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AOP: 323

Title

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

PPARalpha Agonism Leading to Decreased Viable Offspring via Decreased 11-Ketotestosterone

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
PPARa Agonism Impairs Fish Reproduction
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 v2.0

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

Authors

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

Ashley Kittelson, ORISE participant at US Environmental Protection Agency

John Hoang, ORISE participant at US Environmental Protection Agency

Robin Kutsi, ORISE participant at US Environmental Protection Agency

Jennifer H. Olker, US Environmental Protection Agency

Kathleen Jensen, US Environmental Protection Agency

David H. Miller, US Environmental Protection Agency

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
Arthur Author   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Ashley Kittelson
  • John Hoang
  • Robin Kutsi
  • Jennifer Olker
  • Arthur Author

Coaches

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

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

Revision dates for related pages

Page Revision Date/Time
Activation, PPARα December 28, 2020 12:48
Decreased, cholesterol May 24, 2022 11:10
Decreased, plasma 11-ketotestosterone level May 24, 2022 13:51
Impaired, Spermatogenesis April 10, 2024 17:41
Decrease, Population growth rate January 03, 2023 09:09
Decreased, Viable Offspring April 10, 2024 17:43
Activation, PPARα leads to Decreased, cholesterol May 01, 2020 11:10
Decreased, cholesterol leads to Decreased, 11KT May 06, 2020 09:31
Decreased, 11KT leads to Impaired, Spermatogenesis April 19, 2021 13:32
Impaired, Spermatogenesis leads to Decreased, Viable Offspring September 29, 2023 12:58
Decreased, Viable Offspring leads to Decrease, Population growth rate September 29, 2023 10:57
Clofibrate November 29, 2016 18:42
Gemfibrozil March 31, 2020 10:24
Fenofibrate November 29, 2016 18:42

Abstract

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 adverse outcome pathway details the linkage from peroxisome proliferator-activated receptor alpha (PPARα) activation to the adverse effects of decreased viable offspring and decrease in population growth rate in fish. PPARα is a ligand-activated nuclear receptor that, after forming a heterodimer with retinoid X receptor (RXR), promotes transcription of many genes including those involved in fatty acid β-oxidation and cholesterol metabolism. Synthetic ligands have been designed as pharmaceuticals to target PPARα for treatment of human metabolic diseases. Exposure to these pharmaceuticals or other contaminants in environment can disrupt metabolic processes in fish, including the activation of PPARα. In fish, this can lead to decreased cholesterol which in turn causes a decrease in reproductive hormones, notably 11-ketotestosterone (11-KT). A decrease in reproductive hormones impairs the fish’s ability to reproduce. Described here is the pathway in which decreased 11-KT impairs inducement of spermatogenesis and sperm production which results in a reduced number of viable offspring. This can lead to impacts on population growth rate due to the decreased number of viable offspring resulting in a decline in recruitment and contribution of offspring to the next generation.  

AOP Development Strategy

Context

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

This AOP was developed to address one potential effect of per- and polyfluoroalkyl substances (PFAS) on fish. Through review of the human health and in vitro toxicity data on conserved pathways and molecular targets for PFAS disruption, activation of PPARα was identified as a potential target of several PFAS which could result in altered lipid metabolism. This AOP focused primarily on teleost fish using experimental data from prototypical stressors, along with knock-out and genetic mutation experiments, for evidence of causality and essentiality for existing and newly developed KEs and KERs. 

Strategy

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

Biologists under the guidance of experts in the field developed this AOP with a KER by KER approach. This collaborative effort included dividing the KERs for investigation and evaluation, with regular team meetings to review findings with leaders in AOP development and fish toxicity testing (Dr. Daniel Villeneuve, Dr. Gerald Ankley, Kathleen Jensen). Systematic approaches were incorporated into the methods for identification and review of relevant studies for increased transparency and reproducibility.  Literature reviews for fibrates (synthetic ligands for PPARα) were conducted to develop and support the early KERs (PPARα activation through impaired spermatogenesis) whereas the intermediate KERs were supported with empirical evidence from published fish literature on prototypical stressors and hormones that disrupt the endocrine system. Additional sources were reviewed and incorporated based on citation tracing and expert knowledge. The resulting concordance tables and key supporting papers underwent a secondary quality assurance review by a team member (Kathleen Jensen) with extensive experience in fish toxicity testing and endocrinology.

All of the KERs were newly developed for this AOP, using an existing MIE (Activation, PPARα), one existing KE (Decreased, cholesterol), and novel KEs for the remaining steps through the organism level adverse outcome (Decreased, viable offspring). The population level adverse outcome (Decrease, population growth rate) was already relevant for this AOP and did not need to be updated.

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 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 227 Activation, PPARα Activation, PPARα
KE 807 Decreased, cholesterol Decreased, cholesterol
KE 1756 Decreased, plasma 11-ketotestosterone level Decreased, 11KT
KE 1758 Impaired, Spermatogenesis Impaired, Spermatogenesis
AO 2147 Decreased, Viable Offspring Decreased, Viable Offspring
AO 360 Decrease, Population growth rate Decrease, Population growth rate

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 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
teleost fish teleost fish High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Male 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
Attached file:

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

The empirical evidence suggests that this AOP is applicable to adult, reproductively mature, male teleost fish.

Life Stage

The life stage applicable to this AOP is adult, reproductively mature organisms.

Sex

The process of spermatogenesis occurs in reproductively mature males. Therefore, this AOP is only applicable to males.

Taxonomic

This AOP is considered most relevant for teleost fish. Most of the experimental evidence compiled for this AOP is from teleost fish, for which 11-KT is the dominant androgen. However, PPARs including PPARα are highly conserved across humans, rodents, and fish. An evaluation of protein sequence conservation via SeqAPASS (https://seqapass.epa.gov/seqapass/) predicted similarity in cross-species susceptibility to PPARα agonists among humans, zebrafish, medaka, and other fish species. Thus, PPARα agonism and downstream effects on cholesterol, hormone production (not limited to 11-KT), spermatogenesis (a highly conserved biological process), and production of offspring could have more broad taxonomic relevance.

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 of most of key events in this AOP is supported with experimental exposures with prototypical stressors that demonstrate modification of a more upstream KE associated with a corresponding change in downstream KE(s). Several of the key events have further support for essentiality with knock-out and genetic mutations experiments as well as rescue studies. Key studies are listed below.

Although it is challenging to directly measure PPARα activation in fish in vivo studies, there are multiple studies that have shown that fish exposed to fibrates (and thus assumed activation of PPARα) have decreased cholesterol. This relationship has been demonstrated in a variety of fish species [fathead minnow (Runnalls et al., 2007), grass carp (Du et al., 2008; Guo et al., 2015), Nile tilapia (Ning et al., 2017), rainbow trout (Prindiville et al., 2011), medaka (Lee et al., 2019), zebrafish (AL-Habsi et al., 2016; Velasco-Santamaria et al., 2011; Fraz et al., 2018), turbot (Urbatzka et al., 2015)], with temporal and dose concordance in one study (Velasco-Santamaria et al., 2011).

The process of steroid hormone biosynthesis is well understood, and cholesterol is the precursor for all steroid hormones, including 11-KT. The relationship between decreased cholesterol and decreased 11-KT is well-established. There are several experimental exposure studies that showed decreased 11-KT associated with decreased cholesterol with dose and temporal concordance (Lee et al., 2019; Velasco-Santamaria et al., 2011). The essentiality of cholesterol for production of 11-KT is further supported by an ex vivo study which showed that exposure to gemfibrozil (a known PPARα agonist) resulted in decreased 11-KT production unless supplemented with 25OH-cholesterol (Fraz et al., 2018), demonstrating that decreased cholesterol availability was the cause of the decreased steroid synthesis.

11-KT is well documented as a critical androgen for proper male reproduction in teleost fish and has well-documented involvement in spermatogenesis and spermiation. The essentiality of 11-KT for spermatogenesis has been documented in zebrafish knock-out studies with rescue (Zhang et al., 2020) which showed that zebrafish with cyp11c1 knockout have reduced 11-KT levels, smaller genitalia, inability naturally mate, defective Leydig and Sertoli cells, and insufficient spermatogenesis. The treatment of100 nM 11-KA (which is converted to 11-KT in vivo) for 4 hours per day for 10 days corrected these effects, demonstrating that insufficient 11-KT levels was the cause of arrested spermatogenesis.

Successful oocyte fertilization and production of viable offspring is dependent on spermatogenesis and the production of sufficient quality and quantity of sperm. Essentiality is  strongly supported by gene modification studies, such knock-out studies targeting genes associated with spermatogenesis and meiotic division as well as exposure studies with known endocrine disruptors (e.g., DEHP, EE2). Multiple studies with zebrafish have shown that knockouts targeting genes associated with spermatogenesis (e.g., Tdrd12, AR) and meiotic division (e.g., E2f5, Mettl3, mlh1) resulted in interference with spermatogenesis (i.e., delayed or arrested progression, apoptosis, and decrease in sperm density, quality and/or  motility) and male zebrafish that were either infertile or exhibited decreased fertilization rates when mated with WT females (Dai et al., 2017; Leal et al, 2008; Tang et al., 2018; Xia et al., 2018; Xie et al., 2020).

By definition, there must be viable offspring to maintain a population. However, there are other vital rates that are essential here as well, such as survival to reproductive age.

Evidence Assessment

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

The weight of evidence for each of the KERs within this AOP are ranked moderate to high. Each of the KERs is biologically plausible, with the highest ratings for the intermediate KERs (Decreased, cholesterol leading to Decreased, 11-KT and Decreased, 11-KT leading to Impaired, Spermatogenesis). The relationship between the MIE and the first key event is considered moderate for biological plausibility due to challenges in directly measuring the PPARα activation in in vivo studies. Whereas the links to the individual adverse outcome (Decreased, viable offspring) and the population level adverse outcome are considered moderate for biological plausibility due to the other factors that can influence each of these outcomes. There is substantial experimental evidence in fish to support this AOP, however, few studies measured multiple sequential key events and the final link to decreased population growth rate is based on biological plausibility and population modeling. Overall weight of evidence is moderate.

Biological Plausibility

This AOP is considered highly plausible, based on the evaluation of available evidence for the mechanistic (structural or functional) relationships between upstream and downstream KEs that are consistent with established biological knowledge. There is a broad understanding of lipid metabolism pathways and supporting in vivo and in vitro experimental data on the role of PPARα in lipid metabolism. PPARα is conserved across vertebrates and has been documented in multiple fish species, therefore biological plausibility is considered moderate for activation of PPARα leading to decreased cholesterol. The next two KERs are considered highly plausible. The process of steroid hormone biosynthesis is well understood, and cholesterol is the precursor for all steroid hormones including testosterone and 11-ketotestosterone (Norris and Carr, 2020). Similarly, the 11-ketotestosterone is well documented as necessary for spermatogenesis and sperm production (Amer et al., 2001; Borg, 1994; Geraudie et al., 2010). Because there are multiple factors required to produce viable offspring, biological plausibility is considered moderate for the process of impaired spermatogenesis leading to decreased viable offspring. The link from the individual level adverse outcome (decreased viable offspring) to the population level adverse outcome (decrease in population growth rate) is also influenced by multiple factors.  

Empirical Support

There is substantial experimental evidence to support this AOP. Experimental results from a variety of fish studies with prototypical stressors demonstrate concordance and consistency throughout the AOP. However, there were few studies that measured multiple sequential KEs and limited concentration or dose-response data and temporal measurements across diversity of taxa. Due to these limitations, response-response relationships for a quantitative understanding of this AOP could not be evaluated. Concordance of empirical support across the AOP is summarized in Attachment A.

There are multiple studies in fish that demonstrate exposure to known PPARα agonists (considered prototypical stressors or model chemicals) resulted in decreased total cholesterol. These studies include experimental exposure of seven different fish species [fathead minnow (Runnalls et al., 2007), grass carp (Du et al., 2008; Guo et al., 2015), Nile tilapia (Ning et al., 2017), rainbow trout (Prindiville et al., 2011), medaka (Lee et al., 2019), zebrafish (AL-Habsi et al., 2016; Velasco-Santamaria et al., 2011; Fraz et al., 2018), turbot (Urbatzka et al., 2015)] to several different fibrates (clofibrate, clofibric acid, gemfibrozil, fenofibrate, WY-14643). Temporal and dose concordance was demonstrated in one study ( Velasco-Santamaría et al., 2011); however, there is insufficient empirical evidence for development of a quantitative relationship between the KEs.

While the following KER (decreased cholesterol leading to decreased 11-KT) has strong biological plausibility, there are relatively few fish experimental exposure studies that measured both cholesterol and 11-KT. Two exposure studies that measured both KEs showed dose and temporal concordance (Lee et al., 2019; Velasco-Santamaria et al., 2011), and the third study provided strong evidence essentiality of cholesterol for the production of 11-KT (Fraz et al., 2018)

There is substantial empirical evidence showing spermatogenesis in numerous fish species is dependent on 11-KT, with several studies demonstrating temporal and dose concordance for this relationship. These studies include testing of both higher 11-KT (treatments with 11-KT or increased production) and decreased 11-KT. For example, increased 11-KT has been related to measures of successful spermatogenesis such as greater number of spermatids (Agulleiro et al., 2007; Selvaraj et al., 2013), more advanced testicular stages (Cavaco et al., 1998, 2001), and more differentiated and later type spermatogonia (Melo et al., 2015; Miura et al., 1991). Whereas, decreased 11-KT in fish has been associated with negative impacts or delays in spermatogenesis including decreased number of spermatocytes, spermatids, and/or spermatozoa (Agbohessi et al., 2015; Chen et al., 2017; de Waal et al., 2009; Liu et al., 2018; Pereira et al., 2015; Sales et al., 2020; Xia et al,. 2018). Melo et al. (2015) is one example of studies that demonstrated temporal concordance; in this study exposure to adrenosterone (ketoandrostenedione; which is converted to 11-KT in vivo) caused an increase in 11-KT levels at 7 and 14 d, with Type A differentiated spermatogonial numbers also increased 14 d after treatment.

There is substantial empirical evidence demonstrating that impaired spermatogenesis results in decreased oocyte fertilization and a reduction in viable offspring. Much of the cited literature is from fish exposed to prototypical stressors (endocrine disruptors), with several studies demonstrating dose and temporal concordance.  In addition to the gene modification studies previously described for essentiality, exposure studies with endocrine disruptors [e.g., di(2-ethylhexyl) phthalate (DEHP), 17α-ethinylestradiol (EE2), nonylphenol] provide evidence of concordance and consistency of this KER. These include studies with zebrafish, Nile tilapia, Japanese medaka, and marine medaka (Corradetti et al., 2013; Hill & Janz, 2003; Kang et al., 2002, Nash et al., 2004; Seki et al., 2002). Several studies provide evidence of dose-response concordance such as a concentration dependent effect on both spermatogenesis and fertilization rate of when male fish exposed to DEHP are mated with wild-type females (Ma et al., 2018; Uren-Webster et al., 2010; Ye et al., 2014). 

Direct empirical evidence on population size decreases associated with decreased viable offspring is very limited. There are no empirical data suitable for evaluating the dose-response, temporal, or incidence concordance between these two adverse outcomes. This relationship is based on biological plausibility and population modeling (e.g., Miller & Ankley, 2004; Miller et al., 2020).

Uncertainties, inconsistencies, and data gaps

  • There were no notable inconsistencies in the literature that was reviewed for development of this AOP. However, there are several areas of uncertainty. These include:
  • It is challenging to directly measure PPARα agonism in fish in vivo studies. Therefore, we relied on fish exposure studies with pharmaceuticals designed to activate PPARα in humans. However, there is uncertainty of whether all fibrates shown effective in humans are PPARα agonists in fish. This AOP was developed on the assumption that these pharmaceutical also activate PPARα in fish, which is supported by a cross-species comparison in vitro and susceptibility evaluation based on gene sequences support similarity in responses across vertebrates.
  • 11-KT levels can be highly variable between fish species and have seasonal fluctuations within a species (with highest levels at spawning).
  • For the relationship between 11-KT and spermatogenesis, a few studies documented a significant change in one without a significant change in the other, highlighting the complexity of this relationship.
  • Both of the adverse outcomes (Decreased, viable offspring and Decrease, population growth rate) are influenced by multiple factors. The key events in this AOP are just one potential path to these outcomes. In addition, PPARα agonism could result in other toxicity pathways, such as decreased juvenile growth, which were not included in the development of this AOP.  
  • Finally, few studies measured multiple sequential key events; thus evidence had to be compiled KER by KER to support this 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
No known modulating factors have been identified or investigated.

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

At this time available data are insufficient to develop a quantitative AOP linking PPARα agonism with decreased viable offspring or decreased population growth rate.

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
  • The present AOP can inform a tiered testing approach for PPARα agonists (including some PFAS) based on in vitro screening results (e.g., Houck et al., 2021) and targeted in vivo testing (illustrated by Villeneuve et al., 2023).
  • The present AOP can inform the development of microphysiological or computational systems models to evaluated probable effects on reproduction.
  • The present AOP can aid in prediction of potential effects when PPAR agonists are measured in environmental samples and interpretation (along with selection of additional endpoints to measure) when PPAR activity is detected with effects-based environmental monitoring (e.g., Blackwell et al., 2019).

References

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

Agbohessi, P.T., Imorou Toko I., Ouédraogo, A., Jauniaux, T., Mandiki, S.N., & Kestemont, P. (2015). Assessment of the health status of wild fish inhabiting a cotton basin heavily impacted by pesticides in Benin (West Africa). Science of the Total Environment506-507, 567-584. https://doi.org/10.1016/j.scitotenv.2014.11.047

Agulleiro, M.J., Scott, A.P., Duncan, N., Mylonas, C.C., & Cerdà, J. (2007). Treatment of GnRHa-implanted Senegalese sole (Solea senegalensis) with 11-ketoandrostenedione stimulates spermatogenesis and increases sperm motility. Comparative Biochemistry and Physiology Part A: Molecular and Integrative Physiology147(4), 885-92. https://doi.org/10.1016/j.cbpa.2007.02.008

Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (Danio rerio)”, Comparative Biochemistry and Physiology, Part B, Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009

Amer, M.A., Miura, T., Miura, C., & Yamauchi, K. (2001). Involvement of Sex Steroid Hormones in the Early Stages of Spermatogenesis in Japanese Huchen (Hucho perryi ). Biology of Reproduction, 65(4), 1057–1066. https://doi.org/10.1095/biolreprod65.4.1057

Blackwell, B. R., Ankley, G. T., Bradley, P. M., Houck, K. A., Makarov, S. S., Medvedev, A. V., Swintek, J., & Villeneuve, D. L. (2019). Potential Toxicity of Complex Mixtures in Surface Waters from a Nationwide Survey of United States Streams: Identifying in Vitro Bioactivities and Causative Chemicals. Environmental science & technology53(2), 973–983. https://doi.org/10.1021/acs.est.8b05304

Borg, B. (1994). Androgens in teleost fishes. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology, and Endocrinology109(3), 219-245. https://doi.org/10.1016/0742-8413(94)00063-G

Cavaco, J.E.B., Bogerd, J., Goos, H., & Schulz, R.W. (2001). Testosterone inhibits 11-ketotestosterone-induced spermatogenesis in African catfish (Clarias gariepinus). Biology of Reproduction65(6), 1807-1812. https://doi.org/10.1095/biolreprod65.6.1807

Cavaco, J.E.B., Vilrokx, C., Trudeau, V.L., Schulz, R.W., & Goos, H.J.T. (1998). Sex steroids and the initiation of puberty in male African catfish, Clarias gariepinus. American Journal of Physiology275(6), 1793-1802. https://doi.org/10.1152/ajpregu.1998.275.6.R1793

Chen, J., Jiang, D., Tan, D., Fan, Z., Wei, Y., Li, M., & Wang, D. (2017). Heterozygous mutation of eEF1A1b resulted in spermatogenesis arrest and infertility in male tilapia, Oreochromis niloticus. Scientific Reports7, 43733. https://doi.org/10.1038/srep43733

Corradetti, B., Stronati, A., Tosti, L., Manicardi, G., Carnevali, O., & Bizzaro, D. (2013). Bis-(2-ethylexhyl) phthalate impairs spermatogenesis in zebrafish (Danio rerio). Reproductive biology13(3), 195–202. https://doi.org/10.1016/j.repbio.2013.07.003

Dai, X., Shu, Y., Lou, Q., Tian, Q., Zhai, G., Song, J., Lu, S., Yu, H., He, J., & Yin, Z. (2017). Tdrd12 Is Essential for Germ Cell Development and Maintenance in Zebrafish. International journal of molecular sciences18(6), 1127. https://doi.org/10.3390/ijms18061127 de Waal, P.P., Leal, M.C., García-López, A., Liarte, S., de Jonge, H., Hinfray, N., Brion, F., Schulz, R.W., & Bogerd, J. (2009). Oestrogen-induced androgen insufficiency results in a reduction of proliferation and differentiation of spermatogonia in the zebrafish testis. Journal of Endocrinology202(2), 287-97. https://doi.org/10.1677/JOE-09-0050

Du, Z. et al. (2008) “Hypolipidaemic effects of fenofibrate and fasting in the herbivorous grass carp (Ctenopharyngodon Idella) fed a high-fat diet”, British Journal of Nutrition, Vol. 100, Cambridge University Press, pp. 1200-1212. doi:10.1017/S0007114508986840

Fraz, S., A.H. Lee, J.Y. Wilson (2018) “Gemfibrozil and carbamazepine decrease steroid production in zebrafish testes (Danio rerio)”, Aquatic Toxicology, Vol. 198, Elsevier, pp. 1-9. https://doi.org/10.1016/j.aquatox.2018.02.006

Geraudie, P., Gerbron, M., & Minier, C. (2010). Seasonal variations and alterations of sex steroid levels during the reproductive cycle of male roach (Rutilus rutilus). Marine Environmental Research69(S1), S53-S55. https://doi.org/10.1016/j.marenvres.2009.11.008

Guo, X. et al. (2015) “Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (Ctenopharyngodon idella Val.) fed with the high non-protein energy diets”, Fish Physiology and Biochemistry, Vol. 41, Springer, pp. 331-343. doi: 10.1007/s10695-014-9986-8

Hill, R. L., Jr, & Janz, D. M. (2003). Developmental estrogenic exposure in zebrafish (Danio rerio): I. Effects on sex ratio and breeding success. Aquatic toxicology (Amsterdam, Netherlands)63(4), 417–429. https://doi.org/10.1016/s0166-445x(02)00207-2

Houck, K. A., Patlewicz, G., Richard, A. M., Williams, A. J., Shobair, M. A., Smeltz, M., Clifton, M. S., Wetmore, B., Medvedev, A., & Makarov, S. (2021). Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure. Toxicology457, 152789. https://doi.org/10.1016/j.tox.2021.152789

Kang, I. J., Yokota, H., Oshima, Y., Tsuruda, Y., Yamaguchi, T., Maeda, M., Imada, N., Tadokoro, H., & Honjo, T. (2002). Effect of 17beta-estradiol on the reproduction of Japanese medaka (Oryzias latipes). Chemosphere47(1), 71–80. https://doi.org/10.1016/s0045-6535(01)00205-3

Leal, M. C., Feitsma, H., Cuppen, E., França, L. R., & Schulz, R. W. (2008). Completion of meiosis in male zebrafish (Danio rerio) despite lack of DNA mismatch repair gene mlh1. Cell and tissue research332(1), 133–139. https://doi.org/10.1007/s00441-007-0550-z

Lee, G. et al. (2019) Effects of gemfibrozil on sex hormones and reproduction related performances of Oryzias latipes following long-term (155 d) and short-term (21 d) exposure, Ecotoxicology and Environmental Safety, Vol. 173, Elsevier, pp. 174-181. https://doi.org/10.1016/j.ecoenv.2019.02.015

Liu, Z.H., Chen, Q.L., Chen, Q., Li, F., & Li, Y.W. (2018). Diethylstilbestrol arrested spermatogenesis and somatic growth in the juveniles of yellow catfish (Pelteobagrus fulvidraco), a fish with sexual dimorphic growth. Fish Physiology and Biochemistry44(3), 789-803. https://doi.org/10.1007/s10695-018-0469-1

Ma, Yan-Bo, Jia, Pan-Pan, Junaid, Muhammad, Yang, Li, Lu, Chun-Jiao, & Pei, De-Sheng. (2018). Reproductive effects linked to DNA methylation in male zebrafish chronically exposed to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate. Environmental Pollution (1987), 237, 1050-1061.

Melo, M.C., van Dijk, P., Andersson, E., Nilsen, T.O., Fjelldal, P.G., Male, R., Nijenhuis, W., Bogerd, J., de França, L.R., Taranger, G.L., & Schulz R.W. (2015). Androgens directly stimulate spermatogonial differentiation in juvenile Atlantic salmon (Salmo sala). General and Comparative Endocrinology, 211, 52-61. https://doi.org/10.1016/j.ygcen.2014.11.015.

Miller, D. H., & Ankley, G. T. (2004). Modeling impacts on populations: fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17beta-trenbolone as a case study. Ecotoxicology and environmental safety59(1), 1–9. https://doi.org/10.1016/j.ecoenv.2004.05.005

Miller, D. H., Clark, B. W., & Nacci, D. E. (2020). A multidimensional density dependent matrix population model for assessing risk of stressors to fish populations. Ecotoxicology and environmental safety201, 110786. https://doi.org/10.1016/j.ecoenv.2020.110786

Miura, T., Yamauchi, K., Takahashi, H., & Nagahama, Y. (1991). Hormonal induction of all stages of spermatogenesis in vitro in the male Japanese eel (Anguilla japonica). Proceedings of the National Academy of Sciences of the United States of America88(13), 5774–5778. https://doi.org/10.1073/pnas.88.13.5774

Ning, L. et al. (2017) “Nutritional background changes the hypolipidemic effects of fenofibrate in Nile tilapia (Oreochromis niloticus)”, Scientific Reports, Vol. 7(41706), Nature. https://doi.org/10.1038/srep41706

Norris, D. & Carr, J. A. 2020. Vertebrate Endocrinology, 6th Edition. Academic Press. Cambridge, MA, USA, 656 pp. ISBN: 9780128200933

Pereira, T.S., Boscolo, C.N., Silva, D.G., Batlouni, S.R., Schlenk, D., & Almeida, E.A. (2015). Anti-androgenic activities of diuron and its metabolites in male Nile tilapia (Oreochromis niloticus). Aquatic Toxicology164, 10-15. https://doi.org/10.1016/j.aquatox.2015.04.013

Prindiville, J.S. et al. (2011). The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout. Toxicology and Applied Pharmacology, Vol. 251, Elsevier, pp. 201-238. doi:10.1016/j.taap.2010.12.013

Runnalls, T.J., Hala, D.N., & Sumpter, J.P. (2007). Preliminary studies into the effects of the human pharmaceutical Clofibric acid on sperm parameters in adult Fathead minnow. Aquatic Toxicology84(1), 111-118. https://doi.org/10.1016/j.aquatox.2007.06.005

Sales, C.F., Barbosa Pinheiro, A.P., Ribeiro, Y.M., Weber, A.A., Paes-Leme, F.O., Luz, R.K., Bazzoli, N., Rizzo, E., & Melo, R.M.C. (2020). Effects of starvation and refeeding cycles on spermatogenesis and sex steroids in the Nile tilapia Oreochromis niloticusMolecular and Cellular Endocrinology500, 110643. https://doi.org/10.1016/j.mce.2019.110643

Seki, M., Yokota, H., Matsubara, H., Tsuruda, Y., Maeda, M., Tadokoro, H., & Kobayashi, K. (2002). Effect of ethinylestradiol on the reproduction and induction of vitellogenin and testis-ova in medaka (Oryzias latipes). Environmental toxicology and chemistry21(8), 1692–1698.

Selvaraj, S., Ohga, H., Nyuji, M., Kitano, H., Nagano, N., Yamaguchi, A., & Matsuyama, M. (2013). Subcutaneous administration of Kiss1 pentadecapeptide accelerates spermatogenesis in prepubertal male chub mackerel (Scomber japonicus). Comparative Biochemistry and Physiology Part A: Molecular and Integrative Physiology166(2), 228-36. https://doi.org/10.1016/j.cbpa.2013.06.007

Tang, H., Chen, Y., Wang, L., Yin, Y., Li, G., Guo, Y., Liu, Y., Lin, H., Cheng, C.H.K., & Liu, X. (2018). Fertility impairment with defective spermatogenesis and steroidogenesis in male zebrafish lacking androgen receptor. Biology of Reproduction98(2), 227-238. https://doi.org/10.1093/biolre/iox165

Urbatzka, R., Galante-Oliveira, S., Rocha, E., Lobo-da-Cunha, A., Castro, L. F., & Cunha, I. (2015). Effects of the PPARα agonist WY-14,643 on plasma lipids, enzymatic activities and mRNA expression of lipid metabolism genes in a marine flatfish, Scophthalmus maximusAquatic toxicology (Amsterdam, Netherlands)164, 155–162. https://doi.org/10.1016/j.aquatox.2015.05.004

Uren-Webster, Tamsyn M, Lewis, Ceri, Filby, Amy L, Paull, Gregory C, & Santos, Eduarda M. (2010). Mechanisms of toxicity of di(2-ethylhexyl) phthalate on the reproductive health of male zebrafish. Aquatic Toxicology, 99(3), 360-369.

Vandermeer, J.H. & Goldberg, D.E. (2013). Population ecology: first principles. Princeton University Press, Princeton, NJ USA.

Velasco-Santamaría, Y.M., Korsgaard, B., Madsen, S.S., & Bjerregaard, P. (2011). Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio). Aquatic Toxicology105(1-2), 107-118. https://doi.org/10.1016/j.aquatox.2011.05.018

Villeneuve, D. L., Blackwell, B. R., Cavallin, J. E., Collins, J., Hoang, J. X., Hofer, R. N., Houck, K. A., Jensen, K. M., Kahl, M. D., Kutsi, R. N., Opseth, A. S., Santana Rodriguez, K. J., Schaupp, C., Stacy, E. H., & Ankley, G. T. (2023). Verification of In Vivo Estrogenic Activity for Four Per- and Polyfluoroalkyl Substances (PFAS) Identified as Estrogen Receptor Agonists via New Approach Methodologies. Environmental science & technology57(9), 3794–3803. https://doi.org/10.1021/acs.est.2c09315

Xia, H., Zhong, C., Wu, X., Chen, J., Tao, B., Xia, X., Shi, M., Zhu, Z., Trudeau, V. L., & Hu, W. (2018). Mettl3 mutation disrupts gamete maturation and reduced fertility in zebrafish. Genetics, 208(2), 729-743. doi: 10.1534/genetics.117.300574

Xie, H., Kang, Y., Wang, S., Zheng, P., Chen, Z., Roy, S., & Zhao, C. (2020). E2f5 is a versatile transcriptional activator required for spermatogenesis and multiciliated cell differentiation in zebrafish. PLoS genetics, 16(3), e1008655. https://doi.org/10.1371/journal.pgen.1008655

Ye, Ting, Kang, Mei, Huang, Qiansheng, Fang, Chao, Chen, Yajie, Shen, Heqing, & Dong, Sijun. (2014). Exposure to DEHP and MEHP from hatching to adulthood causes reproductive dysfunction and endocrine disruption in marine medaka (Oryzias melastigma). Aquatic Toxicology, 146, 115-126.

Zhang, Q., Ye, D., Wang, H., Wang, Y., Hu, W., Sun, Y. (2020). Zebrafish cyp11c1 Knockout Reveals the Roles of 11-ketotestosterone and Cortisol in Sexual Development and Reproduction. Endocrinology161(6). https://doi.org/10.1210/endocr/bqaa048