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AOP: 295

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

Early-life stromal estrogen receptor activation by endocrine disrupting chemicals in the mammary gland leading to enhanced cancer risk

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Early-life stromal ER-activation by EDCs leads to mammary cancer risk

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Handbook Version v2.0

Graphical Representation

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

Authors

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Andrea R. Hindman^*+, Alissa P. Link^{^} and Ruthann A. Rudel^*

^*Silent Spring Institute, Newton, MA; ⁺Social Science Environmental Health Research Institute, Northeastern University, Boston, MA; ^{^}Research and Instruction, Northeastern University, Boston, MA

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

Cataia Ives (email point of contact)

Contributors

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Andrea Hindman
Cataia Ives

Coaches

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Judy Choi
Rex FitzGerald

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
1.79	Under Development

This AOP was last modified on May 26, 2024 20:39

Revision dates for related pages

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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

This adverse outcome pathway (AOP) links gestational EDC exposure to enhanced breast cancer risk. The molecular initiating event (MIE) is gestational estrogen receptor (ER) activation; particularly, stromal activation at in utero time of exposure. The ER is a master transcriptional regulator, with proliferation as its primary effect, and is the main mediator of breast development [24, 25]. Human-relevant EDC exposure triggers transcriptional activity that promotes altered signaling between the epithelial and stromal tissue compartments leading to disrupted tensional homeostasis [26] and tissue architecture. Inflammation and altered cellular differentiation are major cell- and tissue-level key events (KEs) mediating these disruptions. The pathway converges on the following mammary gland adverse outcomes (AOs) at the tissue- and organ-levels: altered density, structure and hormone sensitivity along with hyperplasia. Epigenetic alterations are a cellular-level AO that propagate gestational EDC exposure to later-life risk through cellular memory that directs ER-mediated gene expression and altered mammary development. Risk of tumorigenesis follows from these AOs.

The industrial estrogen, bisphenol A (BPA) is one of the most data-rich chemicals related to breast cancer and altered mammary gland development [11]. As such, studies in model rodent strains following gestational EDC exposure to bisphenol A (BPA) or DES provide experimental support for this AOP and human-relevance. A thorough search of the literature yielded experimental evidence for this AOP as directed by a mix of natural and MeSH term search logic specifying rodents and non-human primates (population); human-relevant, in utero exposure to BPA or DES (exposure); and mammary gland AOs (outcome) [27-32] (see PECO statement, Table 1 below). Most studies investigating EDC-effects on mammary development heavily describe altered growth and structure, resulting in limited mechanistic understanding. This AOP integrates knowledge and tools from investigations of established breast cancer risk factors such as density and obesity to enhance understanding of the molecular- and cellular-driven etiologies of altered mammary structure and growth. Integrating this knowledge promotes the development of in vitro assays capable of predicting high-risk phenotypes and offers efficient alternatives to in vivo mammary gland evaluation. Ultimately, making these links in the knowledge base will improve screening to identify chemicals that act on gestational development and will more specifically target chemical contributions to later-life breast cancer risk in toxicity testing. Productive intermediate testing endpoints would follow ER-binding, -activation and steroidogenesis (OECD TG-455; EDSP TG-890[33, 34]), precede carcinogenicity (OECD TG-451, and -453) and connect these with EDC-effects on breast cancer due to prenatal exposure (OECD TG-414, -415, -416, -422, -443). This AOP will also describe ‘missed opportunities’ in the existing evidence; not reporting or measuring traditional toxicity testing endpoints, like uterine weight and body weight alongside more sensitive mammary gland growth and structural changes. Failure to do this in parallel within the same study undermines the sensitivity of these endpoints to predict later-life breast cancer risk.

Table 1. PECO statement [27, 28]. A statement of the Population, Exposure, Comparators and Outcomes was prepared to direct objective experimental study collection for this AOP synthesis on breast cancer risk from early-life EDC exposure. The Organization for Economic Co-operation and Development does not cite systematic review methods or objective identification of included evidence in its guidance for AOP development. A narrowed survey of review articles in PubMed, published after 2006 and until November 2018, was performed to assess the state of mechanistic evidence connecting EDC exposure to breast cancer risk and altered mammary gland growth and structure. This step assisted problem formulation by situating human-relevant EDC exposures in the hallmarks of cancer via ‘important reviews.’ There were no systematic reviews. This initial survey of the review literature assisted search logic development and supported an initial sketch of the AOP.

INCLUSION CRITERIA	EXCLUSION CRITERIA
*Population (Experimental animal, in vivo* studies)** Female laboratory rodents Female laboratory non-human primates	Human and non-rodent animals and organisms, including wildlife, aquatic species and plants Males
Exposure Human-relevant exposure to BPA, related BPA analogues or DES In utero exposure. In utero exposure is a requirement but studies that extend exposure to the perinatal period are also included Exposure to controlled doses of BPA via an exposure method (e.g. – diet, drinking water, gavage, injection)	High-dose or pharmacological-dose exposures to BPA or DES Any other EDC Exposure to chemical mixtures in animals Exposures during other developmental windows of risk
Comparators Vehicle-only, concurrently run treatment controls	No controls Historical controls
Outcomes Determination of mammary gland disruption via any methodology intended to address mechanisms mapped in the AOP (see Figure ) including to alterations of tissue density, epigenetics, gland morphology, hormone sensitivity and hyperplasia as precursors to tumorigenesis Assessed in virgin, female laboratory rodents or non-human primates at any stage-of-life (e.g. - postnatal, pubertal or adult development) Uterine weight Body weight	Any other organs Any other stage-of-life
Publication parameters Peer-reviewed Original data Studies must be published in English	Non-peer reviewed; gray literature (e.g. - conference presentations or other studies published in abstract form only, grant awards/ proposals and theses/ dissertations Retracted articles Review articles (only considered for the initial survey of available mechanistic data)

AOP Development Strategy

Context

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Breast cancer risk background: Breast cancer is a significant health concern as the second leading cause of death in women [1]. Only 5-10% of breast cancers are attributable to genetic predisposition and substantial evidence indicates many lifestyle and environmental factors contribute to lifetime risk [2-5]. Early-life developmental disruption by hormone-like, or endocrine disrupting chemicals (EDCs), heightens age-related breast cancer risk. A human model of this disruption emerges from the treatment of pregnant women with synthetic estrogen, diethylstilbestrol (DES), beginning in the 1940’s with the intent to prevent miscarriages. This practice ceased when women exposed in gestation – “DES Daughters” – had a 40x increased incidence of cervical and vaginal cancers [6, 7], highlighting in utero development as a critical window of exposure. The later finding that “DES Daughters” also had a 2-fold increased incidence of breast cancer only detected in women ≥30 years post-exposure, underscores the latency of this disruption in causing disease [7-9]. Studies of the reproductive tract and mammary gland of rodent models have recapitulated these increased risks [10-12]. While synthetic estrogens are no longer prescribed to pregnant women, human biomonitoring data show widespread exposure to EDCs that include weak estrogens [13, 14] and their ability to cross the placental barrier [14-18]. Many EDCs are present at human-relevant exposures in the environment, but these chemicals can act together on the same adverse health outcomes [19], including estrogen action as a relevant target for breast cancer [20-23]. Taken together, this evidence raises concerns that early-life EDC exposure enhances later-life breast cancer risk.

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

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

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

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

Life Stage Applicability

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

Taxonomic Applicability

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Sex Applicability

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

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

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

Evidence Assessment

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

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

Quantitative Understanding

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

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

1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 2017. 67(1): p. 7-30.

2. Kim, B.J. and S.H. Kim, Prediction of inherited genomic susceptibility to 20 common cancer types by a supervised machine-learning method. Proc Natl Acad Sci U S A, 2018. 115(6): p. 1322-1327.

3. Lichtenstein, P., et al., Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med, 2000. 343(2): p. 78-85.

4. Foulkes, W.D., Inherited susceptibility to common cancers. N Engl J Med, 2008. 359(20): p. 2143-53.

5. Peto, J., et al., Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst, 1999. 91(11): p. 943-9.

6. Herbst, A.L. and R.E. Scully, Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer, 1970. 25(4): p. 745-57.

7. Hatch, E.E., et al., Cancer risk in women exposed to diethylstilbestrol in utero. Jama, 1998. 280(7): p. 630-4.

8. Hoover, R.N., et al., Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med, 2011. 365(14): p. 1304-14.

9. Palmer, J.R., et al., Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 2006. 15(8): p. 1509-14.

10. Newbold, R.R., W.N. Jefferson, and E. Padilla-Banks, Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract. Reprod Toxicol, 2007. 24(2): p. 253-8.

11. Soto, A.M., et al., Does cancer start in the womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors. J Mammary Gland Biol Neoplasia, 2013. 18(2): p. 199-208.

12. Boylan, E.S. and R.E. Calhoon, Transplacental action of diethylstilbestrol on mammary carcinogenesis in female rats given one or two doses of 7,12-dimethylbenz(a)anthracene. Cancer Res, 1983. 43(10): p. 4879-84.

13. Calafat, A.M., et al., Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003-2004. Environ Health Perspect, 2008. 116(1): p. 39-44.

14. Woodruff, T.J., A.R. Zota, and J.M. Schwartz, Environmental chemicals in pregnant women in the United States: NHANES 2003-2004. Environ Health Perspect, 2011. 119(6): p. 878-85.

15. Gerona, R.R., et al., Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population. Environ Sci Technol, 2013. 47(21): p. 12477-85.

16. Chen, M., et al., Determination of bisphenol-A levels in human amniotic fluid samples by liquid chromatography coupled with mass spectrometry. J Sep Sci, 2011. 34(14): p. 1648-55.

17. Balakrishnan, B., et al., Transfer of bisphenol A across the human placenta. Am J Obstet Gynecol, 2010. 202(4): p. 025.

18. Nishikawa, M., et al., Placental transfer of conjugated bisphenol A and subsequent reactivation in the rat fetus. Environ Health Perspect, 2010. 118(9): p. 1196-203.

19. Goodson, W.H., 3rd, et al., Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis, 2015. 36(1).

20. Dairkee, S.H., et al., A Ternary Mixture of Common Chemicals Perturbs Benign Human Breast Epithelial Cells More Than the Same Chemicals Do Individually. Toxicol Sci, 2018. 165(1): p. 131-144.

21. Goodson, W.H., 3rd, et al., Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women. Carcinogenesis, 2011. 32(11): p. 1724-33.

22. Silva, E., N. Rajapakse, and A. Kortenkamp, Something from "nothing"--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol, 2002. 36(8): p. 1751-6.

23. Charles, G.D., et al., Analysis of the interaction of phytoestrogens and synthetic chemicals: an in vitro/in vivo comparison. Toxicol Appl Pharmacol, 2007. 218(3): p. 280-8.

24. Couse, J.F., et al., Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology, 1997. 138(11): p. 4613-21.

25. Feng, Y., et al., Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci U S A, 2007. 104(37): p. 14718-23.

26. Northey, J.J., L. Przybyla, and V.M. Weaver, Tissue Force Programs Cell Fate and Tumor Aggression. Cancer Discov, 2017. 7(11): p. 1224-1237.

27. Vandenberg, L.N., et al., A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals. Environ Health, 2016. 15(1): p. 016-0156.

28. Rochester, J.R., A.L. Bolden, and C.F. Kwiatkowski, Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis. Environ Int, 2018. 114: p. 343-356.

29. Lewis, S.J., et al., Developing the WCRF International/University of Bristol Methodology for Identifying and Carrying Out Systematic Reviews of Mechanisms of Exposure-Cancer Associations. Cancer Epidemiol Biomarkers Prev, 2017. 26(11): p. 1667-1675.

30. Ertaylan, G., et al., A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure-Cancer Associations. Cancer Epidemiol Biomarkers Prev, 2017. 26(11): p. 1583-1594.

31. Kushman, M.E., et al., A systematic approach for identifying and presenting mechanistic evidence in human health assessments. Regul Toxicol Pharmacol, 2013. 67(2): p. 266-77.

32. Higgins, J.P.T.a.G.S., Cochrane Handbook for Systematic Reviews of Interventions. Vol. Version 5.1.0 [updated March 2011]. 2011: The Cochrane Collaboration, 2011.

33. OECD, Test No. 455: Performance-Based Test Guideline for Stably Transfected Transactivation In Vitro Assays to Detect Estrogen Receptor Agonists and Antagonists. 2016.

34. EPA, Endocrine Disruptor Screening Program Tier 1 Assays: Considerations for Use in Human Health and Ecological Risk Assessments, O.o.C.S.a.P.a.P.O.a.O.o.P.P. (OPP), Editor. 2013, Environmental Protection Agency: Washington, DC 20460.