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Relationship: 392

Title

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, Plasma 17beta-estradiol concentrations leads to irregularities, ovarian cycle

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Reduction, Plasma 17beta-estradiol concentrations

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

irregularities, ovarian cycle

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	High		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

The development and the function of the female reproductive tract depends upon hormone concentrations and balance. Changes in this fine-tuned hormonal machinery may result in reproductive system dysfunction (e.g. menstrual cycle irregularities, impaired fertility, endometriosis, polycystic ovarian syndrome). Ovarian estrogen is the major component of negative and positive feedback for pituitary release of gonadotrophic hormones; therefore abnormal alterations in the estradiol levels result in irregularities of the ovarian cycle.

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

Estrogens are crucial for female and male fertility, as proved by the severe reproductive defects observed when their synthesis (Simpson, 2004), (Schomberg et al., 1999) are blocked. As a secreted hormone, estradiol modulates the structure and function of female reproductive tissues, such as the uterus and oviduct. Estradiol is also one of the principal determinants of pituitary neuron functioning and is critical in enabling these cells to exhibit fluctuating patterns of biosynthetic and secretory activity and to generate the preovulatory surge of luteinising hormone (LH) (Hillier, 1985). Estradiol also contributes to cyclical variations in sexual female behaviour. Suppression of estradiol levels results in increased serum follicle stimulating hormone (FSH) levels and an absence of LH surges necessary for ovulation (Everett, 1961), (Davis, Maronpot, & Heindel, 1994) and changes the length of the cycle (Eldridge et al., 1994).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

A disruption of cycling caused by xenobiotic treatment can induce changes of length of the phases or cause an irregular pattern with cycles of extended duration and/or impact on ovulation. Measurements of serum estradiol reflect primarily the activity of the ovaries. As such, they are useful in the detection of baseline estrogen in irregularities of ovarian cycle. Suppressed levels of estradiol were found to impact on ovulation (Davis et al., 1994) and cycle duration (Hirosawa, Yano, Suzuki, & Sakamoto, 2006), (Eldridge et al., 1994), (Davis et al., 1994). Table 1 summarises common classes of chemicals shown to cause cycle irregularities through modulation of the hormonal balance.

Compound class	species	KE: Reduced E2	KE: Ovarian cycle irregularities	Reference
Phthalates (DEHP)	rat	Reduced serum E2	prolonged the estrous cycle, anovulation (3000 mg/kg/day)	(Davis et al., 1994)
Phthalates (DEHP)	rat	Reduced serum E2; FSH, pitutiary FSH, LH	irregular estrous cycles, prolongation of the cycle	(Takai et al., 2009)
Phthalates (DEHP)	rat	decreased E2 levels in estrus increased levels in diestrus	alters the estrous cycle	(Laskey & Berman, 1993)
Phthalates (DEHP)	rat	Reduced serum E2; FSH, pituitary FSH and LH	continuous diestrus stage	(Hirosawa et al., 2006)
Chlorotriazines (trazine)	rat	reduced plasma E2 by 63% and 88% at does 100 or 300 mg/kg ,respectively)	cycle lengthening, and increase in days spent in estrus and decrease in proestrus (100 or 300 mg/kg)	(Eldridge et al., 1994)
Phenols (4-tert-octylphenol)	rat	Progesterone elevated	Decreased number of cycles, diestrus was extended	(Laws, 2000)
Phthalates (DEHP)	sheep	Progesterone elevated	Increased mean cycle length, Short cycles (dose-dependent)	(Herreros et al., 2013)
Phthalates (DEHP)	rat		Deficit in growing follicles and corpora lutea	(Schilling, K., Deckardt. K., Gembardt, Chr., and Hildebrand, 1999)
dioxins	rat		Prolonged diestrus	(Li, Johnson, & Rozman, 1995);

Table 1 Summary of the empirical evidence supporting KER. Estradiol (E2), luteinising hormone (LH) and follicle stimulating hormone (FSH).

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

The impact on the ovarian cycle may result from defect in hypothalamic-pituitary-gonadal (HPG) axis signalling, other than by alteration of estradiol level. Table 1 shows some chemicals which impact on other hormones and cause irregularities of ovarian cycle.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

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.

References

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

Davis, B J, R R Maronpot, and J J Heindel. 1994. “Di-(2-Ethylhexyl) Phthalate Suppresses Estradiol and Ovulation in Cycling Rats.” Toxicology and Applied Pharmacology 128 (2) (October): 216–23. doi:10.1006/taap.1994.1200.

Eldridge, J C, D G Fleenor-Heyser, P C Extrom, L T Wetzel, C B Breckenridge, J H Gillis, L G Luempert, and J T Stevens. 1994. “Short-Term Effects of Chlorotriazines on Estrus in Female Sprague-Dawley and Fischer 344 Rats.” Journal of Toxicology and Environmental Health 43 (2) (October): 155–67. doi:10.1080/15287399409531912.

Everett, J. W. 1961. “The Mammalian Female Reproductive Cycle and Its Controlling Mechanisms.” Sex and Internal Secretions I. Herreros, Maria a, Antonio Gonzalez-Bulnes, Silvia Iñigo-Nuñez, Ignacio Contreras-Solis, Jose M Ros, and Teresa Encinas. 2013. “Toxicokinetics of di(2-Ethylhexyl) Phthalate (DEHP) and Its Effects on Luteal Function in Sheep.” Reproductive Biology 13 (1) (March): 66–74. doi:10.1016/j.repbio.2013.01.177.

Hillier, S G. 1985. “Sex Steroid Metabolism and Follicular Development in the Ovary.” Oxford Reviews of Reproductive Biology 7 (January): 168–222.

Hirosawa, Narumi, Kazuyuki Yano, Yuko Suzuki, and Yasushi Sakamoto. 2006. “Endocrine Disrupting Effect of Di-(2-Ethylhexyl)phthalate on Female Rats and Proteome Analyses of Their Pituitaries.” Proteomics 6 (3) (February): 958–71. doi:10.1002/pmic.200401344.

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. Laws, S. C. 2000. “Estrogenic Activity of Octylphenol, Nonylphenol, Bisphenol A and Methoxychlor in Rats.” Toxicological Sciences 54 (1) (March 1): 154–167. doi:10.1093/toxsci/54.1.154.

Li, X, D C Johnson, and K K Rozman. 1995. “Effects of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) on Estrous Cyclicity and Ovulation in Female Sprague-Dawley Rats.” Toxicology Letters 78 (3) (August): 219–22.

Schilling, K., Deckardt. K., Gembardt, Chr., and Hildebrand, B. 1999. “Di-2-Ethylhexyl Phthalate – Two-Generation Reproduction Toxicity Range-Finding Study in Wistar Rats. Continuos Dietary Administration.”

Schomberg, D W, J F Couse, A Mukherjee, D B Lubahn, M Sar, K E Mayo, and K S Korach. 1999. “Targeted Disruption of the Estrogen Receptor-Alpha Gene in Female Mice: Characterization of Ovarian Responses and Phenotype in the Adult.” Endocrinology 140 (6) (June): 2733–44. doi:10.1210/endo.140.6.6823.

Simpson, Evan R. 2004. “Models of Aromatase Insufficiency.” Seminars in Reproductive Medicine 22 (1) (February): 25–30. doi:10.1055/s-2004-823024.

Takai, Ryo, Shuji Hayashi, Junpei Kiyokawa, Yoshika Iwata, Saori Matsuo, Masami Suzuki, Keiji Mizoguchi, Shuichi Chiba, and Toshiaki Deki. 2009. “Collaborative Work on Evaluation of Ovarian Toxicity. 10) Two- or Four-Week Repeated Dose Studies and Fertility Study of Di-(2-Ethylhexyl) Phthalate (DEHP) in Female Rats.” The Journal of Toxicological Sciences 34 Suppl 1 (I) (January): SP111–9.