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Relationship: 396


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

reduction in ovarian granulosa cells, Aromatase (Cyp19a1) leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female adjacent Moderate Elise Grignard (send email) Open for citation & comment EAGMST Under Review

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Aromatase is the cytochrome P450 enzyme complex responsible for the conversion of androgens to estrogens during steroidogenesis [reviewed by (Simpson et al., 1994)], which is a key reaction in the sex differentiation in vertebrates. Reduction in level of aromatase or in the catalytic activity of the aromatase itself will reduce the levels of estrogens in tissues and dramatically disrupt estrogen (E2) hormone action.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Aromatase in the specialized cells of the ovary, hypothalamus, and placenta clearly serves crucial role in reproduction for mammalian and other vertebrates by converting the androgens to estrogens. Therefore, the coordinated and cell-specific expression of the aromatase (Cyp19a1) gene in the ovary plays a key role in the 17beta-estradiol (E2) synthesis. Within the ovary, aromatase expression and activity is primarily localized in the granulosa cells (reviewed in (Havelock, Rainey, & Carr, 2004). C-19 androgens diffuse from the theca cells into granulosa cells where aromatase can catalyze their conversion to C-18 estrogens. Therefore, inhibition, decrease of level or activity of ovarian aromatase can generally be assumed to directly impact E2 synthesis by the granulosa cells.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Upstream events An upstream event has been postulated to involve PPARγ activation, however the studies confirming its role in the reduction of aromatase levels are incomplete. The mechanisms involving Peroxisome Proliferator Activated receptor γ activation leading to aromatase (Cyp19a1) reduction relating to the pathway are described in greater detail in the page Peroxisome Proliferator Activated receptor γ activation indirectly leads to aromatase (Cyp19a1) reduction .

Availability or reduced aromatase levels

Studies by Davis et al showed that MEHP impacts on availability (degradation) of aromatase as the decrease in E2 production is evident after the treatment with transcription and translation blockers (actinomycin D or cycloheximide). MEHP was further decreased E2 production independently of the presence of inhibitors pointing out at mechanisms of degradation rather than aromatase synthesis (Davis et al., 1994). MEHP can indirectly impact on aromatase rates by decreasing necessary cofactors (availability) or activation of aromatase inhibitors. Treinin et al showed in vitro dose dependent inhibition of progesterone production by MEHP in granulosa cells and reduced FSH-stimulated cAMP accumulation in granulosa cells implicating a direct or indirect effect of MEHP on FSH receptor (Treinen, Dodson, & Heindel, 1990). Similar effects of cAMP accumulation were seen in Sertoli cells (Lloyd & Foster, 1988), (Heindel & Chapin, 1989), (Heindel & Powell, 1992). Since granulosa and Sertoli cells share several structural and functional characteristics this mechanism is plausible. Study by Ma et al showed that inhaled DEHP (5 and 25 mg/m3) increased levels of LH and E2 in serum of prepubertal rats, and it increased ovarian Cyp19a1 expression (Ma et al., 2006), which is in disagreement with the key event relationship. This difference might be due to measurements of hormones during different phases of the estrous cycle, alterations in the experimental approaches used (in vivo versus in vitro) as well as exposure routes and doses given.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

See table 1.


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

Davis, B. J., Weaver, R., Gaines, L. J., & Heindel, J. J. (1994). Mono-(2-ethylhexyl) phthalate suppresses estradiol production independent of FSH-cAMP stimulation in rat granulosa cells. Toxicology and Applied Pharmacology, 128(2), 224–8. doi:10.1006/taap.1994.1201

Gupta, R. K., Singh, J. M., Leslie, T. C., Meachum, S., Flaws, J. a, & Yao, H. H.-C. (2010). Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro. Toxicology and Applied Pharmacology, 242(2), 224–30. doi:10.1016/j.taap.2009.10.011

Havelock, J. C., Rainey, W. E., & Carr, B. R. (2004). Ovarian granulosa cell lines. Molecular and Cellular Endocrinology, 228(1-2), 67–78. doi:10.1016/j.mce.2004.04.018

Heindel, J. J., & Chapin, R. E. (1989). Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat Sertoli cell cultures. Toxicology and Applied Pharmacology, 97(2), 377–85.

Heindel, J. J., & Powell, C. J. (1992). Phthalate ester effects on rat Sertoli cell function in vitro: effects of phthalate side chain and age of animal. Toxicology and Applied Pharmacology, 115(1), 116–23.

Kwintkiewicz, J., Nishi, Y., Yanase, T., & Giudice, L. C. (2010). Peroxisome proliferator-activated receptor-gamma mediates bisphenol A inhibition of FSH-stimulated IGF-1, aromatase, and estradiol in human granulosa cells. Environmental Health Perspectives, 118(3), 400–6. doi:10.1289/ehp.0901161

Lloyd, S. C., & Foster, P. M. (1988). Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells. Toxicology and Applied Pharmacology, 95(3), 484–9.

Lovekamp, T. N., & Davis, B. J. (2001). Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicology and Applied Pharmacology, 172(3), 217–24. doi:10.1006/taap.2001.9156

Ma, M., Kondo, T., Ban, S., Umemura, T., Kurahashi, N., Takeda, M., & Kishi, R. (2006). Exposure of prepubertal female rats to inhaled di(2-ethylhexyl)phthalate affects the onset of puberty and postpubertal reproductive functions. Toxicological Sciences : An Official Journal of the Society of Toxicology, 93(1), 164–71. doi:10.1093/toxsci/kfl036

Reinsberg, J., Wegener-Toper, P., van der Ven, K., van der Ven, H., & Klingmueller, D. (2009). Effect of mono-(2-ethylhexyl) phthalate on steroid production of human granulosa cells. Toxicology and Applied Pharmacology, 239(1), 116–23. doi:10.1016/j.taap.2009.05.022

Simpson, E. R., Mahendroo, M. S., Means, G. D., Kilgore, M. W., Hinshelwood, M. M., Graham-Lorence, S., … Michael, M. D. (1994). Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine Reviews, 15(3), 342–55. doi:10.1210/edrv-15-3-342

Treinen, K. A., Dodson, W. C., & Heindel, J. J. (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), 334–40.

Xu, C., Chen, J.-A., Qiu, Z., Zhao, Q., Luo, J., Yang, L., … Shu, W. (2010). Ovotoxicity and PPAR-mediated aromatase downregulation in female Sprague-Dawley rats following combined oral exposure to benzo[a]pyrene and di-(2-ethylhexyl) phthalate. Toxicology Letters, 199(3), 323–32. doi:10.1016/j.toxlet.2010.09.015