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Key Event Title
7α-hydroxypregnenolone synthesis in the brain, decreased
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Inhibition of CYP7B leads to decreased locomotor activity||KeyEvent||Brendan Ferreri-Hanberry (send email)||Not under active development|
|Inhibition of CYP7B activity leads to decreased sexual behavior||KeyEvent||Arthur Author (send email)||Not under active development|
|During development and at adulthood|
Key Event Description
7α-hydroxypregnenolone is an active neurosteroid synthesized in the brain from pregnenolone via a reaction catalyzed by CYP7B (R08943). Pregnenolone can also be synthesized in most vertebrate brain by CYP11A from cholesterol (Tsutsui and Yamazaki, 1995; do Rego et al., 2016).
Compared to other brain regions of the male quail and newt, 7α-hydroxypregnenolone concentration is higher in the diencephalon. In the brain of both salmon and newt, the peak concentrations are measured in the hypothalamus and optic tectum (Matsunaga et al., 2004; Tsutsui et al., 2008; Haraguchi et al., 2015).
7α-hydroxypregnenolone synthesis in the brain is cyclic and driven by a different mechanism according to the specie.
- In male quail, a diurnal animal, it is inhibited by a melatonin-receptor mechanism after melatonin secretion from the pineal gland (Tsutsui et al., 2008).
- In male newt, a nocturnal animal, melatonin secretion stimulates its synthesis in the brain.
- Another regulating mechanism is observed in male newt where 7α-hydroxypregnenolone concentration peaks during the breeding period in response to prolactin signal (Matsunaga et al., 2004).
- In salmon, 7α-hydroxypregnenolone stays high during homing migration (Haraguchi et al., 2015). The endogenous factor regulating its synthesis has yet to be determined.
Thus, 7α-hydroxypregnenolone synthesis is regulated by the circadian cycle and/or by seasonal factors such as breeding and migration.
How It Is Measured or Detected
Detection and quantification of 7α-hydroxypregnenolone can be performed using GC-MS and/or HPLC analysis.
- Cell not expressing CYP7B can be transfected with CYP7B cDNA and incubated in presence of pregnenolone and NADPH. Concentration of 7α-hydroxypregnenolone can be measured by HPLC analysis (Haraguchi et al., 2015).
- To distinguish 7α- and 7β-hydroxypregnenolone, HPLC analysis was performed (Tsutsui et al., 2008). Brain homogenates can be incubated in presence of pregnenolone and NADPH. Concentration of 7α-hydroxypregnenolone can be measured by HPLC analysis Haraguchi et al., 2015).
The extracted steroids derived from brain homogenates and plasma can be measured using GC-MS analysis (Tsutsui et a;., 2008).
Domain of Applicability
The enzyme synthesizing 7α-hydroxypregnenolone is known to be conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog. https://www.ncbi.nlm.nih.gov/homologene/3544
Evidence for Perturbation by Stressor
Haraguchi, S., Koyama, T., Hasunuma, I., Vaudry, H., and Tsutsui, K. (2010). Prolactin increases the synthesis of 7alpha-hydroxypregnenolone, a key factor for induction of locomotor activity, in breeding male Newts. Endocrinology 151, 2211-2222.
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.
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.
Petkam, R., Renaud, R.L., Freitas, A.M., Canario, A.V., Raeside, J.I., Kime, D.E., and Leatherland, J.F. (2003). In vitro metabolism of pregnenolone to 7alpha-hydroxypregnenolone by rainbow trout embryos. Gen Comp Endocrinol 131, 241-249.
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.
Tsutsui, K., and Yamazaki, T. (1995). Avian neurosteroids. I. Pregnenolone biosynthesis in the quail brain. Brain Res 678, 1-9.
Yau, J.L., Noble, J., Graham, M., and Seckl, J.R. (2006). Central administration of a cytochrome P450-7B product 7 alpha-hydroxypregnenolone improves spatial memory retention in cognitively impaired aged rats. J Neurosci 26, 11034-11040.