This AOP is licensed under the BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

AOP: 7


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

Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Aromatase (Cyp19a1) reduction leading to reproductive toxicity
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 v1.0

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool


The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Malgorzata Nepelska, Elise Grignard, Sharon Munn,

Systems Toxicology Unit, Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Via E. Fermi 2749, I-21027 Ispra, Varese, Italy

Corresponding author:;

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
Allie Always   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Elise Grignard
  • Allie Always


This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

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

Revision dates for related pages

Page Revision Date/Time
Reduction, Plasma 17beta-estradiol concentrations September 26, 2017 11:30
Reduction, 17beta-estradiol synthesis by ovarian granulosa cells September 16, 2017 10:14
impaired, Fertility September 14, 2023 12:10
irregularities, ovarian cycle November 29, 2016 19:09
reduction in ovarian granulosa cells, Aromatase (Cyp19a1) May 28, 2021 07:49
Reduction, Plasma 17beta-estradiol concentrations leads to irregularities, ovarian cycle December 03, 2016 16:37
Reduction, 17beta-estradiol synthesis by ovarian granulosa cells leads to Reduction, Plasma 17beta-estradiol concentrations March 20, 2017 12:05
irregularities, ovarian cycle leads to impaired, Fertility December 03, 2016 16:37
reduction in ovarian granulosa cells, Aromatase (Cyp19a1) leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells November 29, 2016 20:10


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 AOP links activation of the Peroxisome Proliferator Activated Receptorγ (PPARγ) to reproductive toxicity in adult female. The development of this AOP relies on evidence collected from rodent models and incorporates human mechanistic and epidemiological data. The PPARγ is a ligand-activated transcription factor that belongs to the nuclear receptor family, which also includes the steroid and thyroid hormone receptors. Interest in PPARγ action as a mechanistic basis for effects on the reproductive system arises from the demonstrated relationships between activation of this receptor and impairment of the steroidogenesis leading to reproductive toxicity in rodents. PPARs play important roles in the metabolic regulation of lipids, of which cholesterol, in particular being a precursor of steroid hormones, makes the link between lipid metabolism to effects on reproduction. The key events in the pathway comprise the activation of PPARγ, followed by the disruption of the hormonal balance which leads to irregularities of the ovarian cycle that may further be cause of impaired fertility. The PPARγ-initiated AOP to rodent female reproductive toxicity is a first step for structuring current knowledge about a mode of action which is neither ER-mediated nor via direct aromatase inhibition. In the current form the pathway lays a strong basis for linking an endocrine mode of action with an apical endpoint, prerequisite requirement for the identification of endocrine disrupting chemicals. This AOP is complemented with a structured data collection which will serve as the basis for further quantitative development of the pathway.

AOP Development Strategy


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


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

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help


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 408 reduction in ovarian granulosa cells, Aromatase (Cyp19a1) reduction in ovarian granulosa cells, Aromatase (Cyp19a1)
KE 219 Reduction, Plasma 17beta-estradiol concentrations Reduction, Plasma 17beta-estradiol concentrations
KE 3 Reduction, 17beta-estradiol synthesis by ovarian granulosa cells Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
AO 406 impaired, Fertility impaired, Fertility
AO 405 irregularities, ovarian cycle irregularities, ovarian cycle

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
Life stage Evidence
Adult, reproductively mature High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
rat Rattus norvegicus High NCBI
mouse Mus musculus Low NCBI
human Homo sapiens Low NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Female High

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

Biological plausibility, coherence, and consistency of the experimental evidence

In the presented AOP it is hypothesized that the key events occur in a biologically plausible order prior to the development of adverse outcomes. However, the experimental support is derived from a limited number of studies. The PPARγ activators have been shown to alter steroidogenesis, ovarian cycle and impair reproduction [see reviews (Kay, Chambers, and Foster 2013), (Froment et al. 2006), (Peraza et al. 2006), (Latini et al. 2008), (Martino-Andrade and Chahoud 2010), (Lyche et al. 2009), (Lovekamp-Swan and Davis 2003)]. The biochemistry of steroidogenesis and the predominant role of the ovaries in synthesis of the sex steroids are well established. During the reproductive years the ovary is the central organ providing hormones necessary for the communication between the reproductive tract and the central nervous system, assuring normal reproductive function. Hormonal imbalance may lead to irregularities of the ovarian cycle that could be one of many possible events resulting in decrease fertility.

Concordance of dose-response relationships

This is a qualitative description of the pathway; the currently available studies provide little quantitative information on dose-response relationships between key events (KEs). The experimental data for selected compounds (phthalates, phenols and parabens) reveals concordance between one KE to the next in the sequence, i.e. that each KE occur at first and on lower dose than the following KE. To establish more reliable and quantitative linkages tailored experiments are required.

Temporal concordance among the key events and the adverse outcome

Most of the gathered evidence relies on the measurement of the effects at the same time point (detailed information captured in KER), thus studies providing evidence for complete temporal concordance are missing.

Strength, consistency, and specificity of association of adverse effect and initiating event

PPARγ-null mutation is embryonically lethal due to a defect in placental development ( PPARγ is necessary for angiogenesis)(Barak et al. 1999). Organ (ovary) targeted knock-out studies are needed to more precisely inform on the mechanistic involvement of the PPAR family in the proposed AOP.

The pathway's weak point lies in the linkages between the initial events in the pathway. However, there is evidence supporting both chemical dependent and independent involvement of PPARγ in the female reproductive function:

Chemical independent studies:

1. disruption of PPARγ in ovary using cre/loxP technology led to ovarian dysfunction and female subfertility (30% of animals infertile, reminders had delayed conception and reduced litter size) (Cui et al. 2002)

2. granulosa cell specific deletion of PPARγ in mice results in marked impairment of ovulation due to defective follicular rupture (Kim et al. 2008)

Chemical dependent studies:

3. Antagonist of PPARγ recovered the decrease of aromatase after treatment with MEHP (PPARγ agonist) (Lovekamp-Swan, Jetten, and Davis 2003)

Alternative mechanism(s) or MIE(s) described which may contribute/synergise the postulated AOP

Alternative mechanisms relating to the pathway are described in greater detail in the descriptions of KERs.

The contributing MIE in the pathway proposed is activation of PPARα supported by experimental evidence of dual activation of PPARα/γ by MEHP leading to decreased expression and activity of aromatase in granulosa cells (Lovekamp-Swan, Jetten, and Davis 2003) and inhibition of aromatase expression upon activation of PPARα by the ligand, fenofibrate, in the ovary of mouse (Toda et al. 2003).

The relation of PPARγ activation to other enzymes in steroidogenesis and reduced estradiol production PPARγ ligands were shown to modulate other enzymes involved in steroidogenesis

  • upstream of aromatase:

• Steroidogenic acute regulatory protein (StAR)

StAR was up regulated by PPARγ ligands (rosiglitazone and pioglitazone) in human granulosa cells in vitro (Seto-Young et al. 2007) and by MEHP in rat granulosa cells (Svechnikova, Svechnikova, and Söder 2011). StAR facilitates that rapid mobilization of cholesterol for initial catalysis to pregnenolone by the P450-side chain cleavage enzyme located within the mitochondria ( see review (Payne and Hales 2013)).

• 3β-hydroxysteroid dehydrogenase (3β-HSD)

Contradictory results were found on the effect of PPARγ ligands on 3β-HSD enzyme. Work on porcine granulosa cells has found that troglitazone competitively inhibits 3β-HSD enzyme activity (Gasic et al. 1998). Opposite results were obtained with another agonist of PPARγ (rosiglitazone) that stimulated 3βHSD protein expression and activity in porcine ovarian follicles (Rak-Mardyła and Karpeta 2014). 3β-HSD catalyses the conversion of pregnenolone to progesterone see review (Payne and Hales 2013)

• 17-alpha-hydroxylase (P450c17, CYP 17) Conflicting reports have arisen regarding the effect of PPARγ agonists on the expression and activity of this enzyme, mRNA production was unchanged following porcine thecal cell exposure to PPARγ ligand (Schoppee 2002), whilst other reports indicate CYP17 expression inhibition by PPARγ (rosiglitazone) agonist in ovarian follicles (Rak-Mardyła and Karpeta 2014). P450c17converts progesterone to androgen see review (Payne and Hales 2013)

  • downstream of aromatase:

Reduced production of estradiol may result from alteration of the enzymes upstream of aromatase (described above) or by increasing estradiol catabolism (altering Cyp1b1 and 17-βHSD IV, which are involved in estradiol conversion to catechol estrogens and estrone respectively).

• 17β-Hydroxysteroid dehydrogenase (17β-HSD)

Agonist of PPARγ (rosiglitazone) was found to inhibit 17β-HSD protein expression in ovarian follicles (Rak-Mardyła and Karpeta 2014), whereas increase in enzyme expression was noted upon treatment of granulosa cells by phthalate (MEHP) (Lovekamp-Swan, Jetten, and Davis 2003). 17β-Hydroxysteroid dehydrogenase (17β-HSD) metabolises estradiol to estrone see review (Payne and Hales 2013). For example, in vitro studies with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) investigating steroid production in human luteinizing granulosa cells (hLGC) showed estradiol decreased without changing either aromatase protein or its enzyme activity (Morán et al. 2000). Studies by the same laboratory identified P450c17 as a molecular target for endocrine disruption of hLGC specifically decreasing the supply of androgens for E2 synthesis (Morán et al. 2003). Reduced levels of estradiol production may result from increased inactivation of E2 via conversion to estrone as shown in isolated mouse small preantral follicles upon phthalate (MEHP) treatment (Lenie and Smitz 2009) and granulosa cells (Lovekamp-Swan, Jetten, and Davis 2003). Taken together, these findings provide strong evidence for the direct effect of PPARγ agonists on ovarian synthesis and secretion of hormones.

Reduced levels of estradiol and irregularities of ovarian cycle

The impact on ovarian cycle may result from a defect in hypothalamic-pituitary-gonadal (HPG) axis signalling, other than by alteration of estradiol level. MEHP inhibited follicle-simulating hormone (FSH) mediated stimulation of adenylate cyclase and progesterone synthesis in primary cultures of rat granulosa cells (Treinen, Dodson, and Heindel 1990).

Uncertainties, inconsistencies and data gaps

The current major uncertainty in this AOP is the basis of the functional relationship between the PPARγ, activation leading to Aromatase (Cyp19a1), reduction in ovarian granulosa cells. The possible mechanisms have been proposed and investigated, however there is lack of dose response and temporal data supporting the relationship (Lovekamp-Swan, Jetten, and Davis 2003), (Fan et al. 2005), (Mu et al. 2001). The pattern of the PPARγ expression in ovarian follicles is not steady, unlike expression of PPARα and δ. This fact adds to the complexity to the interpretation of mechanisms involved in the pathway. The PPARγ is down-regulated in response to the LH surge (C M Komar et al. 2001), but only in follicles that have responded to the LH surge (Carolyn M Komar and Curry 2003). Because PPARγ is primarily expressed in granulosa cells, it may influence development of these cells and their ability to support normal oocyte maturation. PPARγ could also potentially affect somatic cell/oocyte communication not only by impacting granulosa cell development, but by direct effects on the oocyte. Modulation of the PPARγ activity/expression in the ovary therefore, could potentially affect oocyte developmental competence. There is high strength, as well as specificity starting from the association between the reductions of E2 production leading to fertility impairment in females. Consistency of key events in the AOP is supported by several lines of evidence deriving from in vitro and in vivo studies that support PPARγ activation as an important actor in reproductive toxicity in rodents [(Kay, Chambers, and Foster 2013), (Froment et al. 2006), (Peraza et al. 2006), (Latini et al. 2008), (Martino-Andrade and Chahoud 2010), (Lyche et al. 2009), (Lovekamp-Swan and Davis 2003)].


Agonists of PPARγ were found to impact on steroidogenesis; however contradictory data show their effect on different stages of the process as well the direction of the effect(see above). Some in vivo studies also reported two-way effect on the estradiol production by PPARγ agonists. This effect may be attributed to the different measurements during different stages of estrous cycle. The phase of the estrous cycle, in which hormones are measured, may influence the readout of compound effect. In rats treated with DEHP increase in estradiol production was observed in ovarian cells (ex vivo) extracted during diestrus phase, however there was decrease in estradiol when the cells were extracted during estrus stage (Laskey and Berman 1993). In alignment with this result increased levels of estradiol were found in sheep proceeding the estrus phase (Herreros et al. 2013).

Data Gaps: There is a limited number of studies investigating the effect of PPARγ and its role in female reproductive function, in order to establish a more quantitative and temporal coherent linkage of the MIE to the subsequent key events studies are required. For example: the plausible mechanism of activation of a PPARγ, RXR and involvement of NFkappaB and their role in transcriptional repression of the aromatase gene could be investigated in modified transactivation assays to measure NFkappaB repression, rather than transactivation. Similar assays have been already generated, for estrogen receptor-mediated transrepression (Quaedackers et al. 2001).

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

This AOP is relevant for mature females for details see reviews [(Kay, Chambers, and Foster 2013), (Froment et al. 2006), (Peraza et al. 2006), (Latini et al. 2008), (Martino-Andrade and Chahoud 2010), (Lyche et al. 2009), (Lovekamp-Swan and Davis 2003)].

The experimental support for the pathway is based on rodent models and other mammals (pig, sheep) including human mechanistic and epidemiological data. The experimental animal data are assumed relevant for consideration of human risk.

This AOP applies to females only for details see reviews [(Kay, Chambers, and Foster 2013), (Froment et al. 2006), (Peraza et al. 2006), (Latini et al. 2008), (Martino-Andrade and Chahoud 2010), (Lyche et al. 2009), (Lovekamp-Swan and Davis 2003)].

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 - KEs

level of confidence


PPAR gamma, Activation

PPARγ activation was found to indirectly alter the expression of aromatase


Aromatase (Cyp19a1), reduction in ovarian granulosa cells

Aromatase is the cytochrome P450 enzyme complex responsible for the conversion of androgens to estrogens during steroidogenesis which is a key reaction in the sex differentiation in vertebrates. Alterations in the amount of aromatase present or in the catalytic activity of the enzyme will alter the levels of estrogens in tissues and dramatically disrupt estrogen hormone action.


17beta-estradiol synthesis by ovarian granulosa cells

While both brain and adrenal tissue are capable of synthesizing estradiol, the gonads are generally considered the major source of circulating estrogens in vertebrates, including fish (Norris 2007). Consequently, if estradiol synthesis by ovarian granulosa cells is reduced, plasma E2 concentrations would be expected to decrease unless there are concurrent reductions in the rate of E2 catabolism.


Plasma 17beta-estradiol concentrations, Reduction

Estrogens are crucial for female fertility, as proved by the severe reproductive defects observed when their synthesis is blocked.


ovarian cycle irregularities

A sequential progression of interrelated physiological and behavioural cycles underlines the female reproductive function.


Fertility, impaired

Impaired Fertility is the endpoint of reproductive toxicity


Evidence Assessment

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


Biological plausibility

level of confidence

Empirical Support

level of confidence







PPARγ, Activation =>

Aromatase (Cyp19a1), reduction in ovarian granulosa cells

There is functional relationship between PPARγ activation and reduction in aromatase levels. Several mechanisms have been investigated; however there is no established consensus.


  • KEup occurs at lower dose than KEdown(dose response concordance)
  • occurrence of the key events at similar dose and time point
  • Support for solid temporal relationship is lacking


Limited data, for details see KER pages

Aromatase (Cyp19a1), reduction in ovarian granulosa cells =>

17beta-estradiol synthesis by ovarian granulosa cells

Within the ovary, aromatase expression and activity is primarily localized in the granulosa cells. Therefore, changes in ovarian aromatase can generally be assumed to directly impact E2 synthesis by the granulosa cells.


  • KEup occurs at lower dose than KEdown(dose response concordance)
  • occurrence of the key events at similar dose and time point
  • Support for solid temporal relationship is lacking


Limited data

17beta-estradiol synthesis by ovarian granulosa cells, Reduction =>

Plasma 17beta-estradiol concentrations

The gonads are generally considered the major source of circulating estrogens, consequently, if estradiol synthesis by ovarian granulosa cells is reduced, plasma E2 concentrations would be expected to decrease.


  • KEs occur at similar dose levels
  • occurrence of the key events at similar dose Support for solid temporal relationship is lacking


Limited data

Plasma 17beta-estradiol concentrations, Reduction =>

ovarian cycle irregularities

Alterations in relationships among the hypothalamic, pituitary, and ovarian components of the reproductive axis can have marked effects on cyclicity. A toxicological insult to any one of these sites can disrupt the cycle and block ovulation.


  • KEs occur at similar dose levels
  • occurrence of the key events at similar dose and time point
  • Support for solid temporal relationship is lacking



ovarian cycle irregularities =>

Fertility, impaired

A sequential progression of interrelated physiological and behavioural cycles underlines the female's fertility and successful production of offspring.


  • KEs occur at similar dose levels
  • occurrence of the key events at similar dose and with temporal relationship
  • Support for solid temporal relationship is lacking.



Table 1 Weight of Evidence Summary. The underlying questions for the content of table: Dose-response: Does the empirical evidence support that a change in KEup leads to an appropriate change in KEdown?; Temporality: Does KEup occur at lower doses and earlier time points than KE down and is the incidence of KEup > than that for KEdown?; Incidence: Is there higher incidence of KEup than of KEdown?; Inconsistencies/Uncertainties: Are there inconsistencies in empirical support across taxa, species and stressors that don’t align with expected pattern for hypothesized 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

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

1. The AOP describes a pathway which allows for the detection of sex steroid-related endocrine disrupting modes of action, with focus on the identification of substances which affect the reproductive system. In the current form the pathway lays a strong basis for linking endocrine mode of action with an apical endpoint, a prerequisite requirement for identification of endocrine disrupting chemicals (EDC). EDCs require specific evaluation under REACH (1907/2006, Registration, Evaluation, Authorisation and Restriction of Chemicals (EU, 2006)), the revised European plant protection product regulation 1107/2009 (EU, 2009) and use of biocidal products 528/2012 EC (EU, 2012).Amongst other agencies the US EPA is also giving particular attention to EDCs (EPA, 1998).

2. This AOP structurally represents current knowledge of the pathway from PPARγ activation to impaired fertility that may provide a basis for development (and interpretation) of strategies for Integrated Approaches to Testing Assessment (IATA) to identify similar substances that may operate via the same pathway related to sex steroids disruption and effects on reproductive tract and fertility. This AOP forms the starting point on an AOP network mapping modes of action for endocrine disruption.

3. The AOP could inform the development of quantitative structure activity relationships, read-across models, and/or systems biology models to prioritize chemicals for further testing.


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

Cui, Yongzhi, Keiko Miyoshi, Estefania Claudio, Ulrich K Siebenlist, Frank J Gonzalez, Jodi Flaws, Kay-Uwe Wagner, and Lothar Hennighausen. 2002. “Loss of the Peroxisome Proliferation-Activated Receptor Gamma (PPARgamma ) Does Not Affect Mammary Development and Propensity for Tumor Formation but Leads to Reduced Fertility.” The Journal of Biological Chemistry 277 (20) (May 17): 17830–5. doi:10.1074/jbc.M200186200.

Fan, WuQiang, Toshihiko Yanase, Hidetaka Morinaga, Yi-Ming Mu, Masatoshi Nomura, Taijiro Okabe, Kiminobu Goto, Nobuhiro Harada, and Hajime Nawata. 2005. “Activation of Peroxisome Proliferator-Activated Receptor-Gamma and Retinoid X Receptor Inhibits Aromatase Transcription via Nuclear Factor-kappaB.” Endocrinology 146 (1) (January): 85–92. doi:10.1210/en.2004-1046.

Froment, P, F Gizard, D Defever, B Staels, J Dupont, and P Monget. 2006. “Peroxisome Proliferator-Activated Receptors in Reproductive Tissues: From Gametogenesis to Parturition.” The Journal of Endocrinology 189 (2) (May): 199–209. doi:10.1677/joe.1.06667.

Gasic, S, Y Bodenburg, M Nagamani, A Green, and R J Urban. 1998. “Troglitazone Inhibits Progesterone Production in Porcine Granulosa Cells.” Endocrinology 139 (12) (December): 4962–6. doi:10.1210/endo.139.12.6385.

Herreros, Maria A, Teresa Encinas, Laura Torres-Rovira, Rosa A Garcia-Fernandez, Juana M Flores, Jose M Ros, and Antonio Gonzalez-Bulnes. 2013. “Exposure to the Endocrine Disruptor di(2-Ethylhexyl)phthalate Affects Female Reproductive Features by Altering Pulsatile LH Secretion.” Environmental Toxicology and Pharmacology 36 (3) (November): 1141–9. doi:10.1016/j.etap.2013.09.020.

Kay, Vanessa R, Christina Chambers, and Warren G Foster. 2013. “Reproductive and Developmental Effects of Phthalate Diesters in Females.” Critical Reviews in Toxicology 43 (3) (March): 200–19. doi:10.3109/10408444.2013.766149.

Kim, Jaeyeon, Marcey Sato, Quanxi Li, John P Lydon, Francesco J Demayo, Indrani C Bagchi, and Milan K Bagchi. 2008. “Peroxisome Proliferator-Activated Receptor Gamma Is a Target of Progesterone Regulation in the Preovulatory Follicles and Controls Ovulation in Mice.” Molecular and Cellular Biology 28 (5) (March): 1770–82. doi:10.1128/MCB.01556-07.

Komar, C M, O Braissant, W Wahli, and T E Curry. 2001. “Expression and Localization of PPARs in the Rat Ovary during Follicular Development and the Periovulatory Period.” Endocrinology 142 (11) (November): 4831–8. doi:10.1210/endo.142.11.8429.

Komar, Carolyn M, and Thomas E Curry. 2003. “Inverse Relationship between the Expression of Messenger Ribonucleic Acid for Peroxisome Proliferator-Activated Receptor Gamma and P450 Side Chain Cleavage in the Rat Ovary.” Biology of Reproduction 69 (2) (August): 549–55. doi:10.1095/biolreprod.102.012831.

Laskey, J.W., and E. Berman. 1993. “Steroidogenic Assessment Using Ovary Culture in Cycling Rats: Effects of Bis (2-Diethylhexyl) Phthalate on Ovarian Steroid Production.” Reproductive Toxicology 7 (1) (January): 25–33. doi:10.1016/0890-6238(93)90006-S.

Latini, Giuseppe, Egeria Scoditti, Alberto Verrotti, Claudio De Felice, and Marika Massaro. 2008. “Peroxisome Proliferator-Activated Receptors as Mediators of Phthalate-Induced Effects in the Male and Female Reproductive Tract: Epidemiological and Experimental Evidence.” PPAR Research 2008 (January): 359267. doi:10.1155/2008/359267.

Lenie, Sandy, and Johan Smitz. 2009. “Steroidogenesis-Disrupting Compounds Can Be Effectively Studied for Major Fertility-Related Endpoints Using in Vitro Cultured Mouse Follicles.” Toxicology Letters 185 (3) (March 28): 143–52. doi:10.1016/j.toxlet.2008.12.015.

Lovekamp-Swan, Tara, and Barbara J. Davis. 2003. “Mechanisms of Phthalate Ester Toxicity in the Female Reproductive System.” Environmental Health Perspectives 111 (2) (October 28): 139–145. doi:10.1289/ehp.5658.

Lovekamp-Swan, Tara, Anton M Jetten, and Barbara J Davis. 2003. “Dual Activation of PPARalpha and PPARgamma by Mono-(2-Ethylhexyl) Phthalate in Rat Ovarian Granulosa Cells.” Molecular and Cellular Endocrinology 201 (1-2) (March 28): 133–41.

Lyche, Jan L, Arno C Gutleb, Ake Bergman, Gunnar S Eriksen, AlberTinka J Murk, Erik Ropstad, Margaret Saunders, and Janneche U Skaare. 2009. “Reproductive and Developmental Toxicity of Phthalates.” Journal of Toxicology and Environmental Health. Part B, Critical Reviews 12 (4) (April): 225–49. doi:10.1080/10937400903094091.

Martino-Andrade, Anderson Joel, and Ibrahim Chahoud. 2010. “Reproductive Toxicity of Phthalate Esters.” Molecular Nutrition & Food Research 54 (1) (January): 148–57. doi:10.1002/mnfr.200800312.

Morán, F M, A J Conley, C J Corbin, E Enan, C VandeVoort, J W Overstreet, and B L Lasley. 2000. “2,3,7,8-Tetrachlorodibenzo-P-Dioxin Decreases Estradiol Production without Altering the Enzyme Activity of Cytochrome P450 Aromatase of Human Luteinized Granulosa Cells in Vitro.” Biology of Reproduction 62 (4) (April): 1102–8.

Morán, F M, C A VandeVoort, J W Overstreet, B L Lasley, and A J Conley. 2003. “Molecular Target of Endocrine Disruption in Human Luteinizing Granulosa Cells by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin: Inhibition of Estradiol Secretion due to Decreased 17alpha-hydroxylase/17,20-Lyase Cytochrome P450 Expression.” Endocrinology 144 (2) (March): 467–73. doi:10.1210/en.2002-220813.

Mu, Y M, T Yanase, Y Nishi, R Takayanagi, K Goto, and H Nawata. 2001. “Combined Treatment with Specific Ligands for PPARgamma:RXR Nuclear Receptor System Markedly Inhibits the Expression of Cytochrome P450arom in Human Granulosa Cancer Cells.” Molecular and Cellular Endocrinology 181 (1-2) (July 5): 239–48.

Payne, Anita H., and Dale B. Hales. 2013. “Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones.” Endocrine Reviews (July 1).

Peraza, Marjorie a, Andrew D Burdick, Holly E Marin, Frank J Gonzalez, and Jeffrey M Peters. 2006. “The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR).” Toxicological Sciences : An Official Journal of the Society of Toxicology 90 (2) (April): 269–95. doi:10.1093/toxsci/kfj062.

Quaedackers, M E, C E Van Den Brink, S Wissink, R H Schreurs, J A Gustafsson, P T Van Der Saag, and B B Van Der Burg. 2001. “4-Hydroxytamoxifen Trans-Represses Nuclear Factor-Kappa B Activity in Human Osteoblastic U2-OS Cells through Estrogen Receptor (ER)alpha, and Not through ER Beta.” Endocrinology 142 (3) (March): 1156–66. doi:10.1210/endo.142.3.8003.

Rak-Mardyła, Agnieszka, and Anna Karpeta. 2014. “Rosiglitazone Stimulates Peroxisome Proliferator-Activated Receptor Gamma Expression and Directly Affects in Vitro Steroidogenesis in Porcine Ovarian Follicles.” Theriogenology 82 (1) (July 1): 1–9. doi:10.1016/j.theriogenology.2014.02.016.

Schoppee, P. D. 2002. “Putative Activation of the Peroxisome Proliferator-Activated Receptor Impairs Androgen and Enhances Progesterone Biosynthesis in Primary Cultures of Porcine Theca Cells.” Biology of Reproduction 66 (1) (January 1): 190–198. doi:10.1095/biolreprod66.1.190.

Seto-Young, Donna, Dimiter Avtanski, Marina Strizhevsky, Grishma Parikh, Parini Patel, Julia Kaplun, Kevin Holcomb, Zev Rosenwaks, and Leonid Poretsky. 2007. “Interactions among Peroxisome Proliferator Activated Receptor-Gamma, Insulin Signaling Pathways, and Steroidogenic Acute Regulatory Protein in Human Ovarian Cells.” The Journal of Clinical Endocrinology and Metabolism 92 (6) (June): 2232–9. doi:10.1210/jc.2006-1935.

Svechnikova, Konstantin, Irina Svechnikova, and Olle Söder. 2011. “Gender-Specific Adverse Effects of Mono-Ethylhexyl Phthalate on Steroidogenesis in Immature Granulosa Cells and Rat Leydig Cell Progenitors in Vitro.” Frontiers in Endocrinology 2 (January): 9. doi:10.3389/fendo.2011.00009.

Toda, Katsumi, Teruhiko Okada, Chisata Miyaura, and Toshiji Saibara. 2003. “Fenofibrate, a Ligand for PPARalpha, Inhibits Aromatase Cytochrome P450 Expression in the Ovary of Mouse.” Journal of Lipid Research 44 (2) (February): 265–70. doi:10.1194/jlr.M200327-JLR200.

Treinen, K A, W C Dodson, and J J Heindel. 1990. “Inhibition of FSH-Stimulated cAMP Accumulation and Progesterone Production by mono(2-Ethylhexyl) Phthalate in Rat Granulosa Cell Cultures.” Toxicology and Applied Pharmacology 106 (2) (November): 334–40.