Upstream eventAgonism, Androgen receptor
Reduction, Gonadotropins, circulating concentrations
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish)||adjacent||Low||Low|
|fathead minnow||Pimephales promelas||Low||NCBI|
Life Stage Applicability
|Adult, reproductively mature||Not Specified|
Key Event Relationship Description
See biological plausibility, below.
Evidence Supporting this KER
- Circulating concentrations of steroid hormones are tightly regulated via positive and negative feedback loops that operate through endocrine, autocrine, and/or paracrine mechanisms within the hypothalamic-pituitary-gonadal axis (Norris 2007).
- Gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) secretion from the pituitary is a key regulator of gonadal steroid biosynthesis.
- Negative feedback of androgens or estrogens at the level of the hypothalamus and/or pituitary can reduce gonadotropin secretion by pituitary gonadotropes either indirectly due to decreased GnRH signaling from the hypothalamus or directly through intrapituitary regulators of gonadotropin expression (e.g., activin, follistatin, inhibin) (Norris 2007; Habibi and Huggard 1998).
- While similar processes of negative feedback of sex steroids on gonadotropin expression and release have been established in fish (Levavi-Sivan et al. 2010), there are many remaining uncertainties about the exact mechanisms through which feedback takes place in fish as well as other vertebrates. For example, feedback is thought to involve a complex interplay of neurotransmitter signaling, kisspeptins, and the follistatin/inhibin/activin system (Trudeau et al. 2000; Trudeau 1997; Oakley et al. 2009; Cheng et al. 2007).
- In addition, the nature of the feedback produced by androgens is dependent on the concentration, form of the androgen (e.g., aromatizable versus non-aromatizable), life-stage and likely species (Habibi and Huggard 1998; Trudeau et al. 2000; Gopurappilly et al. 2013).
- The specific mechanisms through which negative feedback of AR agonists on the hypothalamus and pituitary are mediated in fish are not fully understood.
- It is thought that GABAergic and dopaminergic neurons may be important mediators of sex steroid feedback on gonadotropin releasing hormone (GnRH) release from the hypothalamus (Trudeau et al. 2000; Trudeau 1997).
- More recent evidence also suggests an important role of kisspeptin neurons, which have been shown to express both AR and ERα are important mediators of feedback response to circulating androgen concentrations (Oakley et al. 2009).
- Follistatin expression in the pituitary has also been cited as a key regulator of gonadotropin expression that is directly regulated by androgens and estrogens (Cheng et al. 2007).
- Regardless of the exact mechanisms, negative feedback of androgens on GnRH and/or gonadotropin release from the hypothalamus and/or pituitary is a well established endocrine phenomenon.
- There is a relatively strong body of evidence demonstrating that gonadectomy and/or treatment with potent AR antagonists can increase circulating concentrations of gonadotropins in fish and that those effects can be reversed by treatment with testosterone (reviewed in (Habibi and Huggard 1998; Levavi-Sivan et al. 2010)).
- However, we are currently unaware of any studies conducted with xenobiotic or pharmaceutical androgen agonists that measured effects on circulating gonadotropins.
- Empirical support for this linkage is largely lacking for most fish species, as antibodies capable of specifically detecting and distinguishing luteinizing hormone and follicle stimulating hormone have not yet been developed, despite many attempts.
- FSH and LH can be specifically measured for salmonids, but measurement methods for most other species are lacking.
Uncertainties and Inconsistencies
Due to uncertainties regarding the exact mechanisms through which exogenous androgens mediate a negative feedback response this initiation of a negative feedback response is not directly observable. Negative feedback would generally be inferred through a decrease in gonadotropin release and associated declines in circulating gonadotropin concentrations.
Quantitative Understanding of the Linkage
Given the uncertainties in the specific mechanism(s) of negative feedback that are involved and the lack of data on circulating gonadotropin concentrations following exposure to exogenous androgen agonists there is currently no quantitative understanding that would translate relative binding affinity and/or effect concentrations in an AR-mediated transcriptional activation assay into expected impacts on circulating gonadotropin concentrations.
Quantitative understanding of this linkage is largely absent for fish due to lack of established methods for measuring the gonaodotropins and uncertainties about the exact mechanisms through which androgens or androgen receptor activation may exert negative feedback control on gonadotropin secretion.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
At present, this relationship is assumed to operate in repeat spawning fish species with asynchronous oocyte development.
The extent to which the negative feedback mechanism proposed here is operable for fish species employing other reproductive strategies and/or for other vertebrates has not been extensively examined, to date.
- Cheng GF, Yuen CW, Ge W. 2007. Evidence for the existence of a local activin follistatin negative feedback loop in the goldfish pituitary and its regulation by activin and gonadal steroids. The Journal of endocrinology 195(3): 373-384.
- Gopurappilly R, Ogawa S, Parhar IS. 2013. Functional significance of GnRH and kisspeptin, and their cognate receptors in teleost reproduction. Frontiers in endocrinology 4: 24.
- Habibi HR, Huggard DL. 1998. Testosterone regulation of gonadotropin production in goldfish. Comparative biochemistry and physiology Part C, Pharmacology, toxicology & endocrinology 119(3): 339-344.
- Levavi-Sivan B, Bogerd J, Mananos EL, Gomez A, Lareyre JJ. 2010. Perspectives on fish gonadotropins and their receptors. General and comparative endocrinology 165(3): 412-437.
- Norris DO. 2007. Vertebrate Endocrinology. Fourth ed. New York: Academic Press.
- Oakley AE, Clifton DK, Steiner RA. 2009. Kisspeptin signaling in the brain. Endocrine reviews 30(6): 713-743.
- Trudeau VL, Spanswick D, Fraser EJ, Lariviére K, Crump D, Chiu S, et al. 2000. The role of amino acid neurotransmitters in the regulation of pituitary gonadotropin release in fish. Biochemistry and Cell Biology 78: 241-259.
- Trudeau VL. 1997. Neuroendocrine regulation of gonadotropin II release and gonadal growth in the goldfish, Carassius auratus. Reviews of Reproduction 2: 55-68.