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Relationship: 336

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

Increase, Vitellogenin synthesis in liver leads to Increase, Plasma vitellogenin concentrations

Upstream event

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

Increase, Vitellogenin synthesis in liver

Downstream event

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

Increase, Plasma vitellogenin concentrations

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
Estrogen receptor agonism leading to reproductive dysfunction	adjacent	High		Undefined (send email)	Under Development: Contributions and Comments Welcome
Estrogen receptor agonism leading to reduced survival and population growth due to renal failure	adjacent	High	Moderate	Camille Baettig (send email)	Under development: Not open for comment. Do not cite
Estrogen receptor agonism leads to reduced fecundity via increased vitellogenin in the liver	adjacent			Jason M. O'Brien (send email)	Under development: Not open for comment. Do not cite

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

Sex Applicability

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

Life Stage Applicability

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

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

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

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

Original text - unknown contributor

High level of physiological plausibility in fish.

Added by C. Baettig on June 24, 2024

The liver is the primary source of VTG synthesis and production and after it is synthesized it is secreted into the blood (Wallace, 1985). Vitellogenin transcription and translation results in protein production, although there is a delay between expression of vtg and actual production/detection of VTG (e.g., Korte et al. 2000).

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 male tilapia, 48 hours after 17β-estradiol (E2) treatment, vtg hepatic mRNA expression was elevated as was plasma VTG (Davis et al., 2008).
In time course studies an increase in vtg mRNA synthesis precedes increases in plasma VTG concentration. For example, a study using male fathead minnows injected with E2, vtg mRNA was detected in the liver within 4 hours, reached a maximum around 48 hours, and returned to normal levels after 6 days. Plasma VTG was detectable within 16 hours of treatment, reached maximum levels at about 72 hours, and did not return to normal levels for at least 18 days (Korte et al., 2000).
Similar results were observed in a flow-through experiment using sheepshead minnows exposed to E2 and p-nonylphenol. A dose dependent increase in hepatic vtg mRNA initially occurred followed by plasma VTG increase. Their results further supported that hepatic vtg mRNA rapidly diminishes after termination of estrogenic exposure, but plasma VTG clearance is concentration and time dependent (Hemmer et al., 2002).
Bowman et al. (2000) also found a time lag between vtg, which was elevated after 4 hours while induction of plasma VTG wasn’t detected until 24 hours in male sheepshead minnows injected with E2.
During waterborne exposures to 17α-ethinylestradiol (EE2), male fathead minnows showed a strong increase of vtg mRNA within 3 days (first sampling time point in the study), which remained elevated for the entirety of the 35-day exposure. Although plasma VTG was first detectable on day 3 it did not significantly increase until day 14 further illustrating the lag between vtg mRNA and plasma increase (Schmid et al., 2002).
In male fathead minnows exposed to E2 and FC-10 diol for 21 days, expression of hepatic vtg was significantly increased as was the plasma VTG (Ankley et al. in prep).

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

There are no known inconsistencies between these KERs which are not readily explained on the basis of the expected dose, temporal, and incidence relationships between these two KERs. This applies across a significant body of literature in which these two KEs have been measured.

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

Models and statistical relationships that define quantitative relationships between circulating E2 concentrations and circulating VTG concentrations have been developed (Ankley et al., 2008; Li et al., 2011; Murphy et al., 2009; Murphy et al., 2005). However, much of this work has focused on decreased VTG as a function of decreased E2, rather than induction.

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

Due to the timeline between induction of mRNA transcription, translation, and the appearance of protein in plasma, as well as variable rates of uptake of VTG from plasma into oocytes, a precise quantitative relationship describing all steps of vitellogenesis transcription/translation has not been described.

However, studies in fish suggest that that the temporal lag between mRNA transcription and increased plasma concentrations takes place within 24 hours. For example, in fish injected with E2 there is generally an increase of vtg mRNA beginning around 4 hours whereas plasma VTG isn’t measurable until 16-24 hours (Bowman et al., 2000; Korte et al., 2000). Additionally, in waterborne exposure of estrone (E1) in juvenile rainbow trout, elevated vtg mRNA occurred on day 4 of exposure while plasma VTG was elevated on day 5 (Osachoff et al., 2016).

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

There is no known feedback as plasma VTG does not appear to regulate expression levels in the liver.

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: Oviparous vertebrates synthesize yolk precursor proteins that are transported in the circulation for uptake by developing oocytes. Many invertebrates also synthesize vitellogenins that are taken up into developing oocytes via active transport mechanisms. However, invertebrate vitellogenins are transported in hemolymph or via other transport mechanisms rather than plasma.

Life stage: This KER is applicable to all life stages following the differentiation of the liver. Embryos prior to liver differentiation should not be included.

Sex: This KER is applicable to both sexes. However, as males do not have the ability to clear plasma VTG via uptake into the oocytes the outcome is more likely to be problematic in males. Therefore, this KER has more relevance in males both in the context of monitoring for exogenous estrogens and potential biological consequences of elevated VTG.

References

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

Ankley, G. T., Miller, D. H., Jensen, K. M., Villeneuve, D. L., & Martinović, D. (2008). Relationship of plasma sex steroid concentrations in female fathead minnows to reproductive success and population status. Aquatic Toxicology, 88(1), 69-74. https://doi.org/https://doi.org/10.1016/j.aquatox.2008.03.005
Bowman, C. J., Kroll, K. J., Hemmer, M. J., Folmar, L. C., & Denslow, N. D. (2000). Estrogen-induced vitellogenin mRNA and protein in sheepshead minnow (Cyprinodon variegatus). General and Comparative Endocrinology, 120(3), 300-313.
Davis, L. K., Pierce, A. L., Hiramatsu, N., Sullivan, C. V., Hirano, T., & Grau, E. G. (2008). Gender-specific expression of multiple estrogen receptors, growth hormone receptors, insulin-like growth factors and vitellogenins, and effects of 17β-estradiol in the male tilapia (Oreochromis mossambicus). General and Comparative Endocrinology, 156(3), 544-551.
Hemmer, M. J., Bowman, C. J., Hemmer, B. L., Friedman, S. D., Marcovich, D., Kroll, K. J., & Denslow, N. D. (2002). Vitellogenin mRNA regulation and plasma clearance in male sheepshead minnows,(Cyprinodon variegatus) after cessation of exposure to 17β-estradiol and p-nonylphenol. Aquatic Toxicology, 58(1-2), 99-112.
Korte, J. J., Kahl, M. D., Jensen, K. M., Pasha, M. S., Parks, L. G., LeBlanc, G. A., & Ankley, G. T. (2000). Fathead minnow vitellogenin: Complementary DNA sequence and messenger RNA and protein expression after 17β‐estradiol treatment. Environmental Toxicology and Chemistry: An International Journal, 19(4), 972-981.
Li, Z., Kroll, K. J., Jensen, K. M., Villeneuve, D. L., Ankley, G. T., Brian, J. V., Sepúlveda, M. S., Orlando, E. F., Lazorchak, J. M., Kostich, M., Armstrong, B., Denslow, N. D., & Watanabe, K. H. (2011). A computational model of the hypothalamic - pituitary - gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone. BMC Systems Biology, 5(1), 63. https://doi.org/10.1186/1752-0509-5-63
Murphy, C. A., Rose, K. A., Rahman, M. S., & Thomas, P. (2009). Testing and applying a fish vitellogenesis model to evaluate laboratory and field biomarkers of endocrine disruption in Atlantic croaker (Micropogonias undulatus) exposed to hypoxia. Environmental toxicology and chemistry, 28(6), 1288-1303. https://doi.org/https://doi.org/10.1897/08-304.1
Murphy, C. A., Rose, K. A., & Thomas, P. (2005). Modeling vitellogenesis in female fish exposed to environmental stressors: predicting the effects of endocrine disturbance due to exposure to a PCB mixture and cadmium. Reproductive Toxicology, 19(3), 395-409. https://doi.org/https://doi.org/10.1016/j.reprotox.2004.09.006
Osachoff, H. L., Brown, L. L. Y., Tirrul, L., van Aggelen, G. C., Brinkman, F. S. L., & Kennedy, C. J. (2016). Time course of hepatic gene expression and plasma vitellogenin protein concentrations in estrone-exposed juvenile rainbow trout (Oncorhynchus mykiss). Comparative Biochemistry and Physiology Part D: Genomics and Proteomics, 19, 112-119. https://doi.org/https://doi.org/10.1016/j.cbd.2016.02.002
Schmid, T., Gonzalez-Valero, J., Rufli, H., & Dietrich, D. R. (2002). Determination of vitellogenin kinetics in male fathead minnows (Pimephales promelas). Toxicology Letters, 131(1), 65-74. https://doi.org/https://doi.org/10.1016/S0378-4274(02)00043-7
Wallace, R. A. (1985). Vitellogenesis and oocyte growth in nonmammalian vertebrates. Oogenesis, 127-177.