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Aop: 295

AOP Title

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

Short name:

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

Graphical Representation

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Click to download graphical representation template

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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

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Andrea Hindman   (email point of contact)

Contributors

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  • Andrea Hindman

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite


This AOP was last modified on May 09, 2019 11:31

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Revision dates for related pages

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Abstract

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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)

 


Background (optional)

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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.


Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Relationships Between Two Key Events
(Including MIEs and AOs)

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Network View

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Stressors

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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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.

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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.

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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.

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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.