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Relationship: 2937


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

Impaired, Spermatogenesis leads to Decreased, Viable Offspring

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). 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

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 Moderate Low Jennifer Olker (send email) Open for citation & comment

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

Spermatogenesis is a multiphase process of cellular transformation that produces mature male gametes known as sperm for sexual reproduction. 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. The fusion of sperm and oocytes is the key step for the beginning of life known as fertilization. Oocyte fertilization and the production of viable offspring from sexual reproduction are dependent on spermatogenesis and sufficient quantity and quality of sperm. When the impairment of spermatogenesis occurs, it can result in impaired reproduction with a decrease in viable offspring.

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

The majority of papers used in evidence supporting the key event relationship were found through AbstractSifter, a Microsoft Excel-based application that extracts papers from PubMed. AbstractSifter ranks abstracts based on their relevance through key search and filter terms. An initial set of papers was identified through Google Scholar with search terms “Impaired spermatogenesis male infertility” and “Impaired spermatogenesis male infertility in fish”; these papers helped identify search and filter terms used in Abstract Sifter. In AbstractSifter, searches were done to curate a subset of 40 papers using search terms “spermatogenesis AND fish” and “spermatogenesis AND zebrafish”. This initial set of papers was filtered with the terms “male, infertility, and reduced”, “male, infertility, and impaired”, and “male and infertil”. The first 2 filter set of words were used for the spermatogenesis and fish search which yielded 9 and 11 papers respectively. The last set of filter terms was used for the spermatogenesis and zebrafish search which yielded a respective 25 papers. Additional sources used towards the weight of evidence were provided through expert knowledge and found through sources in papers initially curated in the AbstractSifter search.

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 1A - Concordance table [authors A-N] (full table as PDF)


Experimental design

Evidence of Impaired Spermatogenesis (IS)

Evidence of Viable Offspring, Decreased (VOD)

IS observed?

VOD observed?




(Danio rerio)

Two generation exposure to 1nM BPA

  • Significant decrease in sperm density of F1 and F2 males compared to control
  • Decreased sperm quality as measured by motility, velocity, ATP content and lipid peroxidation in F1 and F2 males
  • Delayed hatching at 48hpf and increased malformation and mortality were observed in the offspring from BPA- exposed F2; paternal-specific resulting from BPA-exposed males
  • No significant difference in egg production and fertilization of F1 and F2 females


No: F1 and F2

Yes: offspring of F2

Chen et al., 2015

Female-biased sex ratio observed in both F1 and F2 adults

Tilapia (Oreochromis niloticus)

CRISPR/Cas9 mediated mutation of eEF1A1b; F1 sampled at 90, 120, 150 and 180 days after hatch

  • Significant downregulation of key genes involving spermatogenesis
  • Spermatogenesis arrested; reduced number of spermatogonia and spermatocytes
  • Altered morphology 
  • Delayed spermatogenesis
  • Reduced motility
  • Reduced in vitro fertilization rate (5% vs 80% in WT) due to abnormal spermiogenesis



Chen et al., 2017

eEF1A1b - elongation factor 


(Danio rerio)

Adult males exposed to two concentrations of bis-(2-ethylexhyl) phthalate (DEHP; 0.2 or 20 μg/L) for three weeks; 25 ng ethynylestradiol positive control

  • Areas of spermatogonial and spermatid cysts were larger in fish exposed to 20 μg/L DEHP compared with controls
  • Testicular area of spermatocyte cysts was lower in males exposed to 0.2 μg/L DEHP
  • Testicular area occupied by spermatocytes was reduced in fish exposed to DEHP compared to controls, with a concomitant increase in the area occupied by spermatogonia
  • Significant decrease in embryo production (up to 90%) observed in males treated with DEHP (0.2 and 20 μg/L)
  • Hatch rate of embryos significantly lower in DEHP-exposed males



Corradetti et al., 2013

Reproductive performance evaluated with untreated females in clean water


(Danio rerio)

Targeted genetic disruption of tdrd12 through TALEN techniques 

  • Reduced expression of germ cell markers vasa, dnd, piwil1 and amh in mutants
  • Deformed and apoptotic spermatogonia at 35 dpf found in mutants 
  • Lack of spermatozoa at adult stage 
  • Infertile under standard breeding despite being able to induce female egg laying (0% fertilization)



Dai et al., 2017

Tudor domain-related proteins (Tdrds) have been demonstrated to be involved in spermatogenesis and Piwi-interacting RNA (piRNA) pathway 


(Danio rerio)

Fish were exposed from 2 to 60 days post-hatch (dph) to nonylphenol (NP; 10, 30, or 100 μg/L nominal) or ethinylestradiol (EE2; 1, 10, or 100 ng/l nominal); reared until adulthood (120 dph) for breeding studies

  • Majority of fish exposed to 10 ng/l EE lacked differentiated gonadal tissue (undeveloped gonads) at 60 dph
  • One fish at NP-30 μg/l and two fish at NP-100 μg/l were observed to have ovatestes at 60 dph
  • Zebrafish exposed to 10 ng/l of EE exhibited a significant reduction in the percent of viable eggs (clear vs opaque)
  • Significant decrease in hatch and swim-up success observed with EE2 and 100 μg NP/L



Hill and Janz, 2003

Due to high mortality in the 100 ng/l EE group, insufficient fish were available for analyses


(Rutilus rutilus)

Mature adult roach collected from both reference and river (effluent contaminated) sites during two consecutive spawning seasons; artificially induced to spawn in laboratory

  • Volume of milt released from spermiating male fish significantly lower in the intersex fish than in the reference males
  • Most fish that did not spermiate had testes that were clearly immature
  • Fertilization rate significantly reduced when sperm from intersex males used to fertilize eggs collected from females
  • Both proportion of fertilized embryos reaching eyed stage and hatching success decreased with increased feminization



Jobling et al., 2002

Embryo viability was determined after 24 h (fertilization success), at eyed stage and at swim-up stage (hatching success)

Japanese medaka

(Oryzias latipes)

Adult medaka exposed for 21 days to 29.3, 55.7, 116, 227, and 463 ng/L 17β-estradiol (E2)

  • In males exposed to 463 ng/l, a few oocytes were observed in testis, and testicular tissue almost completely replaced by connective tissue
  • Accompanied by presence of macroscopic atrophy and degenerated spermatozoa and spermatocytes suggest a lack of spermatogenesis
  • Total number of egg spawned and fertility significantly reduced at 463 ng/l E2 compared to the control



Kang et al., 2002


(Danio rerio)

Founder fish with originally mlh1 mutation was crossed out twice to WT fish of the TL line from which the founder was generated

  • Significant decrease in weight of spermatids and spermatozoa); some spermatozoa were visible in testes of all mutant fish
  • Increased number and proportion of spermatogenic stages prior to spermatids compared to WT 
  • Increase in apoptotic cells
  • Reduced fertilization rates under standard breeding conditions (0.4%)
  • Eggs fertilized from mutant sperm were malformed and and aneuploid



Leal et al., 2008

Mlh1 is a member of DNA mismatch repair machinery and essential for stabilization of crossovers during first meiotic division 


(Danio rerio)

3-month-old male fish exposed to 10 ug/L of DEHP for 3 months

  • No effect
  • No effect 



Ma et al., 2018



Semi-static exposure; half water renewed daily and whole water renewed weekly; exposed males mated with WT females

3-month-old male fish exposed to 30 ug/L of DEHP for 3 months

  • No effect
  • Concentration-dependent decrease in fertilization rate



3-month-old male fish exposed to 100 ug/L of DEHP for 3 months

  • Percent of spermatocytes increased significantly by 27.4% 
  • Significant decrease of 32.2% in spermatids
  • Significant decrease in fertilization rate by 22% compared to the control




(Danio rerio)

Multi-generational study to 0.5, 5 and 50 ng/L ethynylestradiol (EE2) or 5 ng/L 17β-estradiol (E2)

  • None of the F1 males exposed to 5 ng/L EE2 had normal testes; 43% had gonads not fully differentiated
  • Time-related decrease in egg production and egg viability 14 hpf in F0 generation at 50 ng/L EE2 and no survival of F1 100 hpf; no eggs produced after 10 d exposure
  • Exposure to 5 ng/L EE2 in the F1 caused a 56% reduction in fecundity and no survival past 14 hpf
  • Proportion of nonviable eggs significantly higher for all treatments compared to control



Nash et al., 2004

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

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
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
  • When exposed to 10 and 100 ng/L of EE2 for 62 days leading to spawning, rainbow trout  exhibited an increase in sperm density, concentration, and spermatocrit and decrease in GSI but overall there were no significant changes to spermatogenesis. Despite this, there was a decrease in viability of embryos (Schultz et al., 2003).
  • Two-generation zebrafish study with 1 nM bisphenol A (BPA) showed a significant decrease in sperm density along with decreased sperm quality, however, no significant different in egg fertilization (Chen et al., 2015).
  • There are multiple other factors involved in producing viable offspring, including but not limited to oocyte maturation and ovulation, development including successful organogenesis, and adequate nutrition.

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

Empirical response-response data is very limited; thus, the response-response relationship has not yet been evaluated.

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
  • The duration of spermatogenesis in humans 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 is reported to be 6 days which means there could be a delay of at least 6 days before signs of impaired fertility and downstream effects may be detected (Leal et al., 2009).
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

Feedforward/feedback loops haven’t been evaluated yet. However, given that that oocyte fertilization and production of viable offspring are external to the male it seems unlikely there would feedback that impacts spermatogenesis.

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 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. There are studies on reproduction and spermatogenesis across a multitude of taxa.

Sex Applicability: Spermatogenesis is a male-specific process (Schulz et al., 2010, Tang et al., 2018, Wu 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.


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

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.

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.

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.

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.

Corradetti, B., Stronati, A., Tosti, L., Manicardi, G., Carnevali, O., and Bizzaro, D. (2013). Bis-(2-ethylexhyl) phthalate impairs spermatogenesis in zebrafish (Danio rerio). Reprod Biol. 13(3):195-202.

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.

Griswold M. D. (2016). Spermatogenesis: The Commitment to Meiosis. Physiological reviews, 96(1), 1–17.

Hill, R.L Jr and Janz, D.M. (2003). Developmental estrogenic exposure in zebrafish (Danio rerio): I. Effects on sex ratio breeding success. Aquat Toxicol. 63(4):417-429.

Jobling, S., Coey, S., Whitmore, J.G., Kime, D.E., Van Look, K.J.W., McAllister, B.G., Beresford, N., Henshaw, A.C., Brighty, G., Tyler, C.R., and Sumpter, J.P. (2002). Wild intersex roach (Rutilus rutilus) have reduced fertility. Biol Reprod. 67(2):515–524.

Kang, I.J., Yokota, H., Oshima, Y., Tsuruda, Y., Yamaguchi, T., Maeda, M., Imada, N., Tadokoro, H., and Honjo, T. (2002). Effect of 17β-estradiol on the reproduction of Japanese medaka (Oryzias latipes). Chemosphere 47(1): 71-80,

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.

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.

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.

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.

Nash, J.P, Kime, D.E., Van der Ven, Leo T.M., Wester, P.W., Brion, F., Maack, G., Stahlschmidt-Allner, P., and Tyler, C.R., (2004). Long-term exposure to environmental concentrations of the pharmaceutical ethynylestradiol causes reproductive failure in fish. Environ Health Perspect 112(17):1725-1733.

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.

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.

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.

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.

Schulz, R. W., de França, L. R., Lareyre, J. J., Le Gac, F., Chiarini-Garcia, H., Nobrega, R. H., & Miura, T. (2010). Spermatogenesis in fish. General and comparative endocrinology165(3), 390–411.

Seki, M., Yokota, H., Matsubara, H., Tsuruda, Y., Maeda, M., Tadokoro, H. and Kobayashi, K. (2002). Effect of ethinylestradiol on the reproduction and induction of vitellogenin and testis-ova in medaka (Oryzias latipes). Environ. Toxicol. Chem. 21(8):1692-1698.

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.

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.

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.

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.

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.

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.

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.

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.

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