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CYP7B activity, inhibition leads to Locomotor activity, decreased
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of CYP7B activity leads to decreased reproductive success via decreased locomotor activity||non-adjacent||Low||Low||Florence Pagé-Larivière (send email)||Not under active development|
Life Stage Applicability
|Adult, reproductively mature|
Key Event Relationship Description
CYP7B is expressed in the mammalian brain where it catalyzes synthesis of 7α-hydroxypregnenolone, among other neurosteroids. However, it governs spatial memory and learning rather than locomotor activity. Thus, although CYP7B and 7α-hydroxypregnenolone are present in the brain of vertebrates, there functions are different in mammals and non-mammals.
The importance of CYP7B neurosteroid synthesis is sex dependent in bird and newt. In these species, only male locomotor activity is influenced by CYP7B expression. However, both male and female are affected by CYP7B activity in salmon.
Evidence Collection Strategy
Evidence Supporting this KER
The relationship between CYP7B and locomotor activity is clearly established is quail, newt and salmon. However, the regulation of CYP7B differs in these species.
In diurnal bird such as quail, melatonin secretion during nighttime inhibits CYP7B activity which is reflected by the decreased locomotor activity. Under daylight condition, melatonin secretion is abolished which induces an upregulation of CYP7B and an increase in locomotor activity (Tsutsui et al., 2008).
Oppositely, newt is a nocturnal animal and melatonin secretion acts as an inducer of CYP7B activity. Consequently, CYP7B activity is elevated at night and drives locomotor activity (Koyama et al., 2009).
CYP7B activity is also dependent on the peptide hormone prolactin secreted by the adenohypophysis, at least in male newt. Prolactin is a neuropeptide which secretion varies according to season. In newt, breeding season is characterized by an elevation of locomotor activity which correlates with a peak in brain prolactin concentration.
It is plausible that prolactin induces the same increase in locomotor activity in salmon during homing migration. During this period, both prolactin and CYP7B (7α-hydroxypregnenolone) are known to peak (Haraguchi et al., 2015; Onuma et al., 2010).
- Conazoles are known to cross the blood brain barrier.
- The activity of CYP7B is inhibited by conazoles (Matsunaga et al., 2004; Tsutsui et al., 2008).
- Exposure to ketoconazole inhibited CYP7B activity (decreased 7α-hydroxypregnenolone concentration) and decreased locomotor activity in male quail and newt.
- Depletion of CYP7B substrate (pregnenolone) with intracranial injection of aminoglutethimide (CYPscc inhibitor) decreased locomotor activity in salmon (Haraguchi et al., 2015).
- Penguins treated with voriconazole (6 µg/ml of blood) became lethargic and weak. The side effects dissipated or resolved with discontinuation or dose reduction of voriconazole (Hyatt et al., 2015).
Uncertainties and Inconsistencies
Conazoles are known to inhibit a variety of CYPs. Thus, when an animal is exposed to a chemical of this family, multiple enzymatic targets are likely to be affected. It is plausible that the impacts of the exposure are the result of multiple CYPs inhibition that all converge toward the same phenotype.
Known modulating factors
Quantitative Understanding of the Linkage
No information is available at this moment.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
CYP7B is expressed in the mammalian brain where it synthesizes, among others, 7α-hydroxypregnenolone. However, it governs spatial memory and learning rather than locomotor activity. Thus, although CYP7B and 7α-hydroxypregnenolone are present in the brain of vertebrates, there functions are different in mammals and non-mammals.
Haraguchi, S., Yamamoto, Y., Suzuki, Y., Hyung Chang, J., Koyama, T., Sato, M., Mita, M., Ueda, H., and Tsutsui, K. (2015). 7alpha-Hydroxypregnenolone, a key neuronal modulator of locomotion, stimulates upstream migration by means of the dopaminergic system in salmon. Sci Rep 5, 12546.
Hyatt, M.W., Georoff, T.A., Nollens, H.H., Wells, R.L., Clauss, T.M., Ialeggio, D.M., Harms, C.A., and Wack, A.N. (2015). Voriconazole Toxicity in Multiple Penguin Species. J Zoo Wildl Med 46, 880-888.
Koyama, T., Haraguchi, S., Vaudry, H., and Tsutsui, K. (2009). Diurnal changes in the synthesis of the neurosteroid 7alpha-hydroxypregnenolone stimulating locomotor activity in newts. Ann N Y Acad Sci 1163, 444-447.
Matsunaga, M., Ukena, K., Baulieu, E.E., and Tsutsui, K. (2004). 7alpha-Hydroxypregnenolone acts as a neuronal activator to stimulate locomotor activity of breeding newts by means of the dopaminergic system. Proc Natl Acad Sci U S A 101, 17282-17287.
Onuma, T.A., Ban, M., Makino, K., Katsumata, H., Hu, W., Ando, H., Fukuwaka, M.A., Azumaya, T., and Urano, A. (2010). Changes in gene expression for GH/PRL/SL family hormones in the pituitaries of homing chum salmon during ocean migration through upstream migration. Gen Comp Endocrinol 166, 537-548.
Tsutsui, K., Inoue, K., Miyabara, H., Suzuki, S., Ogura, Y., and Haraguchi, S. (2008). 7Alpha-hydroxypregnenolone mediates melatonin action underlying diurnal locomotor rhythms. J Neurosci 28, 2158-2167.