Upstream eventReduction, Vitellogenin accumulation into oocytes and oocyte growth/development
Reduction, Cumulative fecundity and spawning
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aromatase inhibition leading to reproductive dysfunction||adjacent||Moderate||Moderate|
|Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)||adjacent||Moderate||Moderate|
|Estrogen receptor antagonism leading to reproductive dysfunction||adjacent||Moderate||Moderate|
|Prolyl hydroxylase inhibition leading to reproductive dysfunction via increased HIF1 heterodimer formation||adjacent|
|Unknown MIE leading to reproductive dysfunction via increased HIF-1alpha transcription||adjacent|
|Embryonic Activation of the AHR leading to Reproductive failure, via epigenetic down-regulation of GnRHR||adjacent||Moderate||Moderate|
|fathead minnow||Pimephales promelas||Moderate||NCBI|
|Oryzias latipes||Oryzias latipes||Moderate||NCBI|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
SEE BIOLOGICAL PLAUSIBILITY BELOW
Evidence Supporting this KER
Vitellogenesis is a critical stage of oocyte development and accumulated lipids and yolk proteins make up the majority of oocyte biomass (Tyler and Sumpter 1996). At least in mammals, maintenance of meiotic arrest is supported by signals transmitted through gap junctions between the granulosa cells and oocytes (Jamnongjit and Hammes 2005). Disruption of oocyte-granulosa contacts as a result of cell growth has been shown to coincide with oocyte maturation (Eppig 1994). However, it remains unclear whether the relationship between vitellogenin accumulation and oocyte growth and eventual maturation is causal or simply correlative.
- At present, to our best knowledge there are no studies that definitively demonstrate a direct cause-effect relationship between impaired VTG accumulation into oocytes and impaired spawning. There is, however, strong correlative evidence. Across a range of laboratory studies with small fish, there is a robust and statistically significant correlation between reductions in circulating VTG concentrations and reductions in cumulative fecundity (Miller et al. 2007). To date, we are unaware of any fish reproduction studies which show a large reduction in circulating VTG concentrations, but not reductions in cumulative fecundity.
- Ankley et al. (2003) reported significant reductions in VTG accumulation in oocytes along with significant reductions in cumulative fecundity, although fecundity was significantly impacted at a lower dose (0.05 ug/L 17beta-trenbolone versus 0.5 ug/L for VTG accumulation).
- Kang et al. (2008) reported significant reductions in both VTG accumulation in occytes and cumulative fecundity in Japanese medaka, with cumulative fecundity being impacted at slightly lower concentrations (0.047 ug 17alpha-methyltestosterone/L versus 0.088 ug/L).
Uncertainties and Inconsistencies
Based on the limited number of studies available that have examined both of these KEs, there are no known, unexplained, results that are inconsistent with this relationship.
Quantitative Understanding of the Linkage
Across a range of laboratory studies with fathead minnow, there is a robust and statistically significant correlation between reductions in circulating VTG concentrations and reductions in cumulative fecundity (Miller et al. 2007). At present it is unclear how well that relationship may hold for other fish species or feral fish under the influence of environmental variables. A model based on a statistical relationship between plasma E2 concentrations, spawning interval, and cumulative fecundity has been developed to predict changes in cumulative fecundity from plasma VTG (Li et al. 2011b). However, to date, such models do not specifically consider vitellogenin uptake into oocytes as a quantitative predictor of fecundity. Furthermore, with the exception of a few specialized studies, quantitative measures of VTG content in oocytes are rarely measured in toxicity studies. In contrast, plasma VTG is routinely measured.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
On the basis of the taxonomic relevance of the two KEs linked via this KER, this KER is likely applicable to aquatic, oviparous, vertebrates which both produce vitellogenin and deposit eggs/sperm into an aquatic environment.
- Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MC, Hartig PC, Gray LE. Effects of the androgenic growth promoter 17-beta-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ Toxicol Chem. 2003 Jun;22(6):1350-60.
- Eppig JJ. 1994. Further reflections on culture systems for the growth of oocytes in vitro. Human reproduction 9(6): 974-976.
- Jamnongjit M, Hammes SR. 2005. Oocyte maturation: the coming of age of a germ cell. Seminars in reproductive medicine 23(3): 234-241.
- Kang IJ, Yokota H, Oshima Y, Tsuruda Y, Shimasaki Y, Honjo T. The effects of methyltestosterone on the sexual development and reproduction of adult medaka (Oryzias latipes). Aquat Toxicol. 2008 Apr 8;87(1):37-46. doi: 10.1016/j.aquatox.2008.01.010.
- Li Z, Villeneuve DL, Jensen KM, Ankley GT, Watanabe KH. 2011b. A computational model for asynchronous oocyte growth dynamics in a batch-spawning fish. Can J Fish Aquat Sci 68: 1528-1538.
- Miller DH, Jensen KM, Villeneuve DL, Kahl MD, Makynen EA, Durhan EJ, et al. 2007. Linkage of biochemical responses to population-level effects: a case study with vitellogenin in the fathead minnow (Pimephales promelas). Environ Toxicol Chem 26(3): 521-527.
- Tyler C, Sumpter J. 1996. Oocyte growth and development in teleosts. Reviews in Fish Biology and Fisheries 6: 287-318.