To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:2274

Relationship: 2274

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Impaired, Spermatogenesis leads to impaired, Fertility

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

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

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
PPARalpha Agonism Impairs Fish Reproduction adjacent High Not Specified Ashley Kittelson (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
rodents rodents High NCBI
teleost fish teleost fish High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Male High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
Adult, reproductively mature High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Spermatogenesis is a multiphase process of cellular transformation that produces mature male gametes known as sperm for sexual reproduction (Kang et al., 2015). The process of spermatogenesis can be broken down into 3 phases: the mitotic proliferation of spermatogonia, meiosis, and post meiotic differentiation(spermiogenesis) (Boulanger et al., 2015). Male fertility is dependent on the quantity as well as the proper cellular morphology of the sperm formed in the testes (Chen et al., 2020). The fusion of sperm and oocytes is the key step for the beginning of life known as fertilization (Alavi et al., 2019). Impaired spermatogenesis may impact fertility and, consequently, also reduce reproduction.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

Evidence supporting the KER is shown below. 

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

​​​​​​Spermatogenesis is one of the most conserved biological processes from Drosophila to humans (Wu et al., 2016). The process itself is well understood and gametes produced from spermatogenesis are required for sexual reproduction.

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help
  • When exposed to 10 and 100 ng/L of EE2 for 62 days leading to spawning, Rainbow trout (Oncorhynchus mykiss) experienced a decrease in GSI and increases in sperm concentration and spermatocrit. However, there were no significant changes to spermatogenesis. Despite this, there was a decrease in viability of embryos. (Schultz et al., 2003)
  • Male Sprague-Dawley rats (Rattus norvegicus) fed a high fat diet(allowing them to develop Non-alcoholic fatty liver disease) experienced decreased testosterone levels along with reduced sperm number and motility. However, this did not affect fertility of the rats (Li et al., 2013).
Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
  • Lahnsteiner et al.(1998) determined that fertilization rate in Rainbow Trout (Oncorhynchus mykiss) can be described by sperm motility rate(y=0.72x * 25.99 where y is fertilization rate and x is sperm motility rate, R=0.594, P < 0.001), seminal plasma pH(R2=0.525, P < 0.001), and spermatozoal respiration activation(R2=0.554, P < 0.001). They found a positive correlation between % of motile spermatozoa and total swimming velocity with fertilization rate (P < 0.001) and % of immotile spermatozoa inversely. The 2 parameters accounted for 65% of total variance in fertilization rate.
  • Relative sperm velocity(p=0.008) and longevity (p < 0.0001) showed significant association with sperm competition success in Atlantic salmon (Salmo salar). Males with faster spermatozoa achieved greater fertilization success. (Gage et al., 2004)
  • Highly significant correlations were found between sperm motility (R=0.932, p < 0.001) and fertilization rate in Rainbow Trout (Oncorhynchus mykiss) (Ciereszko and Dabrowski, 1993).
Time-scale
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
  • The duration of spermatogenesis in humans (Homo sapiens) is reported to be 74 days (Griswold, M.D, 2016). Consequently, effects on spermatogenesis may not manifest as observable impacts on fertility until perhaps 74 days after impacts on spermatogenesis began. This may vary depending on the stage(s) of spermatogenesis that are impacted by the stressor.
  • The duration of the meiotic and spermiogenic phases in zebrafish (Danio rerio) is reported to be 6 days which means there could be a delay of at least 6 days before signs of impaired fertility may be detected (Leal et al., 2009).
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
  • Fertilization success in Chinook salmon (Oncorhynchus tshawytscha) was significantly biased towards the male whose sperm swam fastest in the female’s ovarian fluid (Rosengrave et al., 2016).
  • Seminal plasma pH(R2=0.525) is positively correlated with fertilization rate in Rainbow Trout (Oncorhynchus mykiss) and African catfish (Clarias gariepinus) (Lahnsteiner et al., 1998, Mansour et al., 2005).
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Feedforward/feedback loops haven’t been evaluated yet. However, given that fertilization pertains to the interaction between sperm and oocyte, it seems unlikely that fertilization rates (external to the male) would feedback on and impact spermatogenesis.

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help
  • Taxonomic Applicability: Spermatogenesis is one of the most conserved biological processes from Drosophila to humans (Wu et al., 2016). As a result, animals who utilize sexual reproduction as their way to produce offspring are heavily reliant on spermatogenesis being effective and normal (Kang et al., 2015). There are studies on reproduction and spermatogenesis across a multitude of taxas.
  • Sex Applicability: Spermatogenesis is a male-specific process (Tang et al., 2018, Wu et al., 2015, Kang et al., 2015, Wang et al., 2015). Thus, the present relationship is only relevant for males.
  • Life Stage Applicability: Spermatogenesis and reproduction are only relevant for sexually-mature adults.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Aramli, M. S., & Nazari, R. M. (2014). Motility and fertility of cryopreserved semen in Persian sturgeon, Acipenser persicus, stored for 30-60 min after thawing. Cryobiology, 69(3), 500–502. https://doi.org/10.1016/j.cryobiol.2014.10.006

Boulanger, G., Cibois, M., Viet, J., Fostier, A., Deschamps, S., Pastezeur, S., Massart, C., Gschloessl, B., Gautier-Courteille, C., & Paillard, L. (2015). Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice. Molecular and cellular biology, 35(18), 3244–3253. https://doi.org/10.1128/MCB.00074-15

Chen, J., Xiao, Y., Gai, Z., Li, R., Zhu, Z., Bai, C., Tanguay, R. L., Xu, X., Huang, C., & Dong, Q. (2015). Reproductive toxicity of low level bisphenol A exposures in a two-generation zebrafish assay: Evidence of male-specific effects. Aquatic toxicology (Amsterdam, Netherlands), 169, 204–214. https://doi.org/10.1016/j.aquatox.2015.10.020

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 reports, 7, 43733. https://doi.org/10.1038/srep43733

Chen, Y., Tang, H., Wang, L., Wei, T., Liu, X., & Lin, H. (2020). New insights into the role of mTORC1 in male fertility in zebrafish. General and comparative endocrinology, 286, 113306. https://doi.org/10.1016/j.ygcen.2019.113306

Chen, Y., Wang, H., Wang, F., Chen, C., Zhang, P., Song, D., Luo, T., Xu, H., & Zeng, X. (2020). Sperm motility modulated by Trpv1 regulates zebrafish fertilization. Theriogenology, 151, 41–51. https://doi.org/10.1016/j.theriogenology.2020.03.032

Ciereszko, A., & Dabrowski, K. (1994). Relationship between biochemical constituents of fish semen and fertility: the effect of short-term storage. Fish physiology and biochemistry, 12(5), 357–367. https://doi.org/10.1007/BF00004300

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 sciences, 18(6), 1127. https://doi.org/10.3390/ijms18061127

Egeland, Torvald B, Rudolfsen, Geir, Nordeide, Jarle T, & Folstad, Ivar. (2015). On the relative effect of spawning asynchrony, sperm quantity, and sperm quality on paternity under sperm competition in an external fertilizer. Frontiers in Ecology and Evolution, 3, Frontiers in ecology and evolution, 2015-07-14, Vol.3.

Feitsma, H., Leal, M. C., Moens, P. B., Cuppen, E., & Schulz, R. W. (2007). Mlh1 deficiency in zebrafish results in male sterility and aneuploid as well as triploid progeny in females. Genetics, 175(4), 1561–1569. https://doi.org/10.1534/genetics.106.068171

Gage, M. J., Macfarlane, C. P., Yeates, S., Ward, R. G., Searle, J. B., & Parker, G. A. (2004). Spermatozoal traits and sperm competition in Atlantic salmon: relative sperm velocity is the primary determinant of fertilization success. Current biology : CB, 14(1), 44–47.

Griswold M. D. (2016). Spermatogenesis: The Commitment to Meiosis. Physiological reviews, 96(1), 1–17. https://doi.org/10.1152/physrev.00013.2015

Hamaguchi, S., & Sakaizumi, M. (1992). Sexually differentiated mechanisms of sterility in interspecific hybrids between Oryzias latipes and O. curvinotus. The Journal of experimental zoology, 263(3), 323–329. https://doi.org/10.1002/jez.1402630312

Hsu, C. C., Hou, M. F., Hong, J. R., Wu, J. L., & Her, G. M. (2010). Inducible male infertility by targeted cell ablation in zebrafish testis. Marine biotechnology (New York, N.Y.), 12(4), 466–478. https://doi.org/10.1007/s10126-009-9248-4

Lahnsteiner, F, Berger, B, Weismann, T, & Patzner, R.A. (1998). Determination of semen quality of the rainbow trout, Oncorhynchus mykiss, by sperm motility, seminal plasma parameters, and spermatozoal metabolism. Aquaculture, 163(1), 163-181.

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 research, 332(1), 133–139. https://doi.org/10.1007/s00441-007-0550-z

Leal, M. C., Cardoso, E. R., Nóbrega, R. H., Batlouni, S. R., Bogerd, J., França, L. R., & Schulz, R. W. (2009). Histological and stereological evaluation of zebrafish (Danio rerio) spermatogenesis with an emphasis on spermatogonial generations. Biology of reproduction, 81(1), 177–187. https://doi.org/10.1095/biolreprod.109.076299

Li, Y., Liu, L., Wang, B., Xiong, J., Li, Q., Wang, J., & Chen, D. (2013). Impairment of reproductive function in a male rat model of non-alcoholic fatty liver disease and beneficial effect of N-3 fatty acid supplementation. Toxicology letters, 222(2), 224–232. https://doi.org/10.1016/j.toxlet.2013.05.644

Lor, Y., Revak, A., Weigand, J., Hicks, E., Howard, D. R., & King-Heiden, T. C. (2015). Juvenile exposure to vinclozolin shifts sex ratios and impairs reproductive capacity of zebrafish. Reproductive toxicology (Elmsford, N.Y.), 58, 111–118. https://doi.org/10.1016/j.reprotox.2015.09.003

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.

Mansour, Nabil, Ramoun, Adel, & Lahnsteiner, Franz. (2005). Quality of testicular semen of the African catfish Clarias gariepinus (Burchell, 1822) and its relationship with fertilization and hatching success. Aquaculture Research, 36(14), 1422-1428.

Oakes, J. A., Li, N., Wistow, B., Griffin, A., Barnard, L., Storbeck, K. H., Cunliffe, V. T., & Krone, N. P. (2019). Ferredoxin 1b Deficiency Leads to Testis Disorganization, Impaired Spermatogenesis, and Feminization in Zebrafish. Endocrinology, 160(10), 2401–2416. https://doi.org/10.1210/en.2019-00068

Parisi, E., De Prisco, P., Capasso, A., & del Prete, M. (1984). Serotonin and sperm motility. Cell biology international reports, 8(2), 95. https://doi.org/10.1016/0309-1651(84)90075-4

Rahman, M. S., Kwon, W. S., Lee, J. S., Yoon, S. J., Ryu, B. Y., & Pang, M. G. (2015). Bisphenol-A affects male fertility via fertility-related proteins in spermatozoa. Scientific reports, 5, 9169. https://doi.org/10.1038/srep09169

Rodríguez-Marí, A., Wilson, C., Titus, T. A., Cañestro, C., BreMiller, R. A., Yan, Y. L., Nanda, I., Johnston, A., Kanki, J. P., Gray, E. M., He, X., Spitsbergen, J., Schindler, D., & Postlethwait, J. H. (2011). Roles of brca2 (fancd1) in oocyte nuclear architecture, gametogenesis, gonad tumors, and genome stability in zebrafish. PLoS genetics, 7(3), e1001357. https://doi.org/10.1371/journal.pgen.1001357

Rosengrave, P., Montgomerie, R., & Gemmell, N. (2016). Cryptic female choice enhances fertilization success and embryo survival in chinook salmon. Proceedings. Biological sciences, 283(1827), 20160001. https://doi.org/10.1098/rspb.2016.0001

Saito, K., Siegfried, K. R., Nüsslein-Volhard, C., & Sakai, N. (2011). Isolation and cytogenetic characterization of zebrafish meiotic prophase I mutants. Developmental dynamics : an official publication of the American Association of Anatomists, 240(7), 1779–1792. https://doi.org/10.1002/dvdy.22661

Saju, J. M., Hossain, M. S., Liew, W. C., Pradhan, A., Thevasagayam, N. M., Tan, L., Anand, A., Olsson, P. E., & Orbán, L. (2018). Heat Shock Factor 5 Is Essential for Spermatogenesis in Zebrafish. Cell reports, 25(12), 3252–3261.e4. https://doi.org/10.1016/j.celrep.2018.11.090

Schultz, I. R., Skillman, A., Nicolas, J. M., Cyr, D. G., & Nagler, J. J. (2003). Short-term exposure to 17 alpha-ethynylestradiol decreases the fertility of sexually maturing male rainbow trout (Oncorhynchus mykiss). Environmental toxicology and chemistry, 22(6), 1272–1280.

Shawlot, W., Vazquez-Chantada, M., Wallingford, J. B., & Finnell, R. H. (2015). Rfx2 is required for spermatogenesis in the mouse. Genesis (New York, N.Y. : 2000), 53(9), 604–611. https://doi.org/10.1002/dvg.22880

Shimizu, N., & Matsuda, M. (2019). Identification of a Novel Zebrafish Mutant Line that Develops Testicular Germ Cell Tumors. Zebrafish, 16(1), 15–28. https://doi.org/10.1089/zeb.2018.1604

Shive, H. R., West, R. R., Embree, L. J., Azuma, M., Sood, R., Liu, P., & Hickstein, D. D. (2010). brca2 in zebrafish ovarian development, spermatogenesis, and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 107(45), 19350–19355. https://doi.org/10.1073/pnas.1011630107

Song, W., Lu, H., Wu, K., Zhang, Z., Shuk-Wa Lau, E., & Ge, W. (2020). Genetic evidence for estrogenicity of bisphenol A in zebrafish gonadal differentiation and its signalling mechanism. Journal of hazardous materials, 386, 121886. https://doi.org/10.1016/j.jhazmat.2019.121886

Su, Y., He, L., Zhao, K., Zhang, H., Mao, Z., & Liu, C. (2021). Chronic exposure to organic oxygen-demanding pollutants at an environmentally realistic concentration affects sperm motility in zebrafish. Environmental toxicology and pharmacology, 81, 103523. https://doi.org/10.1016/j.etap.2020.103523

Tang, H., Chen, Y., Wang, L., Yin, Y., Li, G., Guo, Y., Liu, Y., Lin, H., Cheng, C., & Liu, X. (2018). Fertility impairment with defective spermatogenesis and steroidogenesis in male zebrafish lacking androgen receptor. Biology of reproduction, 98(2), 227–238. https://doi.org/10.1093/biolre/iox165

Uhrin, P., Dewerchin, M., Hilpert, M., Chrenek, P., Schöfer, C., Zechmeister-Machhart, M., Krönke, G., Vales, A., Carmeliet, P., Binder, B. R., & Geiger, M. (2000). Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility. The Journal of clinical investigation, 106(12), 1531–1539. https://doi.org/10.1172/JCI10768

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.

Wang, H., Zhao, R., Guo, C., Jiang, S., Yang, J., Xu, Y., Liu, Y., Fan, L., Xiong, W., Ma, J., Peng, S., Zeng, Z., Zhou, Y., Li, X., Li, Z., Li, X., Schmitt, D. C., Tan, M., Li, G., & Zhou, M. (2016). Knockout of BRD7 results in impaired spermatogenesis and male infertility. Scientific reports, 6, 21776. https://doi.org/10.1038/srep21776

Wu, H., Sun, L., Wen, Y., Liu, Y., Yu, J., Mao, F., Wang, Y., Tong, C., Guo, X., Hu, Z., Sha, J., Liu, M., & Xia, L. (2016). Major spliceosome defects cause male infertility and are associated with nonobstructive azoospermia in humans. Proceedings of the National Academy of Sciences of the United States of America, 113(15), 4134–4139. https://doi.org/10.1073/pnas.1513682113

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 Reduces Fertility in Zebrafish. Genetics, 208(2), 729–743. https://doi.org/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

Xu, K., Wen, M., Duan, W., Ren, L., Hu, F., Xiao, J., Wang, J., Tao, M., Zhang, C., Wang, J., Zhou, Y., Zhang, Y., Liu, Y., & Liu, S. (2015). Comparative analysis of testis transcriptomes from triploid and fertile diploid cyprinid fish. Biology of reproduction, 92(4), 95. https://doi.org/10.1095/biolreprod.114.125609

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.

Yu, G., Zhang, D., Liu, W., Wang, J., Liu, X., Zhou, C., Gui, J., & Xiao, W. (2018). Zebrafish androgen receptor is required for spermatogenesis and maintenance of ovarian function. Oncotarget, 9(36), 24320–24334. https://doi.org/10.18632/oncotarget.24407 Zhang, Z., Lau, S. W., Zhang, L., & Ge, W. (2015). Disruption of Zebrafish Follicle-Stimulating Hormone Receptor (fshr) But Not Luteinizing Hormone Receptor (lhcgr) Gene by TALEN Leads to Failed Follicle Activation in Females Followed by Sexual Reversal to Males. Endocrinology, 156(10), 3747–3762. https://doi.org/10.1210/en.2015-1039