Aop: 201

Title

Each AOP should be given a descriptive title that takes the form “MIE leading to AO”. For example, “Aromatase inhibition [MIE] leading to reproductive dysfunction [AO]” or “Thyroperoxidase inhibition [MIE] leading to decreased cognitive function [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

Juvenile hormone receptor agonism leading to male offspring induction associated population decline

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
JHR agonism leading to population decline

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

You Song1 and Knut Erik Tollefsen1,2

1 Norwegian Institute for Water Research (NIVA), Section of Ecotoxicology and Risk Assessment, Gaustadalléen 21, N-0349 Oslo, Norway

2 Norwegian University of Life Sciences (NMBU), Faculty of Environmental Science and Technology, Department of Environmental Sciences (IMV). P.O. Box 5003, N-1432 Ås, Norway

Contact: knut.erik.tollefsen@niva.no

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Knut Erik Tollefsen   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Knut Erik Tollefsen
  • You Song

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development
This AOP was last modified on November 29, 2016 18:55
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Activation, Juvenile hormone receptor September 16, 2017 10:17
Induction, Doublesex1 gene September 16, 2017 10:17
Increased, Male offspring December 03, 2016 16:37
Induction, Male reproductive tract September 16, 2017 10:17
Decline, Population December 03, 2016 16:33
Alteration, Food-web structures December 03, 2016 16:37
Activation, Juvenile hormone receptor leads to Induction, Doublesex1 gene December 03, 2016 16:38
Induction, Doublesex1 gene leads to Induction, Male reproductive tract December 03, 2016 16:38
Induction, Male reproductive tract leads to Increased, Male offspring December 03, 2016 16:38
Increased, Male offspring leads to Decline, Population December 03, 2016 16:38
Decline, Population leads to Alteration, Food-web structures December 03, 2016 16:38
fenoxycarb November 29, 2016 18:42
DIOFENOLAN November 29, 2016 18:42
pyriproxyfen November 29, 2016 18:42
(7S)-Hydroprene November 29, 2016 18:42
kinoprene November 29, 2016 18:42

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Endocrine disruption (ED) associated with environmental sex determination (ESD) and reproduction effects has been frequently reported in various ecotoxicologcail studies with crustaceans, such as daphniids (reviewed in (LeBlanc and Medlock, 2015)). Daphniids normally go through parthenogenic reproduction cycles in which only female offspring are produced. When under environmental stress (e.g. chemical exposure, short length of daylight, food shortage and high population density), a switch of reproductive strategy from asexual to sexual reproduction occurs and male offspring are produced. As an indicator of ED, the induction of male offspring is used as an important endpoint in daphnia toxicity tests. It has been widely recognized that analogs of the crustacean juvenile hormone (JH), methyl farnesoate (MF) are able to bind and activate the crustacean JH receptor, methoprene tolerant (Met), thus inducing the putative sex determination genes, doublesex genes, and causing male offspring formation. The induction of male neonates is usually associated with reduced fecundity and population decline as adverse ED effects. The existing evidences from different studies currently support the causal relationships between the biological events occurred in daphniids after exposure to JH analogs and subsequently form an adverse outcome pathway (AOP) as proposed herein.

Background (optional)

This optional subsection should be 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. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. 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

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 1205 Activation, Juvenile hormone receptor Activation, Juvenile hormone receptor
2 KE 1206 Induction, Doublesex1 gene Induction, Doublesex1 gene
3 KE 1209 Induction, Male reproductive tract Induction, Male reproductive tract
4 AO 1208 Increased, Male offspring Increased, Male offspring
5 AO 361 Decline, Population Decline, Population
6 AO 1210 Alteration, Food-web structures Alteration, Food-web structures

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarises 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.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
Adults

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 in relation to this KE. More help
Term Scientific Term Evidence Link
Daphnia magna Daphnia magna NCBI
Daphnia pulex Daphnia pulex NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Female

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

Life Stage Applicability This AOP applies to: juvenile (<24h old) exposed to the MF analogs during a chronic (>14d) exposure (Abe et al., 2014a); and sex-mature adult (>10d old) exposed to MF analogs in the middle of a reproduction cycle for at least three days (Abe et al., 2014a).

Taxonomic Applicability This AOP can be potentially applied to other crustacean species and insects. The ligand binding domain of Met is considered to be conserved across different daphnia species and insects (Miyakawa et al., 2013). The juvenile hormone III (methyl farnesoate) signaling pathway to exert hormonal actions are thought to be similar between daphnids and insects with only two amino acids being different, which enhances the responsiveness of the Met receptor to various juvenile hormone III analogs (Miyakawa et al., 2013).

Sex Applicability This AOP applies to females.

Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. 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.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Molecular Initiating Event Summary

The support for essentiality for MiE is considered to be strong. It has been shown that MF and the MF analog pyriproxyfen activated the cloned Daphnia pulex Met when expressed with the mosquito SRC ortholog (LeBlanc et al., 2013). A two-hybrid in vitro screening bioassay has been developed using transfected Chinese hamster ovary (CHO) cells containing the transcriptional activity of Met/SRC for screening of Met activation by MF analogs (Miyakawa et al., 2013). The application of this screening assay by different studies supported that chemical with MF activities, including MF, juvenile hormone III, fenoxycarb (Miyakawa et al., 2013) and diofenolan (Abe et al., 2015a) were able to activate the Met receptor and initiate downstream transcriptional regulation in a concentration-dependent manner. Evidences generated from this screening assay quantitatively demonstrated the causal relationship between chemical exposure and transcriptional activation of Met.

Key Event Summary The dsx1 gene has shown to be highly responsible for the regulation of male traits development in the embryos of D. magna after exposure to the MF analog fenoxycarb (Kato et al., 2011). The same study has also shown that lack of dsx1 gene expression in male embryos of D. magna resulted in all female phenotypes. A high number of studies have quantitatively assessed the effects of MF-like chemicals on the induction of male offspring in daphnids (Abe et al., 2015b; Abe et al., 2014b; Ginjupalli and Baldwin, 2013; Kim et al., 2011; Lampert et al., 2012; Matsumoto et al., 2008; Oda et al., 2007; Oda et al., 2005; Olmstead and LeBlanc, 2001a, 2003; Olmstead and LeBlanc, 2001b; Tatarazako et al., 2003; Wang et al., 2005). These studies strongly support the induction of male offspring as a results of MF-related ED effects. Therefore, it is evident that the support for essentiality of Met receptor activation by MF analogs leading to the induction of dsx1, male traits and male offspring is strong.

Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

Summary Table The overall weight of evidence (WoE) for this AOP is considered to be moderate. The WoE for each individual KER is summarized in the overview table above. The MiE of Met receptor activation leading to the induction of dsx1 gene is considered to be strong. It has been demonstrated in insects such as Drosophila that the direct target gene following the MF receptor activation was the sex lethal gene (sxl) (Zhang et al., 2014). The sxl protein as an RNA splicing factor then leads to the expression of the transformer (TRA) gene and protein to regulate the doublesex (dsx) genes (Kopp, 2012). However, studies have shown that the tra gene was not involved in the sex determination in daphnids (Kato et al., 2010). Therefore, intermediate targets between the Met receptor activation and the induction of dsx genes still need to be found. Nevertheless, the dsx1 gene has shown to be highly responsible for the regulation of male traits development in the embryos of D. magna after exposure to the MF analog fenoxycarb (Kato et al., 2011). The same study has also shown that lack of dsx1 gene expression in male embryos of D. magna resulted in all female phenotypes. Therefore, it is evident that the support for essentiality of Met receptor activation by MF analogs leading to the induction of dsx1 and male traits formation is strong. The induction of dsx1 genes and male traits development leading to the induction of male offspring is considered to be strong. A study by (Miyakawa et al., 2013) reported good correlation between the EC50s of male offspring induction and EC50s of Met receptor activation for MF-like chemicals, including MF, fenoxycarb, JH III and pyriproxyfen. The induction of male offspring leading to reduction of fecundity is considered to be moderate. A number of studies have shown that the reduction of fecundity often occurred with the increased male:female ratio of offspring in daphnia after exposure to MF analogs (Abe et al., 2015b; Abe et al., 2014b; Ginjupalli and Baldwin, 2013; Kim et al., 2011; Lampert et al., 2012; Matsumoto et al., 2008; Oda et al., 2007; Oda et al., 2005; Olmstead and LeBlanc, 2001a, 2003; Olmstead and LeBlanc, 2001b; Tatarazako et al., 2003; Wang et al., 2005). Although the underlying mechanism and quantitative causal relationship between male formation and reduced reproduction has not been well-characterized, these evidences support the hypothesis that reduction of fecundity may be caused by disrupted sex determination pathway. The reduction of fecundity and induction of male offspring leading to the decline of population size is considered to be weak. Although lack of direct experimental evidences, it may be deduced that the most efficient way of reproduction, parthenogenesis is disrupted, thus the population size in the next generations may decrease. The decline of population size leading to the disturbance of food-web structure is considered to be weak. Although lack of experimental evidences, it may deduced that the food-web structure may be disrupted due to the decline of daphnia population.

Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

Summary Table The mechanistic evidences between the MiE of Met activation and induction of dsx1 gene have been clearly shown by various studies. However, the concentration-response relationship still needs to be obtained. A combination of the two-hybrid screening assay and quantitative real-time reverse transcriptase polymerase chain reaction (qPCR) would greatly facilitate the quantification of this KER. So this KER is considered to be moderate in terms of quantitative considerations. Demonstrations of the KER between the induction of dsx1 gene and male traits formation in the embryos using a combination of qPCR and in situ hybridization have been clearly provided (Kato et al., 2010). However, concentration-response relationship for this KER has not been well determined. So this KER is considered to be moderate in terms of quantitative considerations. The mechanism underlying the induction of male offspring leading to fecundity reduction has not been well characterized, and not quantitative assessment has been performed. So this KER is considered to be weak in terms of quantitative considerations. Linkages between the fecundity reduction, population decline and food-web disturbance have not been well studied. So these KERs are considered to be weak in terms of quantitative considerations.

Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the 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. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

Abe, R., Toyota, K., Miyakawa, H., Watanabe, H., Oka, T., Miyagawa, S., Nishide, H., Uchiyama, I., Tollefsen, K.E., Iguchi, T., Tatarazako, N., 2014. Diofenolan induces male offspring production through binding to the juvenile hormone receptor in Daphnia magna. Aquatic toxicology 159C, 44-51.

Abe, R., Watanabe, H., Yamamuro, M., Iguchi, T., Tatarazako, N., 2014b. Establishment of a short-term, in vivo screening method for detecting chemicals with juvenile hormone activity using adult Daphnia magna. Journal of applied toxicology : JAT.

Ginjupalli, G.K., Baldwin, W.S., 2013. The time- and age-dependent effects of the juvenile hormone analog pesticide, pyriproxyfen on Daphnia magna reproduction. Chemosphere 92, 1260-1266. Kato, Y., Kobayashi, K., Oda, S., Tatarazako, N., Watanabe, H., Iguchi, T., 2010. Sequence divergence and expression of a transformer gene in the branchiopod crustacean, Daphnia magna. Genomics 95, 160-165.

Kato, Y., Kobayashi, K., Watanabe, H., Iguchi, T., 2011. Environmental sex determination in the branchiopod crustacean Daphnia magna: deep conservation of a Doublesex gene in the sex-determining pathway. PLoS genetics 7, e1001345.

Kim, J., Kim, Y., Lee, S., Kwak, K., Chung, W.J., Choi, K., 2011. Determination of mRNA expression of DMRT93B, vitellogenin, and cuticle 12 in Daphnia magna and their biomarker potential for endocrine disruption. Ecotoxicology 20, 1741-1748.

Kopp, A., 2012. Dmrt genes in the development and evolution of sexual dimorphism. Trends Genet 28, 175-184.

Lampert, W., Lampert, K.P., Larsson, P., 2012. Induction of male production in clones of Daphnia pulex by the juvenoid hormone methyl farnesoate under short photoperiod. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 156, 130-133.

LeBlanc, G.A., Medlock, E.K., 2015. Males on demand: the environmental-neuro-endocrine control of male sex determination in daphnids. FEBS J 282, 4080-4093.

LeBlanc, G.A., Wang, Y.H., Holmes, C.N., Kwon, G., Medlock, E.K., 2013. A transgenerational endocrine signaling pathway in Crustacea. PloS one 8, e61715.

Matsumoto, T., Ikuno, E., Itoi, S., Sugita, H., 2008. Chemical sensitivity of the male daphnid, Daphnia magna, induced by exposure to juvenile hormone and its analogs. Chemosphere 72, 451-456.

Miyakawa, H., Toyota, K., Hirakawa, I., Ogino, Y., Miyagawa, S., Oda, S., Tatarazako, N., Miura, T., Colbourne, J.K., Iguchi, T., 2013. A mutation in the receptor Methoprene-tolerant alters juvenile hormone response in insects and crustaceans. Nature communications 4, 1856.

Oda, S., Tatarazako, N., Dorgerloh, M., Johnson, R.D., Ole Kusk, K., Leverett, D., Marchini, S., Nakari, T., Williams, T., Iguchi, T., 2007. Strain difference in sensitivity to 3,4-dichloroaniline and insect growth regulator, fenoxycarb, in Daphnia magna. Ecotoxicology and environmental safety 67, 399-405.

Oda, S., Tatarazako, N., Watanabe, H., Morita, M., Iguchi, T., 2005. Production of male neonates in Daphnia magna (Cladocera, Crustacea) exposed to juvenile hormones and their analogs. Chemosphere 61, 1168-1174.

Olmstead, A.W., LeBlanc, G.A., 2001a. Temporal and quantitative changes in sexual reproductive cycling of the cladoceran Daphnia magna by a juvenile hormone analog. The Journal of experimental zoology 290, 148-155.

Olmstead, A.W., LeBlanc, G.A., 2003. Insecticidal juvenile hormone analogs stimulate the production of male offspring in the crustacean Daphnia magna. Environmental health perspectives 111, 919-924.

Olmstead, A.W., LeBlanc, G.L., 2001b. Low exposure concentration effects of methoprene on endocrine-regulated processes in the crustacean Daphnia magna. Toxicological sciences : an official journal of the Society of Toxicology 62, 268-273.

Tatarazako, N., Oda, S., Watanabe, H., Morita, M., Iguchi, T., 2003. Juvenile hormone agonists affect the occurrence of male Daphnia. Chemosphere 53, 827-833.

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