This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2076

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decreased, 11KT leads to Impaired, Spermatogenesis

Upstream event

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

Decreased, 11KT

Downstream event

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

Impaired, Spermatogenesis

Key Event Relationship Overview

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

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
PPARalpha Agonism Leading to Decreased Viable Offspring via Decreased 11-Ketotestosterone	adjacent	High	Low	Jennifer Olker (send email)	Open for citation & comment
Inhibition of 11β-Hydroxysteroid Dehydrogenase leading to decreased population trajectory	adjacent	High	Moderate	Young Jun Kim (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
teleost fish	teleost fish	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	High

Life Stage Applicability

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

Term	Evidence
Adult, reproductively mature	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Androgens are critical for maintaining the normal male reproductive system (Tang, H., et al. 2018). Of these androgens, 11-KT has been identified as the most important in teleost fish (Borg, B. 1994). 11-KT is produced by the cyp11c1 encoded enzyme, 11ß-hydroxylase (Zheng, et al. 2020). 11-KT has been shown to bind to the androgen receptor with similar affinity as testosterone in zebrafish (Jorgensen, et al. 2007). It is well documented that 11-KT is involved in spermatogenesis, spermiation, male secondary sexual characteristics, and breeding behaviors (Geraudie, P. et al. 2010; Amer, M.A. et al. 2001). 11-KT is needed for the inducement of spermatogenesis and sperm production in teleost fish, with 10 ng/ml 11-KT being sufficient to induce full spermatogenesis in the Japanese eel (Miura, C. and T. Miura 2011). The mechanism through which 11-KT induces spermatogenesis is believed to be via activation of Sertoli cells and activin B (Miura et al. 2011; Miura et al. 2001; Sales, C.F., et al. 2020; Cavaco J.E.B., et al. 1998). 11-KT is not responsible for the acquisition of sperm motility in salmonids (Miura, et al. 1992).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Table 2. Effect of either 11-ketotestosterone (11-KT) treatment or increased testicular production/plasma concentrations of 11-KT on spermatogenesis.

Species	Experimental design	11-KT treatment or response	Spermatogenesis effect	11-KT (+) ¹	Spermatogenesis (+) ¹	Citation
Senegalese sole (Solea senegalensis)	Treated with saline (control) or with 50 μg/kg GnRHa, with or without another implant containing 2 or 7 mg/kg 11-ketoandrostenedione for 28 days	Fish treated with GnRHa + OA saw increased 11-KT levels compared to control and GnRHa alone	Fish treated with GnRHa + OA saw lower number of spermatogonia and spermatocytes and a higher number of spermatids than those of GnRHa or control	Yes	Yes	Agulleiro, M.J., et al. 2007
Japanese huchen (Hucho perryi)	Incubated immature testis fragments	10 ng/ml for 15 days	BrdU (proliferation marker) index reached 34.5% ± 1.7%; percentage of late type B spermatogonia reached about 7.5% compared to 0% in control	Yes	Yes	Amer, M.A. et al. 2001
African catfish (Clarias gariepinus)	Juvenile male catfish implanted with pellets containing 30 μg/g body weight of 11-KT	30 μg/g body weight of 11-KT; plasma 11-KT levels reached 8.3 ± 0.6 ng/ml after 2 weeks	GSI increased compared to control; testicular stage 1 (contain spermatogonia only) and 2 (contain spermatogonia and spermatocytes) increased from about 90% stage 1 and 10% stage 2 in end control to about 25% stage 1 and 75% stage 2	Yes	Yes	Cavaco, J.E.B. et al. 2001
African catfish (Clarias gariepinus)	Male catfish at beginning of spermatogenesis implanted with pellets containing 30 μg/g body weight of 11-KT	Plasma 11-KT levels reached 6.1 ± 0.8 ng/ml after 2 weeks	Testicular stages changed from about 65% stage 1 and 35% stage 2 in the end control to about 65% stage 2 and 35% stage 3 (contain spermatogonia, spermatocytes and spermatids)	Yes	Yes	Cavaco J.E.B., et al. 1998
	Male catfish at beginning of spermatogenesis implanted with pellets containing 30 μg/g body weight of 11β-hydroxyandrostenedione	Plasma 11-KT levels reached 7.3 ± 0.7 ng/ml after 2 weeks	Testicular stages changed from about 65% stage 1 and 35% stage 2 in the end control to about 55% stage 2 and 40% stage 3	Yes	Yes
	Male catfish at beginning of spermatogenesis implanted with pellets containing 30 μg/g body weight of androstenetrione	Plasma 11-KT levels reached 2.4 ± 0.3 ng/ml after 2 weeks	Testicular stages changed from about 65% stage 1 and 35% stage 2 in the end control to about 50% stage 2 and 50% stage 3	Yes	Yes
Atlantic salmon (Salmo salar)	Immature fish injected with 25 μg adrenosterone/g of body weight	After 7 and 14 days, 11-KT plasma levels significantly increased compared to control (7 days post-treatment were higher)	5-fold higher number of type A differentiated spermatogonia than control fish after 14 days (7-day samples lost - no data)	Yes	Yes	Melo, M.C. et al. 2015
Japanese eel (Anguilla japonica)	Immature testes were removed and cultured in medium with varying levels of 11-KT	0.01 ng/ml 11-KT for 15 days	No effect	Yes	No	Miura, T., et al. 1991
		0.1 ng/ml 11-KT for 15 days	No effect	Yes	No
		1 ng/ml 11-KT for 15 days	No effect	Yes	No
		10 ng/ml 11-KT for 15 days	Mitosis occurred in 50-60% of cysts (as effective as 100 ng/ml 11-KT treatment)	Yes	Yes
		100 ng/ml 11-KT for 15 days	Mitosis occurred in 50-60% of cysts (as effective as 10 ng/ml 11-KT treatment)	Yes	Yes
Japanese eel (Anguilla japonica)	Immature testis fragments cultured in media with 11-KT for up to 36 days	10 ng/ml of 11-KT for 9 days	Began mitotic division; produced late-type B spermatogonia	Yes	Yes	Miura, T., et al. 1991
		10 ng/ml of 11-KT for 18 days	Produced zygotene spermatocytes from meiotic prophase	Yes	Yes
		10 ng/ml of 11-KT for 21 days	Spermatids and spermatozoa observed	Yes	Yes
		10 ng/ml of 11-KT for 36 days	All stages of germ cells present	Yes	Yes
Chub mackerel (Scomber japonicus)	Peptide mix containing synthetic peptides corresponding to chub mackerel Kiss1-15 at a final concentration of 250 ng/g fish were injected 3 times at 2-week interval (immature adult)	Treated fish showed significantly higher 11-KT levels	Significantly higher levels of spermatids and spermatozoa	Yes	Yes	Selvaraj, S., et al. 2013
Japanese eel (Anguilla japonica)	Testicular fragment treated with 0.01 ng/ml cortisol	No significant change in 11-KT production compared to control	Nonsignificant increase in BrdU Index compared to control	No	No	Ozaki, Y., et al. 2006
	Testicular fragment treated with 0.1 ng/ml cortisol	No significant change in 11-KT production compared to control	Significant increase in BrdU Index compared to control	No	Yes
	Testicular fragment t treated with 1 ng/ml cortisol	Nonsignificant, slight increase in 11-KT production compared to control	Significant increase in BrdU Index compared to control	No	Yes
	Testicular fragment treated with 10 ng/ml cortisol	Nonsignificant increase in 11-KT production compared to control	Significant increase in BrdU Index compared to control	No	Yes
	Testicular fragment treated with 100 ng/ml cortisol	Significant increase in 11-KT production compared to control	Significant increase in BrdU Index compared to control	Yes	Yes
Zebrafish (Danio rerio)	cyp11c1 knockout rescue via 11-ketoandrostenedione (11-KA) treatment	100 nM 11-KA for 4 hours per day for 10 days	Promoted the juvenile ovary-to-testis transition; genes associated with Leydig cell development/function restored; increased sperm volume	Yes	Yes	Zhang, Q., et al. 2020

¹ (+) represents an effect on the key event has been established.

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

It is well known that 11-KT is a critical androgen for proper male reproduction in teleost fish. The males' primary reproductive role is to fertilize the oocytes.

Seasonal changes in 11-KT are correlated with cyclic spermatogenesis events in teleosts (Basak, R., et al. 2016). In many teleost fish, 11-KT levels peak at spawning (see Table 1 below).

11-KT is proposed to induce spermatogenesis via the activation of Sertoli cells, which in turn regulates factors including activin B (Miura et al. 2011; Miura et al. 2001). Activin B stimulates spermatogonial proliferation (Sales, C.F., et al. 2020; Cavaco J.E.B., et al. 1998).

Zhang et al. (2020) showed that zebrafish with cyp11c1 knockout have reduced 11-KT levels, smaller genitalia, inability naturally mate, defective Leydig and Sertoli cells, and insufficient spermatogenesis. This is corrected by treatment of 100 nM 11-KA (which is converted to 11-KT in vivo) for 4 hours per day for 10 days. This shows that spermatogenesis was arrested due to insufficient 11-KT levels.

Table 1. Plasma concentrations of 11-KT peak during spawning and decline shortly after in a variety of species.

Species	Scientific name	Reproductive strategy¹	Citation
Japanese huchen	Hucho perryi	Single	Amer et al., 2001
Bester	Huso huso L. female x Acipenser ruthenus L. male	Single	Amiri et al., 1996
Spotted snakehead	Channa punctatus	Multiple	Basak et al., 2016
Chanchita	Cichlasoma dimerus	Multiple	Birba et al., 2015
Largemouth bass	Micropterus salmoides salmoides	Multiple	Brown et al., 2019
Chinook salmon	Oncorhynchus tshawytscha	Single	Campbell et al., 2003
Gilthead seabream	Sparus aurata L.	Multiple	Chaves-Pozo et al., 2008
Mummichog	Fundulus heteroclitus	Multiple	Cochran, 1987
Eastern Mosquitofish	Gambusia holbrooki	Multiple	Edwards et al., 2013
Rainbow trout	Salmo gairdneri	Single	Fostier et al., 1984
Senegalese sole	Solea senegalensis	Multiple	García-López et al., 2006
Roach	Rutilus rutilus	Multiple	Geraudine et al., 2010
Sterlet	Acipenser ruthenus	Single	Golpour et al., 2017
Sablefish	Anoplopoma fimbria	Multiple	Guzmán et al., 2018
Brook trout	Salvelinus fontinalis	Single	de Montgolfier et al., 2009
Brill	Scophthalmus rhombus L.	Multiple	Hachero-Cruzado et al., 2012
Three-spined stickleback	Gasterosteus aculeatus	Multiple	Hellqvist et al., 2006
Red-spotted grouper	Epinephelus akaara	Multiple	Li et al., 2007
Japanese dace	Tribolodon hakonesis	Multiple	Ma et al., 2005
Walleye	Stizostedion vitreum	Single	Malison et al., 1994
Florida gar	Lepisosteus platyrhincus	Multiple	Orlando et al., 2003
Chum Salmon	Oncorhynchus keta	Single	Onuma et al., 2009
Hornyhead Turbot	Pleuronichthys verticalis	Multiple	Reyes et al., 2012
Golden mahseer	Tor putitora	Multiple	Shahi et al., 2015
Plainfin midshipman	Porichthys notatus	Single	Sisneros et al., 2004
Amago salmon	Oncorhynchus rhodurus	Single	Ueda et al., 1983; Sakai et al., 1989
Atlantic halibut	Hippoglossus hippoglossus L.	Multiple	Weltzien et al., 200

  ¹ Defined as single spawning species (spawn once/year) or multiple spawning species (spawn multiple clutches of eggs per reproductive period).

Empirical Evidence

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

In African catfish, 11-ketotestosterone, but not testosterone, stimulated spermatogenesis (Cavaco et al., 2001)

Juvenile atlantic salmon injected with adrenosterone, which is converted to 11KT, show increased 11KT in their plasma and increased differentiation of spermatogonia (Melo et al., 2015)

Nile tilapia lacking cyp11c1 show dramatically reduced 11KT levels and delayed spermatogenesis. Spermatogenesis is rescued by 11KT supplementation. Without 11KT supplementation, spermatogenesis occurred later with fewer viable sperm (Zheng et al., 2020)

Injection of female honeycomb grouper, a protogynous hermaphroditic fish, with 11KT induces a female-to-male sex change and stimulates spermatogenesis (Bhandari et al., 2006)

In nile tilapia the absence of functional eukaryotic elongation factor 1 alpha (eEF1A) causes infertility and arrest of spermatogenesis. Heterozygous mutation causes significantly reduced 11KT and abnormal spermiogenesis (Chen et al., 2017)

Dose concordance

Increases in 11-KT levels correspond with increases in spermatogenesis in multiple studies (see Table 2 above). Melo et al. (2015) showed that treatment of adrenosterone - or OA - (which is converted to 11-KT in vivo) increases 11-KT levels, and this sustained increase induces spermatogonial differentiation.

Decreases in 11-KT levels correspond with decreases in spermatogenesis in multiple studies (see Table 3 above). Liu, Z.H., et al. (2018) showed that exposure to 10 ng/L DES for 28 days significantly decreases 11-KT levels and disrupts spermatogenesis. Additionally, exposure to 100 ng/L DES for 28 days has further negative effects on 11-KT levels and spermatogenesis.

Temporal concordance

11-KT peaks at spawning in a number of teleost fish (see Table 1 above).

Melo et a. (2015) showed treatment with adrenosterone (OA) caused an increase in 11-KT levels, which sustained through 7 days after treatment and (to a lesser extent) 14 days after treatment. Type A differentiated spermatogonial numbers also increased 14 days after treatment. There was no spermatogenesis data for 7 days after treatment, due to the samples being lost.

A study by de Waal et al. (2009) showed treatment with 10 nM E2 for 6 and 21 days resulted in decreased 11-KT levels and decreased spermatogonial proliferation. The 21 day treatment saw more spermatogonial arrest than the 6 day treatment.

Table 3. Effect of either decreased plasma concentration or testicular production of 11-ketotestosterone (11-KT) on spermatogenesis.

Species	Experimental design	11-KT treatment or response	Spermatogenesis effect	11-KT (─) ¹	Spermatogenesis (─) ¹	Citation
Guinean tilapia (Tilapia guineensis)	Fish from multiple sites contaminated with pesticides were studied	Levels significantly lower in contaminated sites	Amounts of spermatids and spermatozoa were decreased in contaminated sites	Yes	Yes	Agbohessi, P.T., et al. 2015
African catfish (Clarias gariepinus)		Levels significantly lower in contaminated sites; larger change than in Guinean tilapia	Amounts of spermatozoa were decreased in contaminated sites	Yes	Yes	Agbohessi, P.T., et al. 2015
Nile tilapia (Oreochromis niloticus)	Heterozygous mutation of eEF1A1b (eEF1A1b^+/−) via CRISPR/Cas9	Significantly decreased serum 11-KT at 90 and 180 days after hatch (dah)	Absence of spermatocytes at 90 dah, and decreased number of spermatocytes, spermatids and spermatozoa at 180 dah	Yes	Yes	Chen, J. et al. 2017
Zebrafish (Danio rerio)	Adult fish exposed to 10 nM 17β-estradiol (E2) via water for 6 days	Significantly decreased ex vivo testicular production; 6 day exposure to 10 nM E2	Type B spermatogonia, primary spermatocytes, and secondary spermatocytes decreased to 54-60% of control levels	Yes	Yes	de Waal et al. 2009
Zebrafish (Danio rerio)	Adult fish exposed to 10 nM E2 via water for 21 days	Significantly decreased ex vivo testicular production; 6 day exposure to 10 nM E2	Type B spermatogonia, primary and secondary spermatocytes, and spermatids significantly decreased further (e.g, spermatids to 19% of control)	Yes	Yes	de Waal et al. 2009
Goldfish (Carassius auratus)	Mature fish exposed for 30 days to 100 μg/L anti-androgen vinclozolin (VZ) water	Increase in 11-KT level (compared to control)	Nonsignificant decrease (compared to control) in sperm volume, motility, and velocity	No	No	Hatef, A. et al. 2012
	Mature fish exposed for 30 days to 400 μg/L anti-androgen vinclozolin (VZ) water	No significant change in 11-KT level (compared to control)	Nonsignificant decrease (compared to control) in sperm volume, motility and velocity; spermatozoa without flagella or with damaged flagella were observed	No	Yes
	Mature fish exposed for 30 days to 800 μg/L anti-androgen vinclozolin (VZ) water	Decrease in 11-KT level (compared to control); similar level to E2 negative control	Significant decrease (compared to control) in sperm volume, motility, and velocity; spermatozoa without flagella or with damaged flagella were observed	Yes	Yes
Yellow catfish (Pelteobagrus fulvidraco)	Juvenile fish exposed to 10 ng/L DES for 28 days via water	Plasma levels lightly (but significantly) decreased compared to control	Loss of spermatids; presence of several lacunas	Yes	Yes	Liu, Z.H., et al. 2018
Yellow catfish (Pelteobagrus fulvidraco)	Juvenile fish exposed to 100 ng/L DES for 28 days via water	Plasma levels lightly (but significantly) decreased compared to control	Loss of spermatids; more lacunae than 10 ng/L exposure	Yes	Yes	Liu, Z.H., et al. 2018
Nile tilapia (Oreochromis niloticus)	Sexually mature males exposed via water to 200 ng/L diuron for 25 days	No significant change compared to control	No change to seminiferous tubules, and no change to spermatid or spermatozoa numbers	No	No	Pereira, T.S., et al. 2015
	Sexually mature males exposed to 200 ng/L DCA (diuron metabolite) for 25 days	Significant decrease of 11% compared to control	Seminiferous tubules reduced about 60% and spermatid and spermatozoa amounts decreased by about 10% compared to control	Yes	Yes
	Sexually mature males exposed to 200 ng/L DCPU (diuron metabolite) for 25 days	Significant decrease of 11% compared to control	Seminiferous tubules reduced about 60% and spermatid and spermatozoa amounts decreased by about 10% compared to control	Yes	Yes
	Sexually mature males exposed to 200 ng/L DCPMU (diuron metabolite) for 25 days	Significant decrease of 11% compared to control	Seminiferous tubules reduced about 60% and spermatid and spermatozoa amounts decreased by about 10% compared to control	Yes	Yes
Nile tilapia (Oreochromis niloticus)	Adult males; starvation for 7 days	Significant reduction in plasma 11-KTcompared to control	Significant decrease in number of spermatocytes and spermatozoa	Yes	Yes	Sales, C.F., et al. 2020
	Adult males; starvation for 14 days	Significant reduction in plasma 11-KT compared to control	Significant decrease in number of spermatocytes and spermatozoa	Yes	Yes
	Adult males; starvation for 21 days	Significant reduction in plasma 11-KT compared to control	Significant decrease in number of spermatocytes and spermatozoa; significant decrease type A undifferentiated and differentiated spermatogonia	Yes	Yes
	Adult males; starvation for 28 days	Significant reduction in plasma 11-KT compared to other starvation durations	Significant decrease in number of spermatocytes and spermatozoa; significant decrease type A undifferentiated and differentiated spermatogonia	Yes	Yes
Zebrafish (Danio rerio)	Androgen receptor (ar) knockout	Significantly decreased in adult whole-body homogenate	Significant decrease in number of germ cells, most of which were stopped at early stages of development; some spermatozoon found	Yes	Yes	Tang, H., et al. 2018
Zebrafish (Danio rerio)	Bezafibrate (BZF) administered orally to adult males at 1.7 mg BZF/g food for 21 days	Non-significant decrease compared to control	Did not report results	No	n/a	Velasco-Santamaría, Y.M., et al. 2011
	Bezafibrate (BZF) administered orally to adult males at 33 mg BZF/g food for 21 days	Non-significant decrease compared to control	Did not report results	No	n/a
	Bezafibrate (BZF) administered orally to adult males at 70 mg BZF/g food for 21 days	Significant decrease compared to control	Testicular degeneration; increased syncytia and spermatocytes	Yes	Yes
Zebrafish (Danio rerio)	Adult males exposed for 30 days to 100 ng/L DES (estrogen) via water	Plasma levels decreased 3-fold	Adverse effect on testicular development and spermatogenesis; sperm concentration decreased 3-fold	Yes	Yes	Yin, P. et al. 2017
	Adult males exposed for 30 days to 300 μg/L FLU (anti-androgen)	Plasma levels decreased 2-fold	Adverse effect on testicular development and spermatogenesis; sperm concentration decreased 3-fold	Yes	Yes
	Adult males exposed for 30 days to combo of 100 ng/L DES and 300 μg/L FLU	Plasma levels decreased 6-fold	Adverse effect on testicular development and spermatogenesis; sperm concentration decreased 4-fold	Yes	Yes
Zebrafish (Danio rerio)	Mettl3 mutation	Serum concentration significantly decreased	Little or no mature sperm; 24.4% spermatogonia, 56.1% spermatocytes, and 10.4% spermatozoa (compared to 7.5%, 26.7%, and 50.1% in wild type)	Yes	Yes	Xia, H. et al. 2018
Zebrafish (Danio rerio)	cyp11c1 knockout via CRISPR/Cas9 (homozygous mutation)	Significantly decreased levels	Insufficient spermatogenesis, but not completely blocked; sperm volume significantly decreased	Yes	Yes	Zhang, Q., et al. 2020

¹ (─) represents an effect on the key event has been established.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

In a study by Hatef, A. et al. (2012), treatment with the anti-androgen vinclozolin at 100 μg/L saw an increase in 11-KT levels with no significant change to spermatogenesis. This is consistent with other studies provided. Additionally, treatment at 400 μg/L saw no significant change in 11-KT levels with a decrease in spermatogenesis (although this decrease may not be statistically significant). The reason for these increases in 11-KT remains unknown; however, it is hypothesized that it is due to competitive androgen receptor binding.

Ozaki et al. (2006) showed that treatment with 100 ng/ml of cortisol significantly increased 11-KT levels. However, the less concentrated doses only saw non-significant increases in 11-KT with significant increases in spermatogenesis observed in all but the lowest dose. Despite this, Ozaki et al. make the generalization that cortisol treatment increased 11-KT and, in turn, spermatogenesis.

The study by Runnalls et al. (2007) saw treatment with Clofibric acid caused no significant changes to 11-KT levels, but that the levels did appear lower. Additionally, these treatments saw no significant effect on sperm number, but did see a significant increase in the number of non-viable sperm.

In a study by Zhang, Q., et al. (2020), cyp11c1 knockout did not completely block spermatogenesis. Zhang et al. explain this could be due to other androgens (11β-hydroxyandrostenedione and testosterone) compensating for the reduction in 11-KT, as they can both bind to the androgen receptor to influence downstream signaling.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

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

Response-response Relationship

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

Decreases in 11-KT levels were also seen with decreases in spermatogenesis in several studies (see table above).

10 ng/ml of 11-KT has been shown to be needed to induce full spermatogenesis in Japanese eel (Amer, M.A. et al. 2001; Miura, C. et al. 2011).

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic:

11-KT is the main androgen in teleost fish (Borg, B. 1994).

Sex Applicability:

11-KT is present in both male and female fish; however, spermatogenesis is a male-specific process.

Life Stage Applicability:

Spermatogenesis is observable in male fish that have reached the reproductive stage.

References

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

Agbohessi, P.T., Imorou Toko I., Ouédraogo, A., Jauniaux, T., Mandiki, S.N., & Kestemont, P. (2014). Assessment of the health status of wild fish inhabiting a cotton basin heavily impacted by pesticides in Benin (West Africa). Science of the Total Environment, 506-507, 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 Physiology, 147(4), 885-92. https://doi.org/10.1016/j.cbpa.2007.02.008

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

Amiri, B.M., Maebayashi, M., Adachi, S., & Yamauchi, K. (1996). Testicular development and serum sex steroid profiles during the annual sexual cycle of the male sturgeon hybrid the bester. Journal of Fish Biology, 48(6), 1039-1050. https://doi.org/10.1111/j.1095-8649.1996.tb01802.x

Aoki, K.A., Harris, C.A., Katsiadaki, I., & Sumpter, J.P. (2011). Evidence suggesting that di-n-butyl phthalate has antiandrogenic effects in fish. Environmental Toxicology and Chemistry, 30(6), 1338-1345. https://doi.org/10.1002/etc.502

Baatrup, E. & Junge, M. (2001). Antiandrogenic pesticides disrupt sexual characteristics in the adult male guppy Poecilia reticulata. Environmental Health Perspectives, 109(10), 1063-70. DOI: 10.1289/ehp.011091063

Basak, R., Roy, A. & Rai, U. (2016). Seasonality of reproduction in male spotted murrel Channa punctatus: correlation of environmental variables and plasma sex steroids with histological changes in testis. Fish Physiology and Biochemistry, 42(5), 1249-1258. https://doi.org/10.1007/s10695-016-0214-6

Berglund, I., Antonopoulou, E., Mayer, I., & Borg, B. (1995). Stimulatory and inhibitory effects of testosterone on testes in Atlantic salmon male parr. Journal of Fish Biology, 47(4), 586-598. https://doi.org/10.1111/j.1095-8649.1995.tb01925.x

Bhandari, R.K., Alam, M.A., Soyano, K., & Nakamura, M. (2006). Induction of female-to-male sex change in the honeycomb grouper (Epinephelus merra) by 11-ketotestosterone treatments. Zoological Science, 23(1), 65-69. https://doi.org/10.2108/zsj.23.65

Birba, A., Ramallo, M.R., Nostro, F.L., Moreira, R.G., & Pandolfi, M. (2015). Reproductive and parental care physiology of Cichlasoma dimerus males. General and Comparative Endocrinology, 15, 193-200. https://doi.org/10.1016/j.ygcen.2015.02.004

Borg, B. (1994). Androgens in teleost fishes. Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology, and Endocrinology, 109(3), 219-245. https://doi.org/10.1016/0742-8413(94)00063-G

Brown, M.L., Kasiga, T., Spengler, D.E., & Clapper, J.A. (2019). Reproductive cycle of northern largemouth bass Micropterus salmoides salmoides. Journal of Experimental Zoology Part A: Ecological and Integrative Physiology, 331(10), 540-551. https://doi.org/10.1002/jez.2323

Campbell, B., Dickey, J.T., & Swanson, P. (2003). Endocrine changes during onset of puberty in male spring Chinook salmon, Oncorhynchus tshawytscha. Biology of Reproduction, 69(6), 2109-2117. https://doi.org/10.1095/biolreprod.103.020560

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 Reproduction, 65(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 Physiology, 275(6), 1793-1802. https://doi.org/10.1152/ajpregu.1998.275.6.R1793

Chauvigné, F., Parhi, J., Ollé, J., & Cerdà, J. (2017). Dual estrogenic regulation of the nuclear progestin receptor and spermatogonial renewal during gilthead seabream (Sparus aurata) spermatogenesis. Comparative Biochemistry and Physiology Part A: Molecular and Integrative Physiology, 206, 36-46. https://doi.org/10.1016/j.cbpa.2017.01.008

Chaves-Pozo, E., Arjona, F.J., García-López, A., García-Alcázar, A., Meseguer, J., & García-Ayala A. (2008). Sex steroids and metabolic parameter levels in a seasonal breeding fish (Sparus aurata L.). General and Comparative Endocrinology, 156(3), 531-536. https://doi.org/10.1016/j.ygcen.2008.03.004

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

Cochran, R.C. (1987). Serum androgens during the annual reproductive cycle of the male mummichog, Fundulus heteroclitus. General and Comparative Endocrinology, 65(1), 141-148. https://doi.org/10.1016/0016-6480(87)90233-4

de Montgolfier, B., Faye, A., Audet, C., & Cyr, D.G. (2009). Seasonal variations in testicular connexin levels and their regulation in the brook trout, Salvelinus fontinalis. General and Comparative Endocrinology, 162(3), 276-285. https://doi.org/10.1016/j.ygcen.2009.03.025

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 Endocrinology, 202(2), 287-97. https://doi.org/10.1677/JOE-09-0050

Delvin, R.H. & Nagahama, Y. (2002). Sex determination and sex differentiation in fish: an overview of genetic, physiological, and environmental influences. Aquaculture, 208(3-4), 191-364. https://doi.org/10.1016/S0044-8486(02)00057-1

Edwards, T.M., Miller, H.D., Toft, G., & Guillette, L.J. Jr. (2013). Seasonal reproduction of male Gambusia holbrooki (eastern mosquitofish) from two Florida lakes. Fish Physiology and Biochemistry, 39(5), 1165-1180. https://doi.org/10.1007/s10695-013-9772-z

Fostier, A., Billard, R., & Breton, B. (1984). Plasma 11-oxotestosterone and gonadotrophin in relation to the arrest of spermiation in rainbow trout (Salmo gairdneri). General and Comparative Endocrinology, 54(3), 378–381. DOI: 10.1016/0016-6480(84)90150-3

Fostier, A., Billard, R., & Breton, B. (1984). Plasma 11-oxotestosterone and gonadotrophin in relation to the arrest of spermiation in rainbow trout (Salmo gairdneri). General and Comparative Endocrinology, 54(3), 378-381. DOI: 10.1016/0016-6480(84)90150-3

García-López, A., Fernández-Pasquier, V., Couto, E., Canario, A.V., Sarasquete, C., & Martínez-Rodríguez, G. (2006). Testicular development and plasma sex steroid levels in cultured male Senegalese sole Solea senegalensis Kaup. General and Comparative Endocrinology, 147(3), 343-351. https://doi.org/10.1016/j.ygcen.2006.02.003

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 Research, 69(S1), S53-S55. https://doi.org/10.1016/j.marenvres.2009.11.008

Golpour, A., Broquard, C., Milla, S., Dadras, H., Baloch, A.R., Saito, T., & Pšenička, M. (2017). Gonad histology and serum 11-KT profile during the annual reproductive cycle in sterlet sturgeon adult males, Acipenser ruthenus. Reproduction in Domestic Animals, 52(2), 319-326. https://doi.org/10.1111/rda.12911

Golshan, M. & Alavi, S.M.H. (2019). Androgen signaling in male fishes: Examples of anti-androgenic chemicals that cause reproductive disorders. Theriogenology, 139, 58-71. https://doi.org/10.1016/j.theriogenology.2019.07.020

Golshan, M. & Alvai S.M.H. (2019). Androgen signaling in male fishes: Examples of anti-androgenic chemicals that cause reproductive disorders. Theriogenology, 139, 58-71. https://doi.org/10.1016/j.theriogenology.2019.07.020

Guzmán, J.M., Luckenbach, J.A., da Silva, D.A.M., Hayman, E.S., Ylitalo, G.M., Goetz, F.W., & Swanson, P. (2018). Seasonal variation of pituitary gonadotropin subunit, brain-type aromatase and sex steroid receptor mRNAs, and plasma steroids during gametogenesis in wild sablefish. Comparative Biochemistry and Physiology Part A: Molecular Integrated Physiology, 219-220, 48-57. https://doi.org/10.1016/j.cbpa.2018.02.010.

Hachero-Cruzado, I., Forniés, A., Herrera, M., Mancera, J.M., & Martínez-Rodríguez, G. (2012). Sperm production and quality in Brill scophthalmus rhombus L.: Relation to circulating sex steroid levels. Fish Physiology and Biochemistry, 39(2), 215-220. https://doi.org/10.1007/s10695-012-9692-3

Hatef, A., Alavi, S.M.H., Milla, S., Křišťan, J., Golshan, M., Fontaine, P., & Linhart, O. (2012). Anti-androgen vinclozolin impairs sperm quality and steroidogenesis in goldfish. Aquatic Toxicology, 122-123, 181-187. https://doi.org/10.1016/j.aquatox.2012.06.009.

Hellqvist, A., Schmitz, M., Mayer, I., & Borg, B. (2006). Seasonal changes in expression of LH-beta and FSH-beta in male and female three-spined stickleback, Gasterosteus aculeatus. General and Comparative Endocrinology, 145(3), 263-269. https://doi.org/10.1016/j.ygcen.2005.09.012

Idler, D.R., Bitners, I.I., & Schmidt, P.J. (1961). 11-KETOTESTOSTERONE: AN ANDROGEN FOR SOCKEYE SALMON. Canadian Journal of Biochemistry and Physiology, 39(11), 1737-1742. https://doi.org/10.1139/o61-191

Jensen, K.M., Kahl, M.D., Makynen, E.A., Korte, J.J., Leino, R.L., Butterworth, B.C., & Ankley, G.T. (2004). Characterization of responses to the antiandrogen flutamide in a short-term reproduction assay with the fathead minnow. Aquatic Toxicology, 70(2), 99-110. https://doi.org/10.1016/j.aquatox.2004.06.012

Jørgensen, A., Andersen, O., Bjerregaard, P., & Rasmussen, L.J. (2007). Identification and characterization of an androgen receptor from zebrafish Danio rerio. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 146(4), 561-568. https://doi.org/10.1016/j.cbpc.2007.07.002

Kobayashi, Y., Nozu, R., & Nakamura, M. (2011). Role of estrogen in spermatogenesis in initial phase males of the three-spot wrasse (Halichoeres trimaculatus): effect of aromatase inhibitor on the testis. Developmental Dynamics, 240(1), 116-121. https://doi.org/10.1002/dvdy.22507

Li, G.L., Liu, X.C., & Lin, H.R. (2007). Seasonal changes of serum sex steroids concentration and aromatase activity of gonad and brain in red-spotted grouper (Epinephelus akaara). Animal Reproduction Science, 99(1-2), 156-166. https://doi.org/10.1016/j.anireprosci.2006.05.015

Li, M., Liu, X., Dai, S., Xiao, H., Qi, S., Li, Y., Zheng, Q., Jie, M., Cheng, C.H.K., & Wang, D. (2020). Regulation of spermatogenesis and reproductive capacity by Igf3 in tilapia. Cellular and Molecular Life Sciences, 77(23), 4921-4938. https://doi.org/10.1007/s00018-019-03439-0

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 Biochemistry, 44(3), 789-803. https://doi.org/10.1007/s10695-018-0469-1

Ma, Y.X., Matsuda, K. & Uchiyama, M. (2005). Seasonal variations in plasma concentrations of sex steroid hormones and vitellogenin in wild male Japanese dace (Triboldon hakonesis) collected from different sites of the Jinzu river basin. Zoological Science, 22(8), 861-868. https://doi.org/10.2108/zsj.22.861

Malison, J.A., Procarione, L.S., Barry, T.P., Kapuscinski, A.R., & Kayes, T.B. (1994). Endocrine and gonadal changes during the annual reproductive cycle of the freshwater teleost,Stizostedion vitreum. Fish Physiology and Biochemistry, 13(6), 473-484. DOI: 10.1007/BF00004330

Manire, C.A., Rasmussen, L.E., & Gross, T.S. (1999). Serum steroid hormones including 11-ketotestosterone, 11-ketoandrostenedione, and dihydroprogesterone in juvenile and adult bonnethead sharks, Sphyrna tiburo. Journal of Experimental Zoology, 284(5), 595-603. https://doi.org/10.1002/(SICI)1097-010X(19991001)284:5<595::AID-JEZ15>3.0.CO;2-6

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.

Miura, C. & Miura, T. (2011). Analysis of spermatogenesis using an eel model. Aqua-BioScience Monographs, 4(4), 105-129. doi:10.5047/absm.2011.00404.0105

Miura, C., Kuwahara, R., & Miura, T. (2007). Transfer of spermatogenesis-related cDNAs into eel testis germ-somatic cell coculture pellets by electroporation: methods for analysis of gene function. Molecular Reproduction and Development, 74(4), 420-427. https://doi.org/10.1002/mrd.20653

Miura, C., Takahashi, N., Michino, F., & Miura, T. (2005). The effect of para-nonylphenol on Japanese eel (Anguilla japonica) spermatogenesis in vitro. Aquatic Toxicology, 71(2), 133-141. https://doi.org/10.1016/j.aquatox.2004.10.015

Miura, S., Horiguchi, R., & Nakamura, M. (2008). Immunohistochemical evidence for 11beta-hydroxylase (P45011beta) and androgen production in the gonad during sex differentiation and in adults in the protandrous anemonefish Amphiprion clarkii. Zoological Science, 25(2), 212-219. https://doi.org/10.2108/zsj.25.212

Miura, T. & Miura, C. (2001). Japanese Eel: A Model for Analysis of Spermatogenesis. Zoological Science, 18(8), 1055-1063. https://doi.org/10.2108/zsj.18.1055

Miura, T., Ando, N., Miura, C., & Yamauchi, K. (2002). Comparative studies between in vivo and in vitro spermatogenesis of Japanese eel (Anguilla japonica). Zoological Science, 19(3), 321-329. https://doi.org/10.2108/zsj.19.321

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 America, 88(13), 5774–5778. https://doi.org/10.1073/pnas.88.13.5774

Miura, T., Yamauchi, K., Takahashi, H., & Nagahama, Y. (1992). The role of hormones in the acquisition of sperm motility in salmonid fish. Journal of Experimental Biology, 261(3), 359-363. https://doi.org/10.1002/jez.1402610316

Nader, M.R., Miura, T., Ando, N., Miura, C., & Yamauchi, K. (1999). Recombinant Human Insulin-Like Growth Factor I Stimulates All Stages of 11-Ketotestosterone-Induced Spermatogenesis in the Japanese Eel, Anguilla japonica, In Vitro. Biology of Reproduction, 61(4), 944–947. https://doi.org/10.1095/biolreprod61.4.944

Nagahama, Y., Miura, T., & Kobayashi, T. (1994). The onset of spermatogenesis in fish. Ciba Foundation Symposium, 182, 255-267. DOI: 10.1002/9780470514573.ch14

Ohta, T., Miyake, H., Miura, C., Kamei, H., Aida, K., & Miura, T. (2007). Follicle-Stimulating Hormone Induces Spermatogenesis Mediated by Androgen Production in Japanese Eel, Anguilla japonica. Biology of Reproduction, 77(6), 970–977. https://doi.org/10.1095/biolreprod.107.062299

Onuma, T.A., Sato, S., Katsumata, H., Makino, K., Hu, W., Jodo, A., Davis, N.D., Dickey, J.T., Ban, M., Ando, H., Fukuwaka, M., Azumaya, T., Swanson, P., Urano, A. (2009). Activity of the pituitary-gonadal axis is increased prior to the onset of spawning migration of chum salmon. Journal of Experimental Biology, 212(1), 56-70. doi: 10.1242/jeb.021352.

Orlando, E.F., Binczik, G.A., Thomas, P., & Guillette, L.J. Jr. (2003). Reproductive seasonality of the male Florida gar, Lepisosteus platyrhincus. General and Comparative Endocrinology, 131(3), 365–371. https://doi.org/10.1016/S0016-6480(03)00036-4

Ozaki, Y., Higuchi, M., Miura, C., Yamaguchi, S., Tozawa, Y., & Miura, T. (2006). Roles of 11beta-hydroxysteroid dehydrogenase in fish spermatogenesis. Endocrinology, 147(11), 5139-5146. https://doi.org/10.1210/en.2006-0391

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 Toxicology, 164, 10-15. https://doi.org/10.1016/j.aquatox.2015.04.013

Reyes, J.A., Vidal‐Dorsch, D.E., Schlenk, D., Bay, S.M., Armstrong, J.L., Gully, J.R., Cash, C., Baker, M., Stebbins, T.D., Hardiman, G. & Kelley, K.M. (2012). Evaluation of reproductive endocrine status in hornyhead turbot sampled from southern California’s urbanized costal environments. Environmental Toxicology and Chemistry, 31(12), 2689-2700. https://doi.org/10.1002/etc.2008

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 Toxicology, 84(1), 111-118. https://doi.org/10.1016/j.aquatox.2007.06.005

Sakai, N., Ueda, H., Suzuki, N., & Nagahama, Y. (1989). Steroid production by amago salmon (Oncorhynchus rhodurus) testes at different development stages. General and Comparative Endocrinology, 75(2), 231-240. DOI: 10.1016/0016-6480(89)90075-0

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 niloticus. Molecular and Cellular Endocrinology, 500, 110643. https://doi.org/10.1016/j.mce.2019.110643

Schiavone, R., Zilli, L., Storelli, C., & Vilella, S. (2011). Changes in hormonal profile, gonads and sperm quality of Argyrosomus regius (Pices, Scianidae) during the first sexual differentiation and maturation. Theriogenology, 77(5), 888-898. https://doi.org/10.1016/j.theriogenology.2011.09.014

Scott, A.P., Bye, V.J., Baynes, S.M., & Springate, J.R.C. (1980). Seasonal variations in plasma concentrations of 11‐ketotestosterone and testosterone in male rainbow trout, Salmo gairdnerii Richardson. Journal of Fish Biology, 17(5), 495-505. https://doi.org/10.1111/j.1095-8649.1980.tb02781.x

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 Physiology, 166(2), 228-36. https://doi.org/10.1016/j.cbpa.2013.06.007

Shahi, N., Mallik, S.K., Pande, J., Das, P., & Singh, A.K. (2015). Spermatogenesis and related plasma androgen and progestin level in wild male golden mahseer, Tor putitora (Hamilton, 1822), during the spawning season. Fish Physiology and Biochemistry, 41(4), 909-920. https://doi.org/10.1007/s10695-015-0057-6

Shu, T., Zhai, G., Pradhan, A., Olsson, P.E., & Yin, Z. (2020). Zebrafish cyp17a1 knockout reveals that androgen-mediated signaling is important for male brain sex differentiation. General and Comparative Endocrinology, 295, 113490. https://doi.org/10.1016/j.ygcen.2020.113490

Singh, P.B. & Singh, V. (2008). Cypermethrin induced histological changes in gonadotrophic cells, liver, gonads, plasma levels of estradiol-17beta and 11-ketotestosterone, and sperm motility in Heteropneustes fossilis (Bloch). Chemosphere, 72(3), 422-431. https://doi.org/10.1016/j.chemosphere.2008.02.026

Sisneros, J.A., Forlano, P.M., Knapp, M., & Bass, A.H. (2004). Seasonal variation of steroid hormone levels in an intertidal-nesting fish, the vocal plainfin midshipman. General and Comparative Endocrinology, 136(1), 101-116. https://doi.org/10.1016/j.ygcen.2003.12.007

Takeo, J. & Yamashita, S. (2000). Rainbow trout androgen receptor-alpha fails to distinguish between any of the natural androgens tested in transactivation assay, not just 11-ketotestosterone and testosterone. General and Comparative Endocrinology, 117(2), 200-206. https://doi.org/10.1006/gcen.1999.7398

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 Reproduction, 98(2), 227-238. https://doi.org/10.1093/biolre/iox165

Ueda, H., Nagahama, Y., Tashiro, F., & Crim, L.W. (1983). Some endocrine aspects of precocious sexual maturation in the amago salmon, Oncorhynchus rhodurus. Bulletin of the Japanese Society of Scientific Fisheries, 49(4), 587–596. DOI: 10.2331/suisan.49.587

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 Toxicology, 105(1-2), 107-118. https://doi.org/10.1016/j.aquatox.2011.05.018

Weil, C., & Marcuzzi, O. (1990). Cultured pituitary cell GtH response to GnRH at different stages of rainbow trout spermatogenesis and influence of steroid hormones. General and Comparative Endocrinology, 79(3), 492-498. DOI: 10.1016/0016-6480(90)90080-6

Weltzien, F.A., Taranger, G.L., Karlsen, Ø., Norberg, B. (2002). Spermatogenesis and related plasma androgen levels in Atlantic halibut (Hippoglossus hippoglossus L.). Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 132(3), 567-575. https://doi.org/10.1016/S1095-6433(02)00092-2

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

Yin, P., Li, Y.W., Chen, Q.L., & Liu, Z.H. (2017). Diethylstilbestrol, flutamide and their combination impaired the spermatogenesis of male adult zebrafish through disrupting HPG axis, meiosis and apoptosis. Aquatic Toxicology, 185, 129-137. https://doi.org/10.1016/j.aquatox.2017.02.013

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. Endocrinology, 161(6). https://doi.org/10.1210/endocr/bqaa048

Zheng, Q., Xiao, H., Shi, H., Wang, T., Sun, L., Tao, W., Kocher, T.D., Li, M., & Wang, D. (2020). Loss of cyp11c1 causes delayed spermatogenesis due to the absence of 11-ketotestosterone. Journal of Endocrinology, 244(3), 487-499. https://doi.org/10.1530/JOE-19-0438

Zheng, Q., Xiao, H., Shi, H., Wang, T., Sun, L., Tao, W., Kocher, T.D., Li, M., & Wang, D. (2020). Loss of Cyp11c1 causes delayed spermatogenesis due to the absence of 11-ketotestosterone. Journal of Endocrinology, 244(3), 498-499. DOI: https://doi.org/10.1530/JOE-19-0438