-dicloro-5-(1-metiletoxi)fenil]-5-1,3,4-oxadiazol-2(3H)-ona Foresite Kensogen Ti Oxadiazone Ronstar Δ2-1,3,4-Oxadiazolin-5-one, 2-tert-butyl-4-(2,4-dichloro-5-isopropoxyphenyl)-

DTXSID3024239

51218-45-2

WVQBLGZPHOPPFO-UHFFFAOYNA-N

WVQBLGZPHOPPFO-UHFFFAOYSA-N

Metolachlor

Acetamide, 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)- 2-Chlor-2'-ethyl-N-(2-methoxy-1-methylethyl)-6'-methylacetanilid 2-chloro-2'-ethyl-N-(2-methoxy-1-methylethyl)-6'-methylacetanilide 2-Chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide 2-cloro-2'-etil-N-(2-metoxi-1-metiletil)-6'-metilacetanilida Dual 960 EC Dual II Dual Magnum Dual Triple Jindual Metetilachlor Metoken N-(1-Methyl-2-methoxyethyl)-N-chloroacetyl-2-ethyl-6-methylaniline Pennant Yibingjiacaoan

DTXSID4022448

688-73-3

DBGVGMSCBYYSLD-UHFFFAOYSA-N

Tributyltin

hidruro de tri-n-butilestano Hydridotris(butyl)tin Hydrure de tributylstannane hydrure de tri-n-butyletain Tributylstannane Tributylstannic hydride Tributylstannyl hydride TRIBUTYLTIN HYDRIDE Tri-n-butylstannane tri-n-butyltin hydride Tri-n-butylzinnhydrid

DTXSID0040709

17804-35-2

RIOXQFHNBCKOKP-UHFFFAOYSA-N

Benomyl

Benomyl (Methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate) Carbamic acid, [1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]-, methyl ester [1-[(Butylamino)carbonyl]-1H-benzimidazol-2-yl]carbamic acid methyl ester 2-Benzimidazolecarbamic acid, 1-(butylcarbamoyl)-, methyl ester Agrocit Benlate Benlate 50W Benomil benomilo Benomyl-Imex Carbamic acid, (1-(butylamino)carbonyl)-1H-benzimidazol-2-yl), methyl ester Carbamic acid, N-[1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]-, methyl ester Du Pont 1991 Fundazol Fundazol 50WP Fungicide D-1991 Fungochrom Kribenomyl Methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate Methyl 1-(butylcarbamoyl)-2-benzimidazolylcarbamate Methyl 1-(butylcarbamoyl)benzimidazol-2-ylcarbamate NSC 263489 Tersan 1991 Zetamil

DTXSID5023900

72-55-9

UCNVFOCBFJOQAL-UHFFFAOYSA-N

p,p'-DDE

1,1-Dichloro-2,2-bis(4-chlorophenyl)ethene p,p'-Dichlorodiphenyl dichloroethylene Benzene, 1,1'-(dichloroethenylidene)bis[4-chloro- 1,1'-(Dichloroethenylidene)bis(4-chlorobenzene) 1,1-Bis(4-chlorophenyl)-2,2-dichloroethene 1,1-BIS-(4-CHLORPHENYL)-2,2-DICHLOR-AETHEN 1,1-Bis(p-chlorophenyl)-2,2-dichloroethylene 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene 1,1-Dichloro-2,2-di(p-chlorophenyl)ethylene 2,2-bis(4-Chlorophenyl)-1,1-dichloroethylene 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene 2,2-Bis(p-chlorphenyl)-1,1-dichlorethylen 2,2-bis(p-clorofenil)-1,1-dicloroetileno 2,2-Dichloro-1,1-bis(4-chlorophenyl)ethylene 4,4'-Dichlorodiphenyldichloroethylene Benzene, 1,1'-(2,2-dichloroethenylidene)bis[4-chloro- Benzene, 1,1'-(dichloroethenylidene)bis(4-chloro- Dichloro diphenyl dichloroethane DICHLORODIPHENYLDICHLOROETHYLENE Ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl)- Ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl)-, NSC 1153 p,p'-Dichlorodiphenyldichloroethylene

DTXSID9020374

PR:000006100

PR aromatase

CHEBI:50114

CHEBI estrogen

CHEBI:23965

CHEBI estradiol

FMA:86488

FMA Glandular part of endometrium

PR:000027727

PR estrogen receptor alpha complex

CHEBI:16469

CHEBI 17beta-estradiol

GO:0070330

GO aromatase activity

GO:0035938

GO estradiol secretion

GO:0030520

GO intracellular estrogen receptor signaling pathway

GO:0030284

GO estrogen receptor activity

MP:0005182

MP increased circulating estradiol level

WIKI increased

Vinclozolin

2020-05-14T11:28:31

atrazine

2016-11-29T18:42:27

Isobutylmethylxanthine

2024-11-22T15:21:49

Aldrin

2024-11-22T15:22:32

Technical chlordane

2024-11-22T15:23:18

Cypermethrin

2016-11-29T18:42:27

Methyl parathion

2021-06-24T18:49:51

Endosulfan

2018-02-11T00:30:38

Methoxychlor

2024-11-22T15:24:37

Oxadiazon

2024-11-22T15:24:54

Metolachlor

2024-11-22T15:25:28

Tributyltin

2017-07-24T16:32:02

Benomyl

2016-11-29T18:42:27

p,p'-DDE

2020-05-18T12:15:23

WikiUser_17

mammals

WikiUser_28

Vertebrates

WikiUser_29

Invertebrates

Aromatase, induction

Molecular

Biological state Aromatase (synonyms: Cytochrome P450 aromatase, CYP19) plays a central role in steroidogenesis by converting androgens to estrogens through a three-step reaction that allows the aromatization of the A-ring of the steroid molecule (Mendelson et al., 1985; Thompson and Siiteri, 1974; Simpson and Santen, 2015) (see Fig. 1, Caciolla et al.2020). It is considered the rate-limiting enzyme in estrogen biosynthesis (Simpson and Santen, 2015; Zhao et al., 2016) since it catalyzes the final and key step, i.e., the conversion of C19 steroids to estrogen (Bulun et al., 2005). More specifically, aromatase converts through aromatization androstenedione and testosterone to estrone (E1) and estradiol (E2), respectively. Aromatase has been proposed as an important molecular target for many environmental endocrine disruptors chemicals (Laville et al., 2006). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/11/22/5snxh7oo7e_Figure_1_KE2293.png" /> Figure 1. Estrogen biosynthesis. In particular, the role of human aromatase is highlighted (Caciolla et al., 2020) Biological compartment The enzyme is present in all vertebrates as the product of expression of a single gene, with some exceptions represented by pigs and teleosts, where duplication events have produced three and two isoforms, respectively. The protein is expressed in different tissues in vertebrates, where it plays an essential role in reproductive biology as estrogens are responsible for ovarian differentiation, development of the reproductive system, sex differentiation, and reproduction. Moreover, a critical role of estrogens has also been demonstrated in brain, bone, skin, fat, and cardiovascular tissues (Di Nardo et al., 2021). In the normal endometrium aromatase is not expressed (Bulun 2009; Zhao et al., 2016). General role in biology Estrogen is synthesized by aromatase in the gonads and in several extragonadal organs, such as skin, adipose tissues, liver, heart and brain (Bulun et al., 2005; Simpson 2003, Bulun et al., 2009). Extragonadal estrogen is biologically active in a paracrine or intracrine fashion, although it may escape the local metabolism and enter the circulation (Simpson and Davis, 2001; Simpson, 2003). In premenopausal women, ovary is the primary source of estrogens (primarily in the granulosa cells and corpus luteum), and the cyclic expression of estrogen by the ovaries drives endometrial proliferation (Mihm et al., 2011). Disease-free endometrium lacks aromatase and thus does not produce estrogen locally (Bulun 2009; Zhao et al., 2016). In postmenopausal women, peripheral tissues, especially adipose tissue, become the main site of estrogen synthesis (Davis et al., 2015). The estrogen precursor androstenedione is primarily secreted by the adrenal glands (Zhao et al., 2016), and estrogen (E1, E2) is produced in many extragonadal organs (skin, adipose tissues, liver, heart and brain) (Bulun et al., 2005). After menopause, adipocytes, preadipocytes, and mesenchymal stem cells within fat tissue are the predominant source of aromatase, the enzyme responsible for the conversion of androgens to estrogen E1 and, to a lesser extent E2 (Zhao et al., 2016).

Expression: Aromatase mRNA expression can be measured by RT-PCR [in JEG-3 choriocarcinoma cells cultures (Laville et al., 2006); in H295R Human Adrenocortical Carcinoma Cells (Sanderson et al., 2002); in KGN Human Ovarian Granulose-Like Tumor Cell Line (Morinaga et al., 2004)] and in situ hybridization [endometrial carcinoma tissue samples (Segawa et al., 2005)] Aromatase protein levels can be measured by Western blot from cell cultures and liver microsomal samples (You et al., 2001) and by immunohistochemistry on tissue sections (You et al., 2001, Segawa et al., 2005) Activity: The catalytic aromatase activity was determined by using the tritium release assay (measurement of tritium released after the conversion of tritium-labelled androstenedione into estrone by cells or hepatic microsomes as described previously (Drenth et al., 1998; Lephart and Simpson, 1991) with minor modifications [in JEG-3 choriocarcinoma cells cultures (Laville, 2006); in H295R Human Adrenocortical Carcinoma Cells (Sanderson et al., 2002); in hepatic microsomal samples (You et al., 2001); in KGN Human Ovarian Granulose-Like Tumor Cell Line (Morinaga et al., 2004)]. Indirect methods: Levels of estrogens in serum can offer an indirect measurement of aromatase induction.

Aromatase levels and activity increase as a function of age and adiposity (Simpson et al., 1987; Bulun and Simpson, 1994) and, therefore, contribute to estrogen-induced endometrial proliferation in the postmenopausal woman (Blakemore and Naftolin, 2016; Zhao et al., 2016). Consistent with the role of adipose tissue in estrogen synthesis, obesity is more strongly associated with the development of endometrial cancer than any other cancer type in women (Reeves et al., 2007). In the mouse aromatase is expressed in fewer tissues (gonads, brain) than human aromatase; thus, mouse models do not mirror estrogen production in humans. Aromatase is only present in gonads, brain and male gonadal fat in mice (Zhao et al., 2016). Generation of humanized aromatase (Aromhum) mouse model that contains the full human aromatase gene, allowed to mimic human aromatase expression pattern in the mouse model (Zhao et al., 2012). In the rat, in addition to expression in gonads and brain, aromatase was induced after ovariectomy in liver and subcutaneous adipose tissue (Zhao et al., 2005) Biological domains of applicability <ol> <li>Taxonomic applicability: Vertebrates. Invertebrates of the genus Branchiostoma (Di Nardo et al., 2021).</li> <li>Life stage applicability: All life stages, mainly adulthood (UniProt)</li> <li>Sex applicability: Males, females.</li> </ol> Evidence for the biological domain of applicability Aromatase converts, through aromatization, androstenedione and testosterone to estrone (E1) and estradiol (E2), respectively. Aromatase induction could increase circulating estrogens (E1, E2) available to estrogenic activation pathways in estrogenic sensitive tissues (uterus).

UBERON:0000991

UBERON gonad

CL:0000255

CL eukaryotic cell

Not Specified Unspecific

Not Specified

All life stages

Not Specified Not Specified Not Specified

Blakemore J and Naftolin F, 2016. Aromatase: Contributions to Physiology and Disease in Women and Men. Physiology (Bethesda), 31:258-269. doi: 10.1152/physiol.00054.2015 Bulun SE, Lin Z, Zhao H, Lu M, Amin S, Reierstad S and Chen D, 2009. Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci, 1155:121-131. doi: 10.1111/j.1749-6632.2009.03705.x Bulun SE and Simpson ER, 1994. Regulation of aromatase expression in human tissues. Breast Cancer Research and Treatment, 30:19-29. doi: 10.1007/BF00682738 Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D and Deb S, 2005. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev, 57:359-383. doi: 10.1124/pr.57.3.6 Caciolla J, Bisi A, Belluti F, Rampa A and Gobbi S, 2020. Reconsidering Aromatase for Breast Cancer Treatment: New Roles for an Old Target. Molecules, 25. doi: 10.3390/molecules25225351 Davis SR, Lambrinoudaki I, Lumsden M, Mishra GD, Pal L, Rees M, Santoro N and Simoncini T, 2015. Menopause. Nat Rev Dis Primers, 1:15004. doi: 10.1038/nrdp.2015.4 Di Nardo G, Zhang C, Marcelli AG and Gilardi G, 2021. Molecular and Structural Evolution of Cytochrome P450 Aromatase. Int J Mol Sci, 22. doi: 10.3390/ijms22020631 Drenth H-J, Bouwman CA, Seinen W and Van den Berg M, 1998. Effects of Some Persistent Halogenated Environmental Contaminants on Aromatase (CYP19) Activity in the Human Choriocarcinoma Cell Line JEG-3. Toxicology and Applied Pharmacology, 148:50-55. doi: https://doi.org/10.1006/taap.1997.8307 Laville N, Balaguer P, Brion F, Hinfray N, Casellas C, Porcher J-M and Aït-Aïssa S, 2006. Modulation of aromatase activity and mRNA by various selected pesticides in the human choriocarcinoma JEG-3 cell line. Toxicology, 228:98-108. doi: https://doi.org/10.1016/j.tox.2006.08.021 Lephart ED and Simpson ER, 1991. Assay of aromatase activity. Methods Enzymol, 206:477-483. doi: 10.1016/0076-6879(91)06116-k Mendelson CR, Wright EE, Evans CT, Porter JC and Simpson ER, 1985. Preparation and characterization of polyclonal and monoclonal antibodies against human aromatase cytochrome P-450 (P-450AROM), and their use in its purification. Arch Biochem Biophys, 243:480-491. doi: 10.1016/0003-9861(85)90525-9 Mihm M, Gangooly S and Muttukrishna S, 2011. The normal menstrual cycle in women. Anim Reprod Sci, 124:229-236. doi: 10.1016/j.anireprosci.2010.08.030 Morinaga H, Yanase T, Nomura M, Okabe T, Goto K, Harada N and Nawata H, 2004. A benzimidazole fungicide, benomyl, and its metabolite, carbendazim, induce aromatase activity in a human ovarian granulose-like tumor cell line (KGN). Endocrinology, 145:1860-1869. doi: 10.1210/en.2003-1182 Reeves GK, Pirie K, Beral V, Green J, Spencer E and Bull D, 2007. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ, 335:1134. doi: 10.1136/bmj.39367.495995.AE Sanderson JT, Boerma J, Lansbergen GW and van den Berg M, 2002. Induction and inhibition of aromatase (CYP19) activity by various classes of pesticides in H295R human adrenocortical carcinoma cells. Toxicol Appl Pharmacol, 182:44-54. doi: 10.1006/taap.2002.9420 Segawa T, Shozu M, Murakami K, Kasai T, Shinohara K, Nomura K, Ohno S and Inoue M, 2005. Aromatase Expression in Stromal Cells of Endometrioid Endometrial Cancer Correlates with Poor Survival. Clinical Cancer Research, 11:2188-2194. doi: 10.1158/1078-0432.Ccr-04-1859 Simpson, E., & Santen, R. J. (2015). Celebrating 75 years of oestradiol. Journal of Molecular Endocrinology, 55(3), T1-T20. Retrieved Dec 19, 2024, from https://doi.org/10.1530/JME-15-0128  Simpson ER, 2003. Sources of estrogen and their importance. The Journal of Steroid Biochemistry and Molecular Biology, 86:225-230. doi: https://doi.org/10.1016/S0960-0760(03)00360-1 Simpson ER and Davis SR, 2001. Minireview: Aromatase and the Regulation of Estrogen Biosynthesis—Some New Perspectives. Endocrinology, 142:4589-4594. doi: 10.1210/endo.142.11.8547 Simpson ER and Mendelson CR, 1987. Effect of aging and obesity on aromatase activity of human adipose cells. Am J Clin Nutr, 45:290-295. doi: 10.1093/ajcn/45.1.290 Thompson E.A., Siiteri P.K. Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J. Biol. Chem. 1974;249:5364–5372. doi: 10.1016/S0021-9258(20)79735-8 You L, Sar M, Bartolucci E, Ploch S and Whitt M, 2001. Induction of hepatic aromatase by p,p'-DDE in adult male rats. Mol Cell Endocrinol, 178:207-214. doi: 10.1016/s0303-7207(01)00445-2 Zhao H, Tian Z, Hao J and Chen B, 2005. Extragonadal aromatization increases with time after ovariectomy in rats. Reprod Biol Endocrinol, 3:6. doi: 10.1186/1477-7827-3-6 Zhao H, Pearson EK, Brooks DC, Coon JSt, Chen D, Demura M, Zhang M, Clevenger CV, Xu X, Veenstra TD, Chatterton RT, DeMayo FJ and Bulun SE, 2012. A humanized pattern of aromatase expression is associated with mammary hyperplasia in mice. Endocrinology, 153:2701-2713. doi: 10.1210/en.2011-1761 Zhao H, Zhou L, Shangguan AJ and Bulun SE, 2016. Aromatase expression and regulation in breast and endometrial cancer. J Mol Endocrinol, 57:R19-33. doi: 10.1530/jme-15-0310 AOPWiki 2024-11-22T12:50:41

2025-02-21T14:10:20

Increased, circulating estrogen levels

Organ

AOPWiki 2016-11-29T18:41:29

2016-12-03T16:37:53

Estradiol availability, increased

Increased E2 availability

Tissue

Currently, there is an existing key event in the AOP Wiki (event number 1973) entitled Increased, estrogens which has a role of KE in one AOP (under development) (number 440 - Hypothalamic estrogen receptors inhibition leading to ovarian cancer). Some sections of the KE description were adapted from that event. In the current AOP, “increased E2 availability” is intended as the increased availability of E2 to its intended biological destination, that is the estrogenic signalling pathways in target tissues (estrogen-sensitive tissues). Biological state The three major forms of endogenous estrogens are estrone (E1), oestradiol (E2, or 17β-oestradiol), and estriol (E3).  Estrogen metabolism is complex and multifactorial (Fig.6). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/08/09/7zjvp3k5u5_KE2251_Figure_6.jpg" /> Figure 6. Schematic representation of estrogen metabolism. Dotted circles represent the enzyme system that would influence the bioavailability of oestradiol (Wikoff et al., 2016) Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, E2 is the principal intracellular human estrogen and is substantially more potent than its metabolites, E1 and E3 at the receptor level (NCI Thesaurus (NCIt) in PubChem, available at: <a href="https://ncit.nci.nih.gov/ncitbrowser/">https://ncit.nci.nih.gov/ncitbrowser/</a>, version 22.11d). Oestradiol (E2) is principally produced in the ovaries by follicular thecal and granulosa cells under the regulation of follicle-stimulating hormone (FSH) in the reproductive phase in women (Simpson 2003). Before puberty and after menopause E2 is mainly produced in extragonadal tissues, including kidney, breast, brain, liver and fat (Secky et al., 2013). In males it is mainly produced by the Leydig cells in the testis. Vehiculated via the circulatory system to estrogen-sensitive tissues (female reproductive organs, breasts, hypothalamus and pituitary), E2 becomes available to specific estrogen receptors (subtypes alpha (ERα) and beta (ERβ), triggering the estrogenic signalling pathway: the receptor-ligand complex enters the nucleus of the target and promotes the gene expression necessary for the maintenance of fertility and secondary sexual characteristics in females and other effects, such as mild anabolic and metabolic properties, and increased blood coagulability.  E2 also exerts potent agonism of G Protein-coupled estrogen receptor (GPER), which is recognized an important regulator of E2 rapid effects.   The three major forms of endogenous estrogens are estrone (E1), oestradiol (E2, or 17β-oestradiol), and estriol (E3). Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, oestradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level (NCI Thesaurus (NCIt) in PubChem). In estrogen-responsive organs (uterus, breast, prostate), E2 availability to the estrogen signalling pathway is fine-tuned at cellular level; E2 activation/deactivation is controlled by a local machinery composed by enzymes analogous to those in gonadal tissue (Secky et al., 2013). This “intracrinological” pathway actively contributes to the modification of intracellular levels of E2, modulating its local effects and playing a major role in physiological and pathological conditions in premenopausal and menopausal women, in men and in animal models (Konings et al., 2018). Huhtinen et al., 2012 showed that E2 concentration in the human uterus (endometrium) is up to 10-fold higher in the proliferative phase compared with the secretory phase of the menstrual cycle, and this is accompanied by cyclic changes in intracrine enzyme levels, indicating that steroid exposure is locally cyclically regulated to support endometrial physiology. An important reaction in the intracrine steroidogenesis is the interconversion of 17-keto and 17b-hydroxysteroids controlled by HSD17Bs. 17b-hydroxysteroids (testosterone and E2) have higher affinity for the receptors than the keto-steroids (A4 and E1). This balance determines the final androgenic/estrogenic activity at target tissue level (Konings et al., 2018). In addition, of relevance is the intracellular balance between unconjugated (free, active) and the sulfo-conjugated (inactive) E2. This is controlled by the “sulfatase pathway”, which is based on the interplay between SULT1E1 and STS and contributes to the modulation of E2 effects and protection versus its excess in target tissues (Cui et al., 2013; Cornel, 2018). Biological compartment Gonadal E2 is produced under the control of the hypothalamus-pituitary-ovary (HPO) axis and mainly released into the bloodstream to reach target tissues. In the female reproductive years E2 levels are physiologically subject to cyclic variations in the blood, reaching the highest level immediately before ovulation. Levels of circulating E2 during the follicular phase, pre-ovulatory phase, and luteal phase are 19–140 pg/ml, 110–410 pg/ml, and 19–160 pg/ml, respectively. During the menopause transition, E2 and E1 levels decrease by 85–90% and 65–75% respectively as compared to mean pre-menopausal levels, and in postmenopausal women they are below 35 pg/ml. The above described “intracrinological” pathway actively contributes to the modification of intracellular levels of E2, modulating its local effects and playing a major role in physiological and pathological conditions in premenopausal and menopausal women, in men and in animal models (Konings et al., 2018). As a consequence, cellular E2 levels do not reflect the blood levels (Cornel et al., 2018); in the endometrium they can be up to five-times higher than in serum during the proliferative phase and 1.5-fold higher in the luteal period (Huhtinen et al., 2012, 2014). Levels of estrogens (E2) in both the circulatory (plasma) and tissue compartments should both be considered and could offer a complementary information. Among enzymes relevant in intracrinology, the sulfatase and sulfotransferase (SULT1E1), combined as the sulfatase pathway, represent a major route of estrogen supply and removal in endometrial cells. In physiological conditions the balance of the pathway is shifted towards the formation of free estrone, as indicated by the STS activity, that is few magnitudes higher than that of SULT1E1. Other enzymes relevant for the intracrine regulation and ultimately tissue level of E2 include aromatase CYP19A1 (converting testosterone to oestradiol), hydroxysteroid-dehydrogenase-17B (HSD17B, interconverting estrone and oestradiol)) (reviewed in see Wikoff et al 2015). In addition, other hormones can also contribute to the regulation of E2 at endometrial level. For example, progesterone diminishes estrogenic action in the endometrium by stimulating the local synthesis of 17-hydroxysteroid dehydrogenase and estrogen sulfotransferase, with the effect peaking in the luteal phase. The up regulation of these enzymes decreases intra-tissue estrogen levels and is one of the mechanisms of the uterine antiestrogenic effects of progesterone (Huntinhen et al., 2012). General role in biology Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. E2 is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level (HSD17B in PubChem). In the reproductive phase E2 together with progesterone controls the menstrual cycle and the reproductive functions; it induces endometrial cell proliferation in premenopausal women. E2 effects are mediated by a complex estrogenic signalling, mainly via two nuclear estrogen receptors (ERα and β) and one membrane receptor (GPER); activating genomic and non-genomic actions upon ligand binding (Cornel et al., 2017) Availability of E2 to its receptors is key to trigger the estrogenic signalling in estrogen-sensitive cells. It is related to the levels of circulating estrogens and it is locally fine-tuned by a set of intracellular enzymes (intracrinology). Disruption of estrogen homeostasis resulting in prolonged increased E2 levels, associated with relative decreased progesterone (P4) would be among the leading risk factors for the development of pathological conditions such as endometrial cancer. An estrogen imbalance is associated with endometrial carcinomas in rats (Hilliard and Norris, 1979; Fox, 1984), spontaneous endometrial adenocarcinomas in the Donryu rat (Nagaoka et al., 1990), and in F344 rats (Tang et al., 1984). Epidemiological studies showed increased endometrial cancer risks among postmenopausal women who have increased blood levels of oestradiol (reviewed in Kaaks et al., 2002) as well as of steroid precursors of E2 (testosterone, androstenedione, DHEA, DHEA-S, estrone and estrone-S) compared with healthy controls (Cornel et al., 2017). This can be interpreted in the light of the “unopposed estrogen” hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone.  Since the majority of the endometrial cancer patients are postmenopausal women, local formation of E2 from circulating precursors either from circulating androgens via the aromatase pathway or from E1S via the sulfatase pathway becomes important.

This KE refers to increased E2 availability in the uterus, where availability is intended as the extent E2 becoming completely available to its intended biological destination ER. Circulating E2 levels are relevant in determining E2 levels available to endometrial cells in the uterus. These are measurable by a variety of standardised routine methods in humans and animals. Circulating levels are intracellularly subject to a complex intracrine control mechanism, activating and deactivating E2 available to receptors. The translation of circulating E2 levels into E2 availability in uterus needs further exploration and it is not fully addressed in this Scientific Opinion. It has been acknowledged that availability of E2 in uterus is strongly associated with estrogenic activity. Therefore, E2 availability in target tissue can be measured with standardised methods evaluating estrogenicity, that are listed below. In vivo <ul> <li>OECD TG 440 Uterotrophic bioassay in rodents</li> </ul> Others Overall, no high resolution and/or standardised methods exist to quantify steroids within target tissues. However, in recent decades it has been recognized that steroid concentration within tissues is modulated independently from circulating levels and therefore investigations in this field are initiated (Cobice et al., 2013). Uterine response to estrogens involves the activation of a large pattern of estrogen-sensitive genes: <ul> <li>Expression of Calbindin-D9k (CaBP-9k) gene and protein. The 9 kilodalton vitamin D-dependent calcium binding protein (CaBP9k), calbindin-D9k, is expressed in the intestine and uterus of mammals (bgee.org; L’ Horset et al., 1990) Different studies demonstrated that in the mammals uterus, the expression of CaBP-9k is regulated by hormones such as E2 and P4.  L’Horset et al., 1993; review by Choi et al., 2005).</li> <li>Complement 3 (C3). It has been demonstrated that C3 could be regarded as an estrogen sensitive marker in rat uterus (Diel et al., 2000; Sundstrom et al., 1989)</li> </ul> In addition to this, it has been reported that blood glutamate levels are inversely related to plasma estrogen and progesterone level in plasma (Zlotnik et al., 2011). In the regulatory area standard methods are available for serum estrogen analysis include radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), and multiplex immunoassay. Liquid chromatography/mass spectrometry (LC/MS)-based methods are also becoming more widely used (as cost and sample size requirements decrease), particularly for measurement of estrogens and estrogen metabolites. For E2, rodent-specific immunoassays are commercially available (Andersson, 2013). In the OECD TG 422 dedicated to repeated dose toxicity and reproduction, sex hormones data are not routine endpoints. In OECD TG 408, measurement of sexual hormones is optional and should be considered on a case-by-case basis. However, it is not recommended to include female reproductive hormonal measurements in first-tier toxicity studies of standard design. Indeed, due to the limited standard number of animals per group the average number of each animal in each stage of the cycle is generally too few to permit conclusions (Stanislaus, 2012). Specifically designed and statistically powered investigative studies (with appropriate animal numbers) are best suited to measure serum hormones in female rodents (Andersson, 2013).

Taxonomic Applicability: mammals. Endocrine systems with respect to hormone structure, receptors, synthesis pathways, hormonal axes and degradation pathways are well conserved across vertebrate taxa especially in the case of estrogen, androgen and thyroid hormones and steroidogenesis (OECD TG 150) Life Stage Applicability: This KE is applicable to adulthood - reproductive and post reproductive (menopausal, aging) phases. Sex Applicability: males, females

UBERON:0000995

UBERON uterus

Not Specified Male Not Specified Female

Not Specified

Adult

Not Specified

Adult, reproductively mature

Not Specified

Old Age

Not Specified

Andersson H, Rehm S, Stanislaus D and Wood CE, 2013. Scientific and Regulatory Policy Committee (SRPC) Paper:Assessment of Circulating Hormones in Nonclinical Toxicity Studies III. Female Reproductive Hormones. Toxicologic Pathology, 41:921-934. doi: 10.1177/0192623312466959 Choi J-Y, Lee K-M, Park SK, Noh D-Y, Ahn S-H, Chung H-W, Han W, Kim JS, Shin SG, Jang I-J, Yoo K-Y, Hirvonen A and Kang D, 2005. Genetic Polymorphisms of SULT1A1 and SULT1E1 and the Risk and Survival of Breast Cancer. Cancer Epidemiology, Biomarkers & Prevention, 14:1090-1095. doi: 10.1158/1055-9965.Epi-04-0688 Cobice DF, Mackay CL, Goodwin RJA, McBride A, Langridge-Smith PR, Webster SP, Walker BR and Andrew R, 2013. Mass Spectrometry Imaging for Dissecting Steroid Intracrinology within Target Tissues. Analytical Chemistry, 85:11576-11584. doi: 10.1021/ac402777k Cornel KM, Krakstad C, Delvoux B, Xanthoulea S, Jori B, Bongers MY, Konings GF, Kooreman LF, Kruitwagen RF, Salvesen HB and Romano A, 2017. High mRNA levels of 17β-hydroxysteroid dehydrogenase type 1 correlate with poor prognosis in endometrial cancer. Mol Cell Endocrinol, 442:51-57. doi: 10.1016/j.mce.2016.11.030 Cornel KMC, Delvoux B, Saya T, Xanthoulea S, Konings GFJ, Kruitwagen RPFM, Bongers MY, Kooreman L and Romano A, 2018. The sulfatase pathway as estrogen supply in endometrial cancer. Steroids, 139:45-52. doi: <a href="https://doi.org/10.1016/j.steroids.2018.09.002">https://doi.org/10.1016/j.steroids.2018.09.002</a> Cui J, Shen Y and Li R, 2013. Estrogen synthesis and signaling pathways during aging: from periphery to brain. Trends Mol Med, 19:197-209. doi: 10.1016/j.molmed.2012.12.007 Diel P, Schulz T, Smolnikar K, Strunck E, Vollmer G and Michna H, 2000. Ability of xeno- and phytoestrogens to modulate expression of estrogen-sensitive genes in rat uterus: estrogenicity profiles and uterotropic activity. The Journal of Steroid Biochemistry and Molecular Biology, 73:1-10. doi: <a href="https://doi.org/10.1016/S0960-0760(00)00051-0">https://doi.org/10.1016/S0960-0760(00)00051-0</a> Hilliard GD and Norris HJ, 1979. Pathologic effects of oral contraceptives. Recent Results Cancer Res, 66:49-71. doi: 10.1007/978-3-642-81267-5_2 Huhtinen K, Desai R, Ståhle M, Salminen A, Handelsman DJ, Perheentupa A and Poutanen M, 2012. Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. J Clin Endocrinol Metab, 97:4228-4235. doi: 10.1210/jc.2012-1154 Kaaks R, Lukanova A and Kurzer MS, 2002. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev, 11:1531-1543 Konings G, Brentjens L, Delvoux B, Linnanen T, Cornel K, Koskimies P, Bongers M, Kruitwagen R, Xanthoulea S and Romano A, 2018. Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery. Frontiers in pharmacology, 9:940. doi: <a href="https://doi.org/10.3389/fphar.2018.00940">10.3389/fphar.2018.00940</a> Available online: <a href="http://europepmc.org/abstract/MED/30283331">http://europepmc.org/abstract/MED/30283331</a> L'Horset F, Blin C, Brehier A, Thomasset M and Perret C, 1993. Estrogen-induced calbindin-D 9k gene expression in the rat uterus during the estrous cycle: late antagonistic effect of progesterone. Endocrinology, 132:489-495. doi: 10.1210/endo.132.2.8425470 Nagaoka T, Onodera H, Matsushima Y, Todate A, Shibutani M, Ogasawara H and Maekawa A, 1990. Spontaneous uterine adenocarcinomas in aged rats and their relation to endocrine imbalance. J Cancer Res Clin Oncol, 116:623-628. doi: 10.1007/bf01637084 OECD, 2007. Test No. 440: Uterotrophic Bioassay in Rodents. OECD, 2016. Test No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. OECD, 2018a. Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption. OECD, 2018b. Test No. 408: Repeated Dose 90-Day Oral Toxicity Study in Rodents. Secky L, Svoboda M, Klameth L, Bajna E, Hamilton G, Zeillinger R, Jäger W and Thalhammer T, 2013. The sulfatase pathway for estrogen formation: targets for the treatment and diagnosis of hormone-associated tumors. J Drug Deliv, 2013:957605. doi: 10.1155/2013/957605 Simpson ER, 2003. Sources of estrogen and their importance. The Journal of Steroid Biochemistry and Molecular Biology, 86:225-230. doi: <a href="https://doi.org/10.1016/S0960-0760(03)00360-1">https://doi.org/10.1016/S0960-0760(03)00360-1</a> Stanislaus D, Andersson H, Chapin R, Creasy D, Ferguson D, Gilbert M, Rosol TJ, Boyce RW and Wood CE, 2012. Society of toxicologic pathology position paper: review series: assessment of circulating hormones in nonclinical toxicity studies: general concepts and considerations. Toxicol Pathol, 40:943-950. doi: 10.1177/0192623312444622 Sundstrom SA, Komm BS, Ponce-de-Leon H, Yi Z, Teuscher C and Lyttle CR, 1989. Estrogen regulation of tissue-specific expression of complement C3. J Biol Chem, 264:16941-16947 Tang FY, Bonfiglio TA and Tang LK, 1984. Effect of estrogen and progesterone on the development of endometrial hyperplasia in the Fischer rat. Biol Reprod, 31:399-413. doi: 10.1095/biolreprod31.2.399 Wikoff DS, Rager JE, Haws LC and Borghoff SJ, 2016. A high dose mode of action for tetrabromobisphenol A-induced uterine adenocarcinomas in Wistar Han rats: A critical evaluation of key events in an adverse outcome pathway framework. Regul Toxicol Pharmacol, 77:143-159. doi: 10.1016/j.yrtph.2016.01.018 Zlotnik A, Gruenbaum BF, Mohar B, Kuts R, Gruenbaum SE, Ohayon S, Boyko M, Klin Y, Sheiner E, Shaked G, Shapira Y and Teichberg VI, 2011. The effects of estrogen and progesterone on blood glutamate levels: evidence from changes of blood glutamate levels during the menstrual cycle in women. Biol Reprod, 84:581-586. doi: 10.1095/biolreprod.110.088120 AOPWiki 2024-08-09T17:32:22

2024-11-21T17:40:26

Activation, estrogen receptor alpha

Activation, ERα

Molecular

Some sections of the KE description were derived and adapted from the External Scientific Report (Viviani et al., 2023). Biological state Estrogen Receptor Alpha (ERα) is a receptor covalently bound by estrogens, which following the dimerization can translocate to the nucleus (Björnström and Sjöberg, 2005), where it can bind to estrogen responsive elements and recruit co-activators or co-repressors, which can attract co-regulatory proteins, like histone acetyltransferase, ubiquitin ligases, and protein remodelers (Thomas and Gustafsson, 2011) (Fig.1). A non-genomic signalling of Erα is described (Fig. 7), not requiring the dimerization for the induction of kinases and calcium flux (Levin, 2002; Vasudevan and Pfaff, 2008). The non-genomic action of ERα is able to regulate more genes (Gu et al., 2014). Both signalling pathways are important for the human organism (Pedram et al., 2014; Pedram et al., 2016). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/08/14/6fttmbh7wt_figure_7_ke1065.png" /> Figure 7. Genomic and non-genomic signalling pathways of ERα The ER structure is composed by different domains (A-F) which are responsible for the binding to the ligands, the dimerization, the binding to the DNA and for the activation of transcription (Nilsson et al., 2001) (Fig. 8). The A/B domain, or activation function 1 (AF1) is responsible for transactivation and protein-protein interaction, and it acts independently of ligand binding. Then, there is the C-domain, which is responsible for DNA binding and receptor dimerization. The D-domain instead is the phosphorylation site or ER and has nuclear localization sequences. The E-domain, or activation function 2 (AF2) is the ligand binding domain and the site for the binding with co-activators and co-repressors (Ellmann et al., 2009). Lastly, the F-domain that prevents improper ligand activation and dimerization (Yang et al., 2008). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/08/14/4whefkoqkg_figure_8_ke1065.png" style="height:264px; width:1430px" /> Therefore, ligand binding, dimerization and DNA binding processes are the first steps to inducing the transcription of target genes. But the ER activity largely depends also on the presence and recruitment of different co-activators and co-repressors. Once ER is bound to estrogen responsive elements, it can recruit different proteins that can favour or obstruct the action of the receptor (Thomas and Gustafsson, 2011). The main co-activators are the steroid receptor co-activators (SRC-1 and SRC-3), which are able to recruit co-regulatory proteins (Heldring et al., 2007). The main transcription factors that can be regulated by ER are activating protein 1 (AP1), specificity protein 1 (SP1), cAMP response element-binding protein (CREB), nuclear factor-κB (NF-κB) and p53 (Biswas et al., 2005; Björnström and Sjöberg, 2005; Fox et al., 2009). Instead in absence of ligands, ER can be activated by the phosphorylation from protein kinases which are stimulated by hyperactive growth factor receptors (Britton et al., 2006). ER is also able to rapidly activate other pathways, namely MAPK, PI3K, EGFR, and SRC (Kousteni et al., 2001; Song et al., 2002; Razandi et al., 2004; Shupnik, 2004). Biological compartment ERα is mainly expressed in uterus, prostate (stroma), ovary (theca cells), testes (Leydig cells), epididymis, bone, breast, various regions of the brain, liver, and white adipose tissue (Dahlaman-Wright et al., 2006). At the subcellular compartments, estrogen receptors (ERs), are localized in cytoplasm where they exist as monomers bound to heat shock proteins (HSPs). Estrogen binding alters receptor conformation and triggers release from the HSPs, thereby allowing receptor dimerization and translocation in the nucleus where these dimers bind to specific DNA sequences and recruit numerous co-factors to regulate gene transcription. Unliganded ER are also characterized as monomers in the nucleus and at the plasma membrane (Gourdy et al., 2018) General role in biology The main function of ERα is to mediate the action of estrogens, known to be involved in physiological pathological conditions (endometrial proliferation in menstrual cycle and endometrial carcinoma in postmenopausal women). This receptor is also involved in apoptotic and proliferative functions involving the MAPK/ERK pathway, mainly in breast cancer cells (Zheng et al., 2007; Lin et al., 2010; Zhang et al., 2012; Li et al., 2013). Another player involved in the increased proliferation induced by ERα is c-myc (Dubik and Shiu, 1992). The increased proliferation induced by ER has been linked to tumours (Thomas and Gustafsson, 2011). The interaction between estrogen and ERα and the increased proliferation has been proved in breast and uterine tissues (Ellmann et al., 2009).

Note: considering the AOPs under development the stressors interacting with the estrogen metabolism should be tested negative in all the in vitro assays reported below.  Additional proof of concept supporting the chain of the events herein described is given by a negative result in the in vitro assays but positive outcome in the Uterotrophic Bioassays. Uterotrophic Bioassay is indeed indicative of a single endocrine mechanism i.e., estrogenicity that could be related to mechanism other than direct binding to ER alpha or ER beta receptor. In the regulatory area methods are available to measure ER receptor activity.  OECD in the “Revised Guidance document 150” give insightful information, including limits on their use, on validated and/or widely accepted assays with estrogenic active substance specific endpoints. OECD in vitro assays <ul> <li>OECD TG 493 (July 2015): Performance-Based Test Guideline for Human Recombinant Estrogen Receptor (HRER) In Vitro Assays to Detect Chemicals with ER Binding Affinity</li> <li>OECD TG 455 (June 2021): Performance-Based Test Guideline (PGBT) For Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists. It comprises several mechanistically and functionally similar test methods for the identification of estrogen receptor (i.e., ERα, and/or ERβ). The fully validated reference test methods that provide the basis for this PBTG are: 1) The Stably Transfected TA (STTA) assay using the (h) ERα-HeLa-9903 cell line; and 2) The VM7Luc ER TA assay (3) using the VM7Luc4E2 cell line1 which predominately expresses hERα with some contribution from hERβ.</li> <li>OECD TG 457 (October 2012): BG1luc estrogen receptor transactivation test method for identifying estrogen receptor agonists and antagonists.</li> </ul> OECD in vitro screens assays (non-mammalian) <ul> <li>OECD TG 250 (June 2021): EASZY assay - Detection of Endocrine Active Substances, acting through estrogen receptors, using transgenic tg (CYP19A1b:GFP) Zebrafish embryo</li> <li>OECD TG 230 (September 2009): 21-Day Fish Assay a Short-Term Screening for Oestrogenic and Androgenic Activity, and Aromatase Inhibition</li> </ul>  OECD in vivo mammalian screens and test <ul> <li>OECD TG 440 (October 2007): Uterotrophic bioassay in rodents</li> </ul> Others non-OECD tests <ul> <li>US EPA (2009) Estrogen Receptor Binding Assay Using Rat Uterine Cytosol: This assay identifies chemicals that have the potential to interact with the estrogen receptor (ER) in vitro.  Principle of this particular assay is based on the competitive protein-binding methods. A radiolabelled ligand and an unlabelled ligand are presented together to a specific receptor. The radioactivity measurement provides the quantitative estimation of the bound and unbound fraction of the ligand with the receptor. All cytosolic estrogen receptor subtypes that are expressed in the specific tissue, including ERα and ERβ are used for the determination of estrogen receptor binding. This assay is simple and rapid to perform when optimal conditions for binding are determined. Assay determines if a ligand/chemical can interact and displace the endogenous hormone 17β-oestradiol (Freyberger et al., 2010, from KE ID 1046, AOP Wiki)</li> <li>Yeast estrogen screen (YES) (ISO 19040-1 and 19040-2)</li> <li>T47D-Kbluc assay (Wilson et al., 2004);</li> <li>ToxCast Estrogen Receptor Agonist Pathway Model: The ToxCast estrogen receptor (ER) pathway model is a mathematical model that combines the results from 18 high-throughput screening (HTS) assays from the ToxCast and Tox21 research programs. The HTS assays measure ER binding, dimerization, chromatin binding, transcriptional activation and ER-dependent cell proliferation. The model uses activity patterns across the in vitro assays to predict whether a chemical is an ER agonist or antagonist or is otherwise influencing the assays through a manner dependent on the physics and chemistry of the technology platform (“assay interference”). The output of the model provides an area under the curve (AUC) value for the potential of a chemical to cause ER agonism, normalized with respect to the positive control chemical, oestradiol.</li> <li>QSAR models for ER interaction are available at the website of Danish (<a href="https://qsar.food.dtu.dk/">https://qsar.food.dtu.dk/</a>) and US (<a href="https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface">https://www.epa.gov/tsca-screening-tools/epi-suitetm-estimation-program-interface</a>) EPA and OECD (<a href="https://www.oecd.org/chemicalsafety/risk-assessment/oecdquantitativestructure-activityrelationshipsprojectqsars.htm">https://www.oecd.org/chemicalsafety/risk-assessment/oecdquantitativestructure-activityrelationshipsprojectqsars.htm</a>).</li> </ul>

Endocrine systems with respect to hormone structure, receptors, synthesis pathways, hormonal axes and degradation pathways are well conserved across vertebrate taxa especially in the case of estrogen, androgen and thyroid hormones and steroidogenesis (OECD TG 150) Taxonomic applicability: mammals and vertebrates due to evolutionarily conserved hormone pathways. Life stage Applicability: This KE is applicable to juvenile; adulthood; reproductive and post reproductive (menopausal, aging) phases Sex Applicability: This KE is applicable to females and males.

Not Specified Female Not Specified Male

Not Specified

Adult

Not Specified

Adult, reproductively mature

Not Specified

Old Age

Not Specified

Juvenile

Not Specified Not Specified

Björnström L and Sjöberg M, 2005. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Molecular endocrinology, 19 4:833-842 Gu Y, Chen T, López E, Wu W, Wang X, Cao J and Teng L, 2014. The therapeutic target of estrogen receptor-alpha36 in estrogen-dependent tumors. J Transl Med, 12:16. doi: 10.1186/1479-5876-12-16 Levin ER, 2002. Cellular functions of plasma membrane estrogen receptors. Steroids, 67:471-475. doi: 10.1016/s0039-128x(01)00179-9 Lin SL, Yan LY, Zhang XT, Yuan J, Li M, Qiao J, Wang ZY and Sun QY, 2010. ER-alpha36, a variant of ER-alpha, promotes tamoxifen agonist action in endometrial cancer cells via the MAPK/ERK and PI3K/Akt pathways. PLoS One, 5:e9013. doi: 10.1371/journal.pone.0009013 Pedram A, Razandi M, Blumberg B and Levin ER, 2016. Membrane and nuclear estrogen receptor α collaborate to suppress adipogenesis but not triglyceride content. Faseb j, 30:230-240. doi: 10.1096/fj.15-274878 Pedram A, Razandi M, Lewis M, Hammes S and Levin ER, 2014. Membrane-localized estrogen receptor α is required for normal organ development and function. Dev Cell, 29:482-490. doi: 10.1016/j.devcel.2014.04.016 Razandi M, Pedram A, Merchenthaler I, Greene GL and Levin ER, 2004. Plasma membrane estrogen receptors exist and functions as dimers. Mol Endocrinol, 18:2854-2865. doi: 10.1210/me.2004-0115 Thomas C and Gustafsson J-Å, 2011. The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer, 11:597-608. doi: 10.1038/nrc3093 Vasudevan N and Pfaff DW, 2008. Non-genomic actions of estrogens and their interaction with genomic actions in the brain. Front Neuroendocrinol, 29:238-257. doi: 10.1016/j.yfrne.2007.08.003 Viviani B, Bernardini E, Galbiati V, Maddalon A, Melzi A, Midali M, Serafini M, Corsini E, Melcangi RC, Scanziani E, 2023. Development of Adverse Outcome Pathways relevant for the identification of substances having endocrine disruptors properties. EFSA supporting publication 2023:EN-7748 47 pp. doi:10.2903/sp.efsa.2023.EN-7748. NOTE: Italics indicate edits from John Frisch October 2025.  A full list of updates can be found in the Change Log on the View History page. AOPWiki 2016-11-29T18:41:29

2026-01-28T14:32:29

Plasma estradiol, increased

Plasma E2, increased

Cellular

Increased plasma estradiol (E2) levels are generally due to increased secretion from organs, but can also be caused by birth control pills or hormone replacement therapy.  Estradiol is an 18-carbon steroid hormone (Zinn and Schell 2018).  In females, ovaries are a major source of estradiol, with production of E2 by the ovaries well-established by the two-cell, two gonadotropin model of steroid biosynthesis (for review see Drummond 2006; Kimura et al. 2007; Palermo 2007; Beevors et al. 2024). Luteinizing hormone stimulates steroid production in theca cells, with follicle-stimulating hormone stimulates steroid production in granulosa cells. <img alt="" src="https://aopwiki.org/system/dragonfly/production/2026/01/29/6l2g02j23d_EDSP_AOP_Graphic_Estradiol_Biosynthesis_JPEG.jpg" style="height:960px; width:1707px" />   Table 1: List of steroid synthesis enzymes with identifier of enzyme (Uniprot, 2025). <table cellspacing="0" class="Table" style="border-collapse:collapse; width:521px"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:384px"> Enzyme </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:137px"> Identifier </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> Steroidogenic acute regulatory protein, mitochondrial (STAR) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> Cholesterol side-chain cleavage enzyme, mitochondrial (CYP11A) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> EC:1.14.15.6 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> 3 beta-hydroxysteroid dehydrogenase (3B-HSD) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> EC:1.1.1.145 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> Steroid 17-alpha-hydroxylase (CYP17A1) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> EC:1.14.14.19 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> 17-beta-hydroxysteroid dehydrogenase (17B-HSD) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> EC:1.1.1.105 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> Aromatase (CYP19A1) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> EC:1.14.14.14 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> 3-oxo-5-alpha-steroid 4-dehydrogenase 2 (SRD5A2) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom"> EC:1.3.1.22 </td> </tr> </tbody> </table>

Estradiol can be measured via immunoassay, mass spectrometry or Western blotting, with immunoassay the preferred technique (for review of techniques see Rosner et al. 2013).  Studies that utilized immunoassay include (Sashida and Johnson 1976; Spears et al. 1998; Li et al. 2008; Murray et al. 2008; Gan et al. 2024), and include commercially available ELISA kits (e.g. Neogen 402110 (non-species specific); ALPCO 11-ESTHU-E01 (human); Cayman Chemical 501890 (non-species specific)).  Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

Life Stage: Adult, reproductively mature, juveniles. Sex: Applies to both males and females as both sexes require signalling for hormone pathways. Taxonomic: Primarily studied in laboratory rodents and humans.  Plausible for most mammals due to conserved hormone pathways regulating hypothalamus-pituitary-gonadal axis processes.  Plasma estradiol widespread among vertebrates, including mammals (Bondesson et al. 2015), birds (Hanlon et al. 2022), fish (Li et al. 2019), reptiles (Cruz-Cano et al. 2023), and amphibians (Bondesson et al. 2015).

UBERON:0001969

UBERON blood plasma

High Unspecific

Moderate

Adult, reproductively mature

Moderate

Juvenile

Moderate

Beevors LI, Sundar S, Foster PA. 2024. Steroid metabolism and hormonal dynamics in normal and malignant ovaries. Essays in Biochemistry 68(4): 491-507. Bondesson M, Hao R, Lin CY, Williams C, Gustafsson JA. 2015.  Estrogen receptor signaling during vertebrate development. Biochimica et Biophysica Acta 1849(2): 142-151.  Cruz-Cano NB, Sanchez-Rivera UA, Alvarez-Rodriguez C, Cardenas-Leon M, Martinez-Torres M. 2023.  Sex steroid receptors in the ovarian follicles of the lizard Sceloporus torquatus. Zygote. 31(4): 386-392. Drummond AE. 2006.  The role of steroids in follicular growth. Reproductive Biology and Endocrinology 4:16.  Hanlon C, Ziezold CJ, Bedecarrats GY. 2022.  The Diverse Roles of 17β-Estradiol in Non-Gonadal Tissues and Its Consequential Impact on Reproduction in Laying and Broiler Breeder Hens. Frontiers in Physiology 13: 942790.  Kimura S, Matsumoto T, Matsuyama R, Shiina H, Sato T, Takeyama K, Kato S. 2007. Androgen receptor function in folliculogenesis and its clinical implication in premature ovarian failure. Trends in Endocrinology and Metabolism 18(5): 183-189. Li M, Sun L, Wang D. 2019.  Roles of estrogens in fish sexual plasticity and sex differentiation. General and Comparative Endocrinology 277: 9-16. Murray AA, Swales AK, Smith RE, Molinek MD, Hillier SG, Spears N.  2008.  Follicular growth and oocyte competence in the in vitro cultured mouse follicle: effects of gonadotrophins and steroids. MHR-Basic Science of Reproductive Medicine 14(2): 75-83. Palermo R. 2007. Differential actions of FSH and LH during folliculogenesis. Reproductive BioMedicine Online 15(3): 326-337. Rosner W, Hankinson SE, Sluss PM, Vesper HW, Wierman ME. 2013. Challenges to the measurement of estradiol: an endocrine society position statement. The Journal of Clinical Endocrinology and Metabolism. 98(4): 1376-1387. Sashida T, Johnson DC. 1976.  Stimulation of the estrogen synthesizing system of the immature rat ovary by exogenous and endogenous gonadotropins. Steroids 27(4): 469-79.  Spears N, Murray AA, Allison V, Boland NI, Gosden RG. 1998.  Role of gonadotrophins and ovarian steroids in the development of mouse follicles in vitro. Journal of Reproduction and Fertility 113(1): 19-26.   The UniProt Consortium.  UniProt: the Universal Protein Knowledgebase in 2025. https://www.uniprot.org/ (retrieved 2 November 2025).   Zinn S, Schnell M. 2018. Flexibility at the Fringes: Conformations of the Steroid Hormone β-Estradiol. ChemPhysChem 19(21): 2915-2920.   NOTE: Italics indicate edits from John Frisch January 2026.  A full list of updates can be found in the Change Log on the View History page.     AOPWiki 2024-11-22T16:31:12

2026-04-06T14:50:24

<upstream-id>53d2bd88-2339-4cc8-b92f-abbe219a35bc</upstream-id> <downstream-id>ae34bbe5-9620-4a2f-80f7-859f00c70e1a</downstream-id>

Description for KER is based on literature and books on the topic.

The biological plausibility of the current KERs is related to the physiological role of aromatase in estrogen metabolism. Aromatase plays a central role in steroidogenesis by converting androgens to estrogens (Mendelson et al., 1985; Thompson and Siiteri, 1974; Simpson and Santen, 2015). It converts, through aromatization, androstenedione and testosterone to estrone (E1) and estradiol (E2), respectively. Aromatase is physiologically expressed in gonads and in many extra-gonadal tissues. Increased expression or activity of aromatase thus could increase the circulating levels of estrogens (E1, E2). <div> <div> <div> </div> </div> </div>

Not investigated in detail. Association of obesity with the development of endometrial cancer in women (Reeves et al., 2007). This association has been well established and follows a dose-response relationship, with the incidence of endometrial cancer increasing as body mass index (BMI) increases (WCRF and AICR. 2013. Continuous Update Project Report. Food: Nutrition, Physical Activity, and the Prevention of Endometrial Cancer. Available at: <a href="http://www.dietandcancerreport.org">http://www.dietandcancerreport.org</a>). Essentiality Direct evidence <ul> <li>Aromatase knock out mice (ArKO mice). Female ArKO mice at 9 weeks of age displayed underdeveloped external genitalia and uteri. Ovaries contained numerous follicles with abundant granulosa cells and evidence of antrum formation that appeared arrested before ovulation. No corpora lutea were present. Additionally, the stroma was hyperplastic with structures that appeared to be atretic follicles. Development of the mammary glands approximated that of a prepubertal female. Whereas serum estradiol levels were at the limit of detection, testosterone levels were elevated, as were the levels of follicle-stimulating hormone and luteinizing hormone (Fisher et al., 1998).</li> <li>Aromatase inhibitors (e.g., letrozole, anastrozole and exemestane) used to treat breast cancer in postmenopausal women (not investigated in detail)</li> </ul>

Not Specified Unspecific

Not Specified

All life stages

Not Specified

Fisher CR, Graves KH, Parlow AF and Simpson ER, 1998. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A, 95:6965-6970. doi: 10.1073/pnas.95.12.6965 Mendelson CR, Wright EE, Evans CT, Porter JC and Simpson ER, 1985. Preparation and characterization of polyclonal and monoclonal antibodies against human aromatase cytochrome P-450 (P-450AROM), and their use in its purification. Arch Biochem Biophys, 243:480-491. doi: 10.1016/0003-9861(85)90525-9 Reeves GK, Pirie K, Beral V, Green J, Spencer E and Bull D, 2007. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ, 335:1134. doi: 10.1136/bmj.39367.495995.AE WCRF and AICR, online. Continuous Update Project Report. Food: Nutrition, Physical Activity, and the Prevention of Endometrial Cancer. Available online: <a href="https://www.wcrf.org/diet-activity-and-cancer/">https://www.wcrf.org/diet-activity-and-cancer/</a> AOPWiki 2024-11-22T13:51:44

2024-12-16T16:07:06

<upstream-id>ae34bbe5-9620-4a2f-80f7-859f00c70e1a</upstream-id> <downstream-id>fcad16d0-e6c0-4ce1-a311-e01a4a81c777</downstream-id>

AOPWiki 2024-11-22T16:35:15

2024-11-22T16:35:15

<upstream-id>ae34bbe5-9620-4a2f-80f7-859f00c70e1a</upstream-id> <downstream-id>3deb96f5-2546-492e-b3b3-00026d3ace4f</downstream-id>

AOPWiki 2024-11-22T16:34:39

2024-11-22T16:34:39

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AOPWiki 2024-11-22T16:34:47

2024-11-22T16:34:47

<upstream-id>fcad16d0-e6c0-4ce1-a311-e01a4a81c777</upstream-id> <downstream-id>9afdafab-b744-4f07-bb9f-94c82ad2de6c</downstream-id>

The biological plausibility of this KERs is linked to the physiological role of E2 on estrogen-responsive tissues of all mammals. The uterus in rodents and the human undergoes cyclical changes of growth and degeneration (Fig. 10 and 11). In both species, estrogens produced from the developing follicles stimulate endometrial growth, and progesterone is responsible for converting the estrogen primed endometrium into a receptive state. In rodents, if pregnancy does not occur, dioestrus (secretory phase in humans, cycle days 15–28) terminates with regression of the corpus luteum, and the endometrium is resorbed (menstruation in humans, cycle days 1–5). During proestrus (proliferative phase in humans, cycle days 6–14) follicles develop and start to produce estrogens that stimulate endometrial growth. During oestrous (peri-ovulatory period in humans, cycle days 13–15) ovarian follicles mature. The magnitude of uterine growth stimulation is largely dependent upon the duration of bioavailable E2 and receptor interaction (Groothius et al., 2007). <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/11/15/736v98ln59_Figure_10_ker3391.png" /> <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/11/15/2f5jo3ae5h_Figure_11_ker3391.png" /> Bergman et al., 1992 studied the role of oestradiol during the mouse oestrus cycle. The study demonstrated that on proestrus, when plasma E2 levels are at the highest, the cell nuclear ER concentration in uterus was greater than metestrus. This increase was attributable to an increase in total cellular ER (cytosolic and nuclear) and secondarily to activation of ER (measured by its distribution from cytosolic to the nuclear fraction) (Tables 4 and 5). Table 4. Uterine weight, DNA, RNA, and plasma concentrations of E2 during the estrous cycle of C57BL/6J mice. from Bergman et al., 1992 <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/11/15/33t4jnod7y_table_4_ker3391.png" /> Table 5. Uterine weight, DNA, RNA, and plasma concentrations of E2 in E2-treated OVX mice. from Bergman et al., 1992 <img alt="" src="https://aopwiki.org/system/dragonfly/production/2024/11/15/2vlar3pfiz_table5_KER3391.png" /> Overall, this study demonstrated in mice a strong association between E2 and the biosynthesis and intracellular distribution of the uterine ER and its mRNA. The study indicated that the basis for increased nuclear ER on proestrus involves two estrogen-dependent components: 1. activation of ER to a nucleophilic state and 2. increased concentration of ER available for activation, the latter accounting for most of the increase in nuclear ER. The process probably begins early on the day of proestrus with increased activation of ER in response to the rising levels of E2. Increased activation of ER leads to increased DNA binding of ER, which increases ER mRNA and ER. Increased ER provides the substrate for a further increase in DNA-bound ER, which serves to amplify the effect of the rising E2 in a feed-forward cascade that ultimately leads to the dramatic increases in ER mRNA, ER, and polyadenylated RNA that are observed at midday on proestrus (Bergman et al., 2005).

The mechanism of action for E2 in uterus is well-known as well as its interaction with ER and consequent activation of the signalling cascade. One study has been included in support of the empirical evidence of the current KERs in the context of the postulated AOP. OESTRADIOL (see Table 6) Table 6. Empirical evidence table assembled for KER2, Oestradiol <table align="center" cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:630px"> <thead> <tr> <td style="background-color:white; height:65px; vertical-align:top; width:75px"> Species, life-stage, sex tested </td> <td style="background-color:white; height:65px; vertical-align:top; width:74px"> Stressor(s) </td> <td style="background-color:white; height:65px; vertical-align:top; width:77px"> Upstream Effect: increased E2 availability in uterus(Y/N) </td> <td style="background-color:white; height:65px; vertical-align:top; width:85px"> Downstream Effect: ER activation in uterus(Y/N) </td> <td style="background-color:white; height:65px; vertical-align:top; width:114px"> Effect on increased E2 availability in uterus (descriptive) </td> <td style="background-color:white; height:65px; vertical-align:top; width:114px"> Effect on ER activation in uterus (descriptive) </td> <td style="background-color:white; height:65px; vertical-align:top; width:90px"> Citation </td> </tr> <tr> <td style="background-color:white; height:65px; vertical-align:top; width:75px"> C57BL/6J mice female 3-6 months old. 2 OVX </td> <td style="background-color:white; height:65px; width:74px"> E2 </td> <td style="background-color:white; height:65px; width:77px"> Y (indirect measurment) </td> <td style="background-color:white; height:65px; width:85px"> Y </td> <td style="background-color:white; height:65px; vertical-align:top; width:114px"> E2 administered in OVX mice simulated this KE. Implanted. </td> <td style="background-color:white; height:65px; vertical-align:top; width:114px"> Increase of nuclear ER and ER mRNA </td> <td style="background-color:white; height:65px; vertical-align:top; width:90px"> Bergman et al., 1992 </td> </tr> </thead> </table> OTHER Stressors Empirical evidence may be extrapolated from different studies investigating the MoA of specific stressors; however, the KE upstream and KE downstream have never been investigated directly and together in the same experiment. The current empirical support is based on indirect evidence. TBBPA (see Table 7) <ul style="margin-left:40px"> <li>Sanders et al., 2016 investigated the mechanism responsible for the increased incidence of uterine lesions in TBBPA-treated rats as observed in a chronic toxicity study conducted by the National Toxicology Program (NTP). Data involving a direct evaluation of a potential increase in circulating or tissue-specific levels of oestradiol following exposure to TBBPA are not available. The authors determined that the most sensitive and efficient method to test the hypothesis that uterine lesions correlate with TBBPA-mediated disruption of estrogen homeostasis at the site-of-action was to search for TBBPA-mediated effects on genes associated with specific pathways of estrogen biosynthesis and metabolism. These changes may correlate with increased E2 or estrogen-derived reactive metabolites in the tissue; as a matter of facts, at the phenotypic level, increases in estrogen and its related signalling can cause uterine tissues to rapidly grow in size, as demonstrated by the common use of the rat uterus as a target organ for the in vivo screening of estrogen agonists and antagonists. As reported in the review by Wikoff et al.,2016 it is important to note that in the study by Sanders et al., 2016 not all gene expression changes related to estrogen signalling were increased. For example, TBBPA resulted in decreased expression of ESR2 in the proximal uterus. However, there are some lines of evidence showing that, in some instances, ESR2 may act as a repressor of ESR1 in which lower expression of ESR2 may lead to enhanced oestradiol action via increased ESR1 levels in endometrial cancer.</li> <li>Kitamura et al., 2005 investigated the effect of administered TBBPA in a uterotrophic assay.  Uterine weight is a very useful index of estrogenicity (ER activation) in the immature or adult ovariectomized female rats. As a matter of facts, uterine weight (indicative of ER activation) increases many folds during proestrus under the influence of estrogen.</li> </ul> Table 7. Empirical evidence table assembled for KER2, TBBPA <table align="center" cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:669px"> <thead> <tr> <td style="background-color:white; height:.45in; vertical-align:top; width:80px"> Species, life-stage, sex tested </td> <td style="background-color:white; height:.45in; vertical-align:top; width:70px"> Stressor(s) </td> <td colspan="2" style="background-color:white; height:.45in; vertical-align:top; width:100px"> Upstream Effect: increased E2 availability in uterus(Y/N) </td> <td style="background-color:white; height:.45in; vertical-align:top; width:80px"> Downstream Effect: ER activation in uterus(Y/N) </td> <td style="background-color:white; height:.45in; vertical-align:top; width:121px"> Effect on increased E2 availability in uterus (descriptive) </td> <td style="background-color:white; height:.45in; vertical-align:top; width:121px"> Effect on ER activation in uterus (descriptive) </td> <td style="background-color:white; height:.45in; vertical-align:top; width:96px"> Citation </td> </tr> <tr> <td colspan="8" style="background-color:white; height:12px; vertical-align:top; width:669px"> In vivo </td> </tr> <tr> <td style="background-color:white; height:112px; width:80px"> Wistar Han rats, circa 9 wks old, female </td> <td style="background-color:#d9e2f3; height:112px; width:70px"> TBBPA </td> <td style="background-color:white; height:112px; width:90px"> Y (indirect measurement) </td> <td colspan="2" style="background-color:white; height:112px; width:90px"> Y (indirect measurement) </td> <td style="background-color:white; height:112px; width:121px"> ↑ of estrogen stimulated genes in proximal (near the cervix) and distal section (near the ovaries) of uterus (e.g., Thra, esr1, Ppara, Igf1, Cyp1b1, Ugt1a1), Ccnd2 in distal uterus Changes observed for ESR2, ttr in proximal uterus, Thrb in distal uterus, glucocorticoid receptor (GR) in proximal uterus ↓ Cyp11a1 in uterus, Hsd17B2 in distal uterus 250 mg/kg bw per day after 5 days of exposure </td> <td style="background-color:white; height:112px; width:121px"> ↑ of estrogen stimulated genes in proximal (near the cervix) and distal section (near the ovaries) of uterus (e.g., Thra, esr1, Ppara, Igf1, Cyp1b1, Ugt1a1), Ccnd2 in distal uterus Changes observed for ESR2, ttr in proximal uterus, Thrb in distal uterus, glucocorticoid receptor (GR) in proximal uterus ↓ Cyp11a1 in uterus, Hsd17B2 in distal uterus 250 mg/kg bw per day after 5 days of exposure </td> <td style="background-color:white; height:112px; width:96px"> Sanders et al., 2016 </td> </tr> <tr> <td style="background-color:white; height:112px; width:80px"> B6C3F1 mice (ovariectomized), 8 wks old, female </td> <td style="background-color:#d9e2f3; height:112px; width:70px"> TBBPA </td> <td style="background-color:white; height:112px; width:90px"> Y (indirect measurement) </td> <td colspan="2" style="background-color:white; height:112px; width:90px"> Y (indirect measurement) </td> <td style="background-color:white; height:112px; width:121px"> ↑ uterus/body weight in vivo with weak activity on ERE luciferase assay indicative that the substance does not bind directly to the ER 20 mg/kg bw per day after 3 days of exposure </td> <td style="background-color:white; height:112px; width:121px"> ↑ uterus/body weight in vivo with weak activity on ERE luciferase assay indicative that the substance does not bind directly to the ER 20 mg/kg bw per day after 3 days of exposure </td> <td style="background-color:white; height:112px; width:96px"> Kitamura et al., 2005 </td> </tr> </thead> </table> Triclosan (see Table 8) <ul style="margin-left:40px"> <li>Jung et al., 2012; modulation of complement 3 (C3) mRNA in uterus is demonstrated to be an estrogen sensitive marker. Triclosan was found to up-regulate the expression of such gene. The mRNA expression is blocked by the steroid antagonists ICI and RU</li> <li>Jung et al., 2012; Uterotrophic assay. Triclosan was found to induce uterine weight. The increase uterine is reversed by the treatment with steroid antagonists ICI and RU</li> <li>Jung et al., 2012; Calbindin-D9k (CaBP-9k) has been shown to be a novel biomarker for detecting endocrine disrupting chemicals (EDCs). The CaBP-9k is an intracellular calcium binding protein and may increase calcium ion (Ca2+) absorption by buffering Ca2+ in the intestine. CaBP-9k has two calcium-binding domains that interact with Ca2+ with high affinity in the cytoplasm. The CaBP-9k gene is expressed in various tissues, including intestine, kidney, uterus, placenta, pituitary gland, and bone. The expression of the CaBP-9k gene in uterus is up-regulated by estrogen and down-regulated by progesterone (P4) during the oestrous cycle and during early pregnancy in the rat uterus. In the study by Jung et al., 2012 TCS effects on the induction of CaBP-9k mRNA and protein expression were examined by real-time PCR and Western blot analysis in the uteri of immature rats and in GH3 cells. In addition, the steroid antagonists, ICI 182,780 (ICI) and RU 486 (RU), were used to examine the involvement of E2 receptor and/or P4 receptor to verify endocrine effects of TCS. The antimicrobial agent Triclosan was found to up-regulate the expression of uterine CaBP-9k.</li> <li>Stoker et al., 2010; the present study demonstrates that Triclosan alters female postnatal reproductive development and uterine response to exogenous estrogen in the developing female rat. These responses suggest that Triclosan augments estrogen action and that there is the potential for Triclosan to alter estrogen-dependent function.</li> </ul> Table 8. Empirical evidence table assembled for KER2, Triclosan <table align="center" cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:630px"> <thead> <tr> <td style="background-color:white; height:84px; vertical-align:top; width:75px"> Species, life-stage, sex tested </td> <td style="background-color:white; height:84px; vertical-align:top; width:66px"> Stressor(s) </td> <td style="background-color:white; height:84px; vertical-align:top; width:85px"> Upstream Effect: increased E2 availability in uterus(Y/N) </td> <td style="background-color:white; height:84px; vertical-align:top; width:85px"> Downstream Effect: ER activation in uterus(Y/N) </td> <td style="background-color:white; height:84px; vertical-align:top; width:114px"> Effect on increased E2 availability in uterus (descriptive) </td> <td style="background-color:white; height:84px; vertical-align:top; width:114px"> Effect on ER activation in uterus (descriptive) </td> <td style="background-color:white; height:84px; vertical-align:top; width:90px"> Citation </td> </tr> <tr> <td colspan="7" style="background-color:white; height:18px; vertical-align:top; width:630px"> In vivo </td> </tr> <tr> <td style="background-color:white; height:43px; width:75px"> Sprague-Dawley rats, immature </td> <td style="background-color:#fff2cc; height:43px; width:66px"> Triclosan </td> <td style="background-color:white; height:43px; width:85px"> Y (indirect measurement) </td> <td style="background-color:white; height:43px; width:85px"> Y (indirect measurement) </td> <td style="background-color:white; height:43px; width:114px"> The antimicrobial agent Triclosan  was found to up-regulate the expression of uterine CaBP-9k. Triclosan  was found to up-regulate the expression of mRNA C3 in uterus. 37.5 mg/kg bw per day after 3 days of exposure Increased uterus weight/bw ratio in TCS rats treated compared to vehicle. 7.5 mg/kg bw per day after 3 days of exposure   </td> <td style="background-color:white; height:43px; width:114px"> The antimicrobial agent Triclosan  was found to up-regulate the expression of uterine CaBP-9k. Triclosan  was found to up-regulate the expression of mRNA C3 in uterus. 37.5 mg/kg bw per day after 3 days of exposure Increased uterus weight/bw ratio in TCS rats treated compared to vehicle. 7.5 mg/kg bw per day after 3 days of exposure   </td> <td style="background-color:white; height:43px; width:90px"> Jung et al., 2012 </td> </tr> <tr> <td style="background-color:white; height:43px; width:75px"> Female, Wistar rats, PND19 </td> <td style="background-color:#fff2cc; height:43px; width:66px"> Triclosan </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. The increase uterine weight/bw ratio was observed only in co-treatment with ethylinoestradiol </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. The increase uterine weight/bw ratio was observed only in co-treatment with ethylinoestradiol </td> <td style="background-color:white; height:43px; width:90px"> Stoker et al., 2010 </td> </tr> <tr> <td style="background-color:white; height:43px; width:75px"> Female, Wistar rats, PND22 </td> <td style="background-color:#fff2cc; height:43px; width:66px"> Triclosan </td> <td style="background-color:white; height:43px; width:85px"> Y (indirect measurement) </td> <td style="background-color:white; height:43px; width:85px"> Y (indirect measurement) </td> <td style="background-color:white; height:43px; width:114px"> Female pubertal assay: increase blotted and wet uterine absolute and relative weights at PND 42 at 150 mkd . This picture could be indicative of an estrogenic condition at uterine level but it is not informative on the MoA. 150 mg/kg bw per day after 21 days of exposure </td> <td style="background-color:white; height:43px; width:114px"> Female pubertal assay: increase blotted and wet uterine absolute and relative weights at PND 42 at 150 mkd . This picture could be indicative of an estrogenic condition at uterine level but it is not informative on the MoA. 150 mg/kg bw per day after 21 days of exposure </td> <td style="background-color:white; height:43px; width:90px"> Stoker et al., 2010 </td> </tr> <tr> <td style="background-color:white; height:43px; width:75px"> Female, Wistar rats, PND18 </td> <td style="background-color:#fff2cc; height:43px; width:66px"> Triclosan </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. Doses 0, 0.8, 2.4, 8.0 mg/kg bw per day </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. Doses 0, 0.8, 2.4, 8.0 mg/kg bw per day </td> <td style="background-color:white; height:43px; width:90px"> Montagnini et al., 2018 </td> </tr> <tr> <td style="background-color:white; height:43px; width:75px"> Female, Wistar rats, PND21 </td> <td style="background-color:#fff2cc; height:43px; width:66px"> Triclosan </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. Doses 0, 1, 10, 50 mg/kg bw per day </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. Doses 0, 1, 10, 50 mg/kg bw per day </td> <td style="background-color:white; height:43px; width:90px"> Rodriguez-Sanchez 2010 </td> </tr> <tr> <td style="background-color:white; height:43px; width:75px"> Wistar rats (Charles River) PND 13 </td> <td style="background-color:#fff2cc; height:43px; width:66px"> Triclosan </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:85px"> N (indirect measurement) </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. </td> <td style="background-color:white; height:43px; width:114px"> No effect in a uterotrophic assay. </td> <td style="background-color:white; height:43px; width:90px"> Louis et al., 2013 </td> </tr> </thead> </table> Parabens (i.e., Methylparabens/Ethylparabens) (see Table 9) Sun et al., 2016: In this study, the uterotrophic activities of methylparaben (MP) and ethylparaben (EP) at doses close to the acceptable daily intake as allocated by JECFA were demonstrated in immature Sprague-Dawley rats by intragastric administration, and up-regulations of estrogen-responsive biomarker genes were found in uteri of the rats by quantitative real-time RT–PCR (Q-RT-PCR). Table 9. Empirical evidence table assembled for KER2, Parabens <table align="center" cellspacing="0" class="Table" style="background:white; border-collapse:collapse; width:630px"> <thead> <tr> <td style="background-color:white; height:65px; vertical-align:top; width:75px"> Species, life-stage, sex tested </td> <td style="background-color:white; height:65px; vertical-align:top; width:70px"> Stressor(s) </td> <td style="background-color:white; height:65px; vertical-align:top; width:81px"> Upstream Effect: increased E2 availability in uterus(Y/N) </td> <td style="background-color:white; height:65px; vertical-align:top; width:85px"> Downstream Effect: ER activation in uterus(Y/N) </td> <td style="background-color:white; height:65px; vertical-align:top; width:114px"> Effect on increased E2 availability in uterus (descriptive) </td> <td style="background-color:white; height:65px; vertical-align:top; width:114px"> Effect on ER activation in uterus (descriptive) </td> <td style="background-color:white; height:65px; vertical-align:top; width:90px"> Citation </td> </tr> <tr> <td colspan="7" style="background-color:white; height:18px; vertical-align:top; width:630px"> In vivo </td> </tr> <tr> <td style="background-color:white; height:43px; width:75px"> Sprague-Dawley rats, female, PND20 </td> <td style="background-color:#fbe4d5; height:43px; width:70px"> Parabens * </td> <td style="background-color:white; height:43px; width:81px"> Y </td> <td style="background-color:white; height:43px; width:85px"> Y </td> <td style="background-color:white; height:43px; width:114px"> ↑ expression of estrogen-responsive genes (i.e., icabp, CaBP-9k, itmap1, pgr) Starting from 4 mg/kg bw per day after 3 days of exposure ↑ Uterus weight Starting from 20 mg/kg bw per day after 3 days of exposure </td> <td style="background-color:white; height:43px; width:114px"> ↑ expression of estrogen-responsive genes (i.e., icabp, CaBP-9k, itmap1, pgr) Starting from 4 mg/kg bw per day after 3 days of exposure ↑ Uterus weight Starting from 20 mg/kg bw per day after 3 days of exposure </td> <td style="background-color:white; height:43px; width:90px"> Sun et al., 2016 </td> </tr> </thead> </table> * Methylparaben, Ethylparaben. Dose and temporal concordance In accordance with the OECD handbook for the AOP developers this section should include the extent of the evidence that KE upstream is generally impacted at doses (or stressor severities) equal to or less than those at which KE downstream is impacted. In the case of the current KER the evidence is poor, and many inconsistencies were identified. The dose and temporal concordance tables for stressors TBBPA, Triclosan and Parabens were included in <a href="https://efsa.onlinelibrary.wiley.com/action/downloadSupplement?doi=10.2903%2Fj.efsa.2023.7744&file=efs27744-sup-0003-Annex-A.3.xlsx">Annex A.3</a> of the Scientific Opinion.

<ul> <li style="text-align:justify">E2 availability in uterus is rarely measured as stand-alone endpoint. The evidence collected on different stressors indicates the induction of specific estrogen-responsive genes; however, there is still little knowledge in this field</li> <li>There are few studies indicating which genes can be used as biomarkers indicative of an increase of E2 availability in uterus / ER activation in uterus.</li> <li>It is well-known that there is large variability in the uterotrophic assay (Brown et al., 2015), this can be explained by the differences in the experimental design</li> <li>The presence of phytoestrogen in the diet could influence the outcome of the experiments</li> </ul>

It is acknowledged that the increase of oestradiol (E2) content in malignant endometrium compared to macroscopically normal looking endometrium supports the idea of an important role of excessive estrogenic stimulation in the development and further progression of endometrial cancer in endometrial cancer. However, further investigation on the impact of these modulation factors on quantitative aspects of the response-response function that describe the relationships between KEs should be performed

In AOP504, there is only one study where the increase of E2 bioavailability in uterus and ER activation has been measured in the same experiment in vivo (Bergman et al., 1992). Therefore, there are not enough data available to make any definitive quantitative correlations.

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Bergman MD, Schachter BS, Karelus K, Combatsiaris EP, Garcia T and Nelson JF, 1992. Up-regulation of the uterine estrogen receptor and its messenger ribonucleic acid during the mouse estrous cycle: the role of estradiol. Endocrinology, 130:1923-1930. doi: 10.1210/endo.130.4.1547720 Jung EM, An BS, Choi KC and Jeung EB, 2012. Potential estrogenic activity of Triclosan  in the uterus of immature rats and rat pituitary GH3 cells. Toxicol Lett, 208:142-148. doi: 10.1016/j.toxlet.2011.10.017 Kitamura S, Suzuki T, Sanoh S, Kohta R, Jinno N, Sugihara K, Yoshihara Si, Fujimoto N, Watanabe H and Ohta S, 2005. Comparative Study of the Endocrine-Disrupting Activity of Bisphenol A and 19 Related Compounds. Toxicological Sciences, 84:249-259. doi: 10.1093/toxsci/kfi074 Louis GW, Hallinger DR and Stoker TE, 2013. The effect of Triclosan  on the uterotrophic response to extended doses of ethinyl estradiol in the weanling rat. Reprod Toxicol, 36:71-77. doi: 10.1016/j.reprotox.2012.12.001 Montagnini BG, Pernoncine KV, Borges LI, Costa NO, Moreira EG, Anselmo-Franci JA, Kiss ACI and Gerardin DCC, 2018. Investigation of the potential effects of Triclosan  as an endocrine disruptor in female rats: Uterotrophic assay and two-generation study. Toxicology, 410:152-165. doi: 10.1016/j.tox.2018.10.005 Rodríguez PE and Sanchez MS, 2010. Maternal exposure to Triclosan  impairs thyroid homeostasis and female pubertal development in Wistar rat offspring. J Toxicol Environ Health A, 73:1678-1688. doi: 10.1080/15287394.2010.516241 Sanders JM, Coulter SJ, Knudsen GA, Dunnick JK, Kissling GE and Birnbaum LS, 2016. Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A. Toxicology and Applied Pharmacology, 298:31-39. doi: <a href="https://doi.org/10.1016/j.taap.2016.03.007">https://doi.org/10.1016/j.taap.2016.03.007</a> Stoker TE, Gibson EK and Zorrilla LM, 2010. Triclosan  exposure modulates estrogen-dependent responses in the female wistar rat. Toxicol Sci, 117:45-53. doi: 10.1093/toxsci/kfq180 Sun L, Yu T, Guo J, Zhang Z, Hu Y, Xiao X, Sun Y, Xiao H, Li J, Zhu D, Sai L and Li J, 2016. The estrogenicity of methylparaben and ethylparaben at doses close to the acceptable daily intake in immature Sprague-Dawley rats. Sci Rep, 6:25173. doi: 10.1038/srep25173 Wikoff DS, Rager JE, Haws LC and Borghoff SJ, 2016. A high dose mode of action for tetrabromobisphenol A-induced uterine adenocarcinomas in Wistar Han rats: A critical evaluation of key events in an adverse outcome pathway framework. Regul Toxicol Pharmacol, 77:143-159. doi: 10.1016/j.yrtph.2016.01.018 AOPWiki 2024-11-15T14:01:45

2024-11-21T17:53:22

Aromatase induction leading to estrogen receptor alpha activation via increased estradiol

Martina Panzarea

<div> Anna Lanzoni Martina Panzarea </div>

BY-SA

2.7

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<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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AOPWiki 2024-11-22T15:12:56

2025-04-03T15:56:52