AOP: 504

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

SULT1E1 inhibition leading to uterine adenocarcinoma via increased estrogen availability at target organ level

Short name

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SULT1E1 inhibition and increased oestradiol availability

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.6

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Anna Lanzoni

Martina Panzarea

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Ana-Andreea Cioca (email point of contact)

Contributors

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Ana-Andreea Cioca
anna lanzoni
MARTINA PANZAREA
Travis Karschnik

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on November 22, 2024 16:55

Revision dates for related pages

Page	Revision Date/Time
Inhibition of Sulfotransferase E1 (SULT1E1)	November 21, 2024 17:36
Estradiol availability, increased	November 21, 2024 17:40
Activation, estrogen receptor alpha	November 21, 2024 17:42
SULT1E1 inhibition leads to Increased E2 availability	November 21, 2024 17:48
Increased E2 availability leads to Activation, estrogen receptor alpha	November 21, 2024 17:53
17beta-Estradiol	November 29, 2016 18:42
Polychlorinated biphenyls; mixture of specific PCBs	November 19, 2024 17:16
Tetrabromobisphenol A	July 20, 2018 05:36
1-Ethyl-1-nitrosourea	November 19, 2024 17:19
Triclosan	November 12, 2020 18:00
Cyclizine	November 19, 2024 17:20

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

As for other steroids, the circulatory transport and action of estrogens in target tissues are regulated by a complex interplay between sulfation and desulfation pathways. Non-sulfated estrogens may exert their biological effect by binding to the cognate nuclear receptor or may be downstream converted to more active steroids. Sulfated steroids are highly soluble, and this facilitates not only their renal excretion, but also their circulatory transit fuelling peripheral steroid metabolism. Sulfated steroids, as such, are inert and unable to bind and activate their nuclear receptor; active transportation into the cell and intracellular desulfation are required (Foster and Mueller, 2018). The expression and activities of enzymes involved in these pathways is regulated by hormonal factors, and it shows a cyclic pattern in the human endometrium. Sulfation and desulfation pathways dramatically alter the levels of available active steroids and in disease, such as steroid dependent cancer, where the SULT pathway is down-regulated (decreased enzyme expression and activity), while steroid sulfatase (STS) activity is elevated (reviewed in Mueller et al., 2015). Potent inhibitors of estrogen sulfotransferases have the potential to increase the bioavailability of E2 in target tissues (e.g. uterus), thereby causing an estrogenic effect.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Please refer to the EFSA Scientific Opinion for an overview of the Context and Strategy of the AOP development.

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

2155

Inhibition of Sulfotransferase E1 (SULT1E1)

SULT1E1 inhibition

2251

Estradiol availability, increased

Increased E2 availability

1065

Activation, estrogen receptor alpha

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

SULT1E1 inhibition leads to Increased E2 availability	adjacent
Increased E2 availability leads to Activation, estrogen receptor alpha	adjacent

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
17beta-Estradiol
Polychlorinated biphenyls; mixture of specific PCBs
Tetrabromobisphenol A
1-Ethyl-1-nitrosourea
Triclosan
Cyclizine

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Adults

Taxonomic Applicability

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Term	Scientific Term	Evidence	Link
mammals	mammals		NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Female

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life stage applicability: the relevant life stage for this AOP is adulthood.

Taxonomic Applicability: Based on the majority of the available evidence the taxonomic applicability domains of this AOP is mammals. Most evidence for this AOP has been gathered primarily from laboratory rodents and humans.

Sex Applicability: This AOP applies to females. Inhibition of SULT1E1 in pre- and post-menopausal period can have impacts on the E2 bioavailability and consequently on the ER activation in uterus.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Essentiality MIE1. SULT1E1 inhibition

Direct evidence

None

Indirect evidence (because this evidence is not related to the blockage of KEupstream, but is related to evidence that modulating the KE upstream the KE downstream is changed):

The antimicrobial agent Triclosan was found to up-regulate the expression of uterine CaBP-9k and complement C3; the mRNA expression is blocked by the steroid antagonists ICI and RU (Jung et al., 2012)
Barbosa et al., 2020 (review). Several classes of drugs may indirectly modulate SULT1E1 activity. For instance, glucocorticoids, such as dexamethasone (Dex), have been shown to reduce estrogenic activity in vivo and in vitro by increasing the expression of SULT1E1. The induction of SULT1E1 and the resultant inhibition of estrogen activity by Dex were consistent with previous reports that glucocorticoids can inhibit estrogen responses.
Qian et al., 2001. Evidence from mutation and knockout models demonstrated that targeted disruption, in male mice, of estrogen sulfotransferase (EST), causes structural and functional lesions in the male reproductive system. Although knockout males were fertile and phenotypically normal initially, they developed age dependent Leydig cell hypertrophy/hyperplasia and seminiferous tubule damage. Development of these lesions in the testis could be recapitulated by exogenous E2 administration in younger knockout mice, suggesting that they arose in older knockout mice from chronic estrogen stimulation. These finding suggested a role of estrogen metabolism in intracrine and paracrine estrogen regulation.
Tong et al., 2005. Another study is showing that ablation of the mouse Sult1e1 gene caused placental thrombosis and spontaneous fetal loss. The fetal death is caused by estrogen excess related to the lack of SULT1E1 in placenta. Similar placental defects were induced in wild-type (WT) animals exposed to high doses of estrogen.
Hirata et al., 2008. increase single nucleotide polymorphism for SULT1A1 and SULT1E1 genes may be risk factor for endometrial cancer in Caucasian.

Essentiality KE1: Estradiol availability, increased

Direct evidence

Ovariectomized (OVX) rodents are commonly used for studying the influence of estrogen deprivation in intact organisms; proliferation of the vagina and uterus in rodents is stimulated by ovarian estrogen, and ovariectomy induces regression of these tracts. OVX rodents are also quite used to study the effect of menopause and of estrogen-based treatments in reversing menopausal changes in women.
Evidence that the Uterotrophic action of E2 depends on its binding to receptors was first provided by experiments with specific binding inhibitors. Certain substances, such as ethamoxytriphetol (MER-25, Richardson-Merrell), clomiphene, nafoxidine (Upjohn-11,100), and CI-628 (Parke-Davis) (Fig. I), which had been known to inhibit the uterotrophic action of oestradiol, were shown to prevent the characteristic uptake of estrogens by target tissues in vivo (reviewed by Jensen and DeSombre, 1973).

Evidence that a decrease of oestradiol availability in estrogen responsive tissues such as uterus is leading to the implication related to a lack of estrogen receptor activation is observed in menopausal women that develop symptoms such as, loss of bone density, hot flushes and cardiovascular problems (Paterni et al., 2014).
E2-induced uterine epithelial cell proliferation is mediated by stromal ERα. ERα knockout mice showed no expression of estrogen responsive genes in the uterus, and the basic levels of PR mRNA in the aERKO uterus were equal to those in wild type mice (Yu et al., 2022).
In Sprague Dawley rats Triclosan was found to increase uterine weight of immature rats and up-regulate the expression of calbidin-D9k (CaBP-9k) and complement C3 (C3) indicating that TCS can induce their expression mediated by estrogenic activity. Co-treatment with steroid antagonists ICI 182,780 (ICI) and RU 486 in conjunction with TCS (37.5 mg/kg) reversed TCS-induced uterine weight and CaBP-9k mRNA and protein expression increases in immature rats (Jung et al., 2012).
In Sprague Dawley rats MP and EP were found to increase uterine weight. The uterotrophic effects were antagonized in rats treated with 25 μ g/kg bw/day E2, 20 mg/kg bw/day MP, or 20 mg/kg bw/day EP in combination with 10 mg/kg bw/day fulvestrant (FULV) (Sun et al.,2013)

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

KER title

Biological Plausibility

Empirical Support

Essentiality

Brief Explanation (summary)

KER 1: SULT1E1 inhibition leads to Increased E2 availability

L->M

Biological Plausibility. The role of SULT1E1 in estrogen sulfatation with consequent inactivation of E2 is a consolidated scientific concept (dogma). As consequence, the inhibition of SULT1E1 leading to higher free E2 level in target tissue is considered a high biological plausible KER.

Empirical Support. There are no studies reporting a dependent change in both events following the exposure to a specific stressor. In fact, the endpoints described by the two KEs have never been measured in the same study. The empirical support was therefore considered low.

Essentiality. Indirect evidence where the estrogenic effects of SULT1E1 inhibitor is reversed by steroid antagonists is reported for specific stressor (Jung et al., 2012). Moreover, several classes of drugs may indirectly modulate SULT1E1 activity: mouse uterine estrogen responses were inhibited by Dexamethasone, a glucocorticoid drug, in a SULT1E1 dependent manner. In fact, glucocorticoids are known to interact with the glucocorticoid receptor (GR) which acts as a transcriptional factor promoting the upregulation of one of its transcriptional target, SULT1E1. Consequently, SULT1E1 induction is responsible for reducing the level of active estrogen resulting in inhibition of estrogen activity (reviewed by Barbosa et al., 2020). The available evidence on KO models is mainly in support of the KER and highlighted that modulation of MIE is associated to effects indicative of an increase of E2 availability; this evidence is mainly available in males. Evidence on mutation and knockout models demonstrated that targeted disruption, in male mice, of estrogen sulfotransferase (EST), causes structural and functional lesions in the male reproductive system. Although knockout males were fertile and phenotypically normal initially, they developed age dependent Leydig cell hypertrophy/hyperplasia and seminiferous tubule damage. Development of these lesions in the testis could be recapitulated by exogenous E2 administration in younger knockout mice, suggesting that they arose in older knockout mice from chronic estrogen stimulation. These finding suggested a role of estrogen metabolism in intracrine and paracrine estrogen regulation (Qian et al., 2001). Ablation of the mouse Sult1e1 gene caused placental thrombosis and spontaneous foetal loss. The foetal death is caused by estrogen excess related to the lack of SULT1E1 in placenta. Similar placental defects were induced in wild-type (WT) animals exposed to high doses of estrogen (Tong et al., 2005). Moreover, increase single nucleotide polymorphisms in SULT1E1 is associated to increase risk of endometrial cancer (an estrogen-dependent cancer) in Caucasians (Hirata et al., 2007). The total available evidence is limited and mainly based on indirect data; the essentiality was therefore graded low to moderate.

KER 2: Increased E2 availability leads to Activation, estrogen receptor alpha

H -> M

M -> H

Biological Plausibility. The biological plausibility of this KERs is linked to the physiological role of E2 on estrogen-responsive tissues of all mammals and is a consolidated scientific concept (dogma). The biological plausibility is therefore high.

Empirical support. Empirical evidence for this KE is extrapolated from a study investigating the interaction between E2 and estrogen receptor in uterus of mice: the E2 administration in OVX mice increase the expression of E2 and ER mRNA in the cells (Bergman et al., 1992). In addition, empirical evidence may be extrapolated from different studies investigating the MoA of specific stressors (i.e., TBBPA, Parabens and Triclosan ); however, in these cases the evidence is indirect since the two events are not measured in the same experiment.

Essentiality. Ovariectomized (OVX) rodents are commonly used for studying the influence of estrogen deprivation in intact organisms; proliferation of the vagina and uterus in rodents is stimulated by ovarian estrogen, and ovariectomy induces regression of these tracts. OVX rodents are also quite used to study the effect of menopause and of estrogen-based treatments in reversing menopausal changes in women. In addition to this, one of the first study investigating the role of E2 in in vivo organisms, underlined that the uptake of E2 by target tissues in vivo is prevented by treatment with inhibitors of uterotrophic action of oestradiol providing evidence that the reactivity of oestradiol depends on its binding to estrogen receptor (Jensen and Sombre, 1973). The essentiality of this KER is also supported by direct evidence with specific stressors: in Sprague Dawley rats Triclosan was found to increase uterine weight of immature rats and up-regulate the expression of calbidin-D9k (CaBP-9k) and complement C3 (C3) indicating that TCS can induce their expression mediated by estrogenic activity. Co-treatment with steroid antagonists ICI 182,780 (ICI) and RU 486 in conjunction with TCS reversed TCS-induced uterine weight and CaBP-9k mRNA and protein expression increases in immature rats (Jung et al.,2012); in Sprague Dawley rats MP and EP were found to increase uterine weight. The uterotrophic effects of methyl and ethylparaben were antagonized in rats treated with E2, MP, or EP in combination with fulvestrant (FULV) (Sun et al., 2016). The essentiality has been graded moderate to high. The evidence is strong; however, there are further data that can be used in support of this that were not evaluated/assessed as part of this AOP.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

At present, the overall quantitative understanding of the AOP is insufficient to directly link a measure of chemical potency as a SULT1E1 inhibitor to a quantitative prediction of effect on uterine adenocarcinoma trough an increase of oestradiol bioavailability in uterus.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Barbosa ACS, Feng Y, Yu C, Huang M and Xie W, 2019. Estrogen sulfotransferase in the metabolism of estrogenic drugs and in the pathogenesis of diseases. Expert Opin Drug Metab Toxicol, 15:329-339. doi: 10.1080/17425255.2019.1588884

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

Foster PA and Mueller JW, 2018. Sulfation pathways: insights into steroid sulfation and desulfation pathways. Journal of Molecular Endocrinology, 61, T271–t283

Hirata H, Hinoda Y, Okayama N, Suehiro Y, Kawamoto K, Kikuno N, Rabban JT, Chen LM and Dahiya R, 2008. CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility. Cancer, 112:1964-1973. doi: https://doi.org/10.1002/cncr.23392

Jensen EV and DeSombre ER, 1973. Estrogen-receptor interaction. Science, 182:126-134. doi: 10.1126/science.182.4108.126

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

Mueller JW, Gilligan LC, Idkowiak J, Arlt W and Foster PA, 2015. The Regulation of Steroid Action by Sulfation and Desulfation. Endocrine Reviews, 36, 526–563.

Paterni I, Granchi C, Katzenellenbogen JA and Minutolo F, 2014. Estrogen receptors alpha (ERα) and beta (ERβ): subtype-selective ligands and clinical potential. Steroids, 90:13-29. doi: 10.1016/j.steroids.2014.06.012

Qian YM, Sun XJ, Tong MH, Li XP, Richa J and Song W-C, 2001. Targeted Disruption of the Mouse Estrogen Sulfotransferase Gene Reveals a Role of Estrogen Metabolism in Intracrine and Paracrine Estrogen Regulation. Endocrinology, 142:5342-5350. doi: 10.1210/endo.142.12.8540

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

Tong MH, Jiang H, Liu P, Lawson JA, Brass LF and Song WC, 2005. Spontaneous fetal loss caused by placental thrombosis in estrogen sulfotransferase-deficient mice. Nat Med, 11:153-159. doi: 10.1038/nm1184