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Event: 405

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

irregularities, ovarian cycle

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
irregularities, ovarian cycle
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Individual

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
ovulation cycle disrupted

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Aromatase (Cyp19a1) reduction leading to reproductive toxicity AdverseOutcome Elise Grignard (send email) Open for citation & comment EAGMST Under Review
Inhibition of ALDH1A leading to reduced fertility, female KeyEvent Terje Svingen (send email) Under development: Not open for comment. Do not cite Under Development

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 KE.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 in relation to this KE. More help
Term Scientific Term Evidence Link
mice Mus sp. Low NCBI
rat Rattus norvegicus Moderate NCBI

Life Stages

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

Sex Applicability

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

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Biological state

The female ovarian cycle is the result of a balanced cooperation between several organs and is determined by a complex interaction of hormones. Ovarian cycle irregularities include disturbances in the ovarian cycle (e.g. longer cycle, persistent estrus) and/or ovulation problems (deferred ovulation or anovulation). The estrous cycle (also oestrous cycle) comprises the recurring physiologic changes that are induced by reproductive hormones in females. Estrous cycles start after sexual maturity in females and are interrupted by anestrous phases or pregnancies. During this cycle numerous well defined and sequential alterations in reproductive tract histology, physiology and cytology occur, initiated and regulated by the hypothalamic-pituitary-ovarian (HPO) axis. The central feature of the mammalian estrous cycle is the periodic maturation of eggs that will be released at ovulation and luteinisation of the follicles after ovulation to form corpora lutea. Adapted from www.oecd.org/chemicalsafety/testing/43754807.pdf Biological compartments

The cyclic changes that occur in the female reproductive tract are initiated and regulated by the hypothalamic-pituitary-ovarian (HPO) axis. Although folliculogenesis occurs independently of hormonal stimulation up until the formation of early tertiary follicles, the gonadotrophins luteinising hormone (LH) and follicle stimulating hormone (FSH) are essential for the completion of follicular maturation and development of mature preovulatory (Graafian) follicles. The oestrous cycle consists of four stages: prooestrus, oestrus, metoestrus (or dioestrus 1) and dioestrus (or dioestrus 2) orchestrated by hormones. Levels of LH and FSH begin to increase just after dioestrus. Both hormones are secreted by the same secretory cells (gonadotrophs) in the pars distalis of the anterior pituitary (adenohypophysis). FSH stimulates the development of the zona granulosa and triggers expression of LH receptors by granulosa cells. LH initiates the synthesis and secretion of androstenedione and, to a lesser extent, testosterone by the theca interna; these androgens are utilised by granulosa cells as substrates in the synthesis of estrogen. Pituitary release of gonadotrophins thus drives follicular maturation and secretion of estrogen during prooestrus. Gonadotrophin secretion by the anterior pituitary is regulated by luteinising hormone-releasing hormone (LHRH), produced by the hypothalamus. LHRH is transported along the axons of hypothalamic neurones to the median eminence where it is secreted into the hypothalamic-hypophyseal portal system and transported to the anterior pituitary. The hypothalamus secretes LHRH in rhythmic pulses; this pulsatility is essential for the normal activation of gonadotrophs and subsequent release of LH and FSH. Adapted from www.oecd.org/chemicalsafety/testing/43754807.pdf

Follicles that produce estrogens have sequestered pituitary FSH which in turn stimulates the aromatase reaction. Such follicles can undergo normal development and ovulation and contain eggs that readily resume meiosis when released. In the absence of an active local aromatase (i.e., no follicle-stimulating hormone), the follicles and oocytes become atretic and regress without ovulating. If aromatase is present, the estrogen and follicle stimulating hormone can further develop the follicular cells for normal luteal function after ovulation takes place (Ryan, 1982).

General role in biology

A sequential progression of interrelated physiological and behavioural cycles underlines the female's successful production of young. In many but not all species the first and most basic of these is estrous cycle, which is itself a combination of cycles.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

The pattern of events in the estrous cycle may provide a useful indicator of the normality of reproductive neuroendocrine and ovarian function in the nonpregnant female. It also provides a means to interpret hormonal, histologic, and morphologic measurements relative to stage of the cycle, and can be useful to monitor the status of mated females. Regular cyclicity is one of the key parameters in assessment of female reproductive function in rodents. Parameters assessed for cyclicity: - Number of cycling females - Number of females with regular cycles - Number of cycles - Estrous cycle length - Percentage of time spent in the various estrous cycle stages Estrous cyclicity provides a method for evaluating the endocrine disrupting activity of each test chemical under physiologic conditions where endogenous concentrations of estrogen vary. Abnormal cycles were defined as one or more estrous cycles in the 21-day period with prolonged estrus (≥3 days) and/or prolonged metestrus or diestrus (≥4 days) within a given cycle (Goldman, Murr, & Cooper, 2007).

Estrous cycle normality can be monitored in the rat and mouse by observing the changes in the vaginal smear cytology. Visual observation of the vagina is the quickest method, requires no special equipment, and is best used when only proestrus or estrus stages need to be identified. For details see: (Westwood, 2008), (Byers, Wiles, Dunn, & Taft, 2012) and OECD guidelines (www.oecd.org).

The observation that animals do not ovulate while exhibiting estrous cycles indicates that estrous cyclicity alone may not be a sufficient surrogate of healthy function of ovaries; the measurements of serum hormones and particularly FSH can contribute to more sensitivity indicators of healthy function of ovaries (Davis, Maronpot, & Heindel, 1994).

Monitoring of oestrus cyclicity is included in OECD test guidelines (Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents, 2008) [1], (Test No. 416: Two-Generation Reproduction Toxicity, 2001)[2] and (Test No. 443: Extended One-Generation Reproductive Toxicity Study, 2012) [3]and in USA EPA OCSPP 890.1450.

In vitro testing

The follicle culture models were developed for the in-vitro production of mature oocytes and used to study the process of folliculogenesis and oogenesis in vitro (Cortvrindt & Smitz, 2002). These in vitro cultures demonstrate near-identical effects to those found in vivo, therefore might be able to acquire a place in fertility testing, replacing some in-vivo studies for ovarian function and female gamete quality testing (Stefansdottir, Fowler, Powles-Glover, Anderson, & Spears, 2014).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

The estrous cycle comprises the recurring physiologic changes that are induced by reproductive hormones in most mammalian females. Many of the mechanisms involved in the regulation of the reproductive axis are similar across species (particularly those mediated through the estrogen receptor), assessments of rodent estrous cyclicity can offer insight into potential adverse effects in humans (Goldman, Murr, & Cooper, 2007). While evaluations of vaginal cytology in the laboratory rodent can provide a valuable reflection of the integrity of the hypothalamic-pituitary-ovarian axis, other indices are more useful in humans to determine the functional status of the reproductive system (e.g. menses, basal body temperature, alterations in vaginal pH, cervical mucous viscosity, and blood hormone levels). Nevertheless, since many of the mechanisms involved in the regulation of the reproductive axis are similar across species (particularly those mediated through the estrogen receptor), assessments of rodent estrous cyclicity can offer insight into potential adverse effects in humans (Rasier, Toppari, Parent, & Bourguignon, 2006).

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Chemicals may be found to interfere with reproductive function in the female rat. This interference is commonly expressed as a change in normal morphology of the reproductive tract or a disturbance in the duration of particular phases of the estrous cycle. This key event lies within the scope of testing for endocrine disrupting activity of chemicals and therefore for testing of female reproductive and developmental toxicity. Monitoring of oestrus cyclicity is included in OECD test guidelines (Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents, 2008), (Test No. 416: Two-Generation Reproduction Toxicity, 2001) and (Test No. 443: Extended One-Generation Reproductive Toxicity Study, 2012) and in USA EPA OCSPP 890.1450. While an evaluation of the estrous cycle in laboratory rodents can be a useful measure of the integrity of the hypothalamic-pituitary-ovarian reproductive axis, it can also serve as a way of insuring that animals exhibiting abnormal cycling patterns are excluded from a study prior to exposure to a test compound. When incorporated as an adjunct to other endpoint measures, a determination of a female's cycling status can contribute important information about the nature of a toxicant insult to the reproductive system. In doing so, it can help to integrate the data into a more comprehensive mechanistic portrait of the effect, and in terms of risk assessment, may provide some indication of a toxicant's impact on human reproductive physiology. Significant evidence that the estrous cycle (or menstrual cycle in primates) has been disrupted should be considered an adverse effect (OECD, 2008). Included should be evidence of abnormal cycle length or pattern, ovulation failure, or abnormal menstruation.

References

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

Byers, S. L., Wiles, M. V, Dunn, S. L., & Taft, R. A. (2012). Mouse estrous cycle identification tool and images. PloS One, 7(4), e35538. doi:10.1371/journal.pone.0035538

Cortvrindt, R. G., & Smitz, J. E. J. (2002). Follicle culture in reproductive toxicology: a tool for in-vitro testing of ovarian function? Human Reproduction Update, 8(3), 243–54.

Davis, B. J., Maronpot, R. R., & Heindel, J. J. (1994). Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats. Toxicology and Applied Pharmacology, 128(2), 216–23. doi:10.1006/taap.1994.1200

Goldman, J. M., Murr, A. S., & Cooper, R. L. (2007). The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Research. Part B, Developmental and Reproductive Toxicology, 80(2), 84–97. doi:10.1002/bdrb.20106

OECD. (2008). No 43: Guidance document on mammalian reproductive toxicity testing and assessment.

Rasier, G., Toppari, J., Parent, A.-S., & Bourguignon, J.-P. (2006). Female sexual maturation and reproduction after prepubertal exposure to estrogens and endocrine disrupting chemicals: a review of rodent and human data. Molecular and Cellular Endocrinology, 254-255, 187–201. doi:10.1016/j.mce.2006.04.002

Ryan, K. J. (1982). Biochemistry of aromatase: significance to female reproductive physiology. Cancer Research, 42(8 Suppl), 3342s–3344s.

Stefansdottir, A., Fowler, P. A., Powles-Glover, N., Anderson, R. A., & Spears, N. (2014). Use of ovary culture techniques in reproductive toxicology. Reproductive Toxicology (Elmsford, N.Y.), 49C, 117–135. doi:10.1016/j.reprotox.2014.08.001

Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents. (2008). OECD Publishing. doi:10.1787/9789264070684-en

Test No. 416: Two-Generation Reproduction Toxicity. (2001). OECD Publishing. doi:10.1787/9789264070868-en

Test No. 443: Extended One-Generation Reproductive Toxicity Study. (2012). OECD Publishing. doi:10.1787/9789264185371-en

Westwood, F. R. (2008). The female rat reproductive cycle: a practical histological guide to staging. Toxicologic Pathology, 36(3), 375–84. doi:10.1177/0192623308315665