SNAPSHOT

1386: CYP7B activity, inhibition

Short Name: CYP7B activity, inhibition

AOPs Including This Key Event

Stressors

Ketoconazole

It is clearly demonstrated that ketoconazole directly inhibits CYP7B (Matsunaga et al., 2004). It is expected for the other members of the conazole family to have the same effect.

Some other azoles such as clotrimazole can also inhibit CYP7B activity (Liu et al., 2011; Rose et al., 1997). 

Tebuconazole

In vitro, tebuconazole was shown to bind to the catalytic site of the human recombinant CYP7B and to inhibit its catalytic activity (Yantsevich et al., 2014). 

Propiconazole

In vitro, propiconazole was shown to bind to the catalytic site of the human recombinant CYP7B and to inhibit its activity (Yantsevich et al., 2014).

Tioconazole

In vitro, tioconazole was shown to bind to the catalytic site of the human recombinant CYP7B and to inhibit its activity (Yantsevich et al., 2014).

Miconazole

In vitro, miconazole was shown to bind to the catalytic site of the human recombinant CYP7B and to inhibit its activity (Yantsevich et al., 2014).

Fluconazole

In vitro, fluconazole was shown to bind to the catalytic site of the human recombinant CYP7B and to inhibit its activity (Yantsevich et al., 2014).

Voriconazole

In vitro, voriconazole was shown to bind to the catalytic site of the human recombinant CYP7B and to inhibit its activity (Yantsevich et al., 2014).

Clotrimazole

Clotrimazoles can inhibit CYP7B activity (Liu et al., 2011; Rose et al., 1997). 

Evidence for Perturbation of this Molecular Initiating Event by Stressor

The binding of inhibitors to CYP7B is demonstrated in vitro with purified recombinant protein in presence of the inhibitor. Ligand-induced spectral changes is analyzed using spectrophotometric titration as a shift of the heme (Yantsevich et al., 2014). 

Ketoconazole and other conazole are known to bind to CYPs preventing its enzymatic activity.

• CYP7B inhibitor (ketoconazole, 10^-4 M) decreased the synthesis of 7α-hydroxypregnenolone
• CYP7B inhibitor (intracerebroventricular injection of ketoconazole) decreased the synthesis of 7α-hydroxypregnenolone in the male quail and newt brain, in vivo (Matsunaga et al., 2004; Rose et al., 1997; Tsutsui et al., 2008). 
• The heme prosthetic group (catalytic site) of human recombinant CYP7B thightly bound to various imidazole- and triazole-based drugs in an in vitro spectrometric titration assay. The drugs with the highest affinities were the industrial pesticides tebuconazole (0.11 μm), propiconazole (0.13 μm) and the antifungal drugs tioconazole (0.15 μm) and miconazole (0.23 μm). Voriconazole and metyrapone (non-azole compound) also interacted with CYP7B (Yantsevich et al., 2014). 

Biological Organization

Taxonomic Applicability

Life Stage Applicability

Sex Applicability

CYP7B 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

1387: 7α-hydroxypregnenolone synthesis in the brain, decreased

Short Name: 7α-hydroxypregnenolone synthesis in the brain, decreased

AOPs Including This Key Event

Stressors

Biological Organization

Taxonomic Applicability

Life Stage Applicability

Sex 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

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). 

1388: Dopamine release in the brain, decreased

Short Name: Dopamine release in the brain, decreased

AOPs Including This Key Event

Biological Organization

Taxonomic Applicability

Life Stage Applicability

Sex Applicability

Dopamine is used as a neurotransmitter in multicellular animals (Barron et al., 2010). Across a wide range of vertebrates, dopamine has an "activating" effect on behavior-switching and response selection, comparable to its effect in mammals. 

1389: Locomotor activity, decreased

Short Name: Locomotor activity, decreased

AOPs Including This Key Event

Biological Organization

Taxonomic Applicability

Sex Applicability

Measurement of locomotor activity can be performed on any motile animal. 

1141: Decreased, Reproductive Success

Short Name: Decreased, Reproductive Success

AOPs Including This Key Event

Biological Organization

442: Decreased, Population trajectory

Short Name: Decreased, Population trajectory

AOPs Including This Key Event

Biological Organization

CYP7B activity, inhibition leads to 7α-hydroxypregnenolone synthesis in the brain, decreased

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

The vertebrate brain expresses all the enzymes involved in the different steroidogenic pathways (do Rego and Vaudry, 2016; Tsutsui et al., 1999).

The physiological function of 7α-hydroxypregnenolone is more understood in birds, newts, and rats than in human. However, the direct causal effect between CYP7B inhibition and the decrease in 7α-hydroxyPREG was demonstrated in human, fish and other vertebrates (Haraguchi et al., 2015; Yantsevich et al., 2014; Yau et al., 2006). 

Therefore, it is plausible that this KER is applicable to all vertebrates. 

How Does This Key Event Relationship Work

Neurosteroids are steroids synthesized in the brain that interact with cell surface receptors or ligand-gated ion channels in order to modify the neuronal excitability (Paul and Purdy, 1992). They are involved in numerous biological functions including locomotor activity, memory, learning, sexually-dimorphic behaviors and anxiety.

Neurosteroids are synthesized from pregnenolone or its derivatives by different cytochromes P450. Among these CYPs is CYP7B hydroxylase which synthesizes the neurosteroid 7α-hydroxypregnenolone. CYP7B is the only enzyme responsible for the synthesis of this neurosteroid. Therefore, its inhibition induces a decrease in 7α-hydroxypregnenolone concentration in the brain.

The expression of CYP7B and the synthesis of its molecular product vary cyclically on a daily and/or seasonal basis. In male quail, a diurnal animal, CYP7B expression and 7α-hydroxypregnenolone are inhibited by melatonin secretion, a hormone involved in circadian rhythm and sleep regulation. Oppositely, in a nocturnal animal such a newt, melatonin acts as an inducer of CYP7B expression and 7α-hydroxypregnenolone synthesis. These results indicate that CYP7B expression and therefore 7α-hydroxypregnenolone synthesis follow a circadian rhythm regulation.  

In addition to this daily variation, CYP7B and its product are regulated by seasons in salmon and male newt where it peaks during homing migration (salmon) and breeding (newt) period (Haraguchi et al., 2009). It is plausible that the same seasonal variation occurs in avian.

Weight of Evidence

Biological Plausibility

The vertebrate brain expresses all the enzymes involved in the different steroidogenic pathways, including CYP7B (review do Rego and Vaudry, 2016; Tsutsui and Yamazaki, 1995).  These enzymes in the brain are known to convert cholesterol into pregnenolone, the precursor of 7α-hydroxypregnenolone Therefore, the brain possesses both the molecular precursor and the enzyme required to synthesized 7α-hydroxypregnenolone. Since CYP7B is the only enzyme known to synthesize 7α-hydroxypregnenolone, its inhibition is assumed to decrease 7α-hydroxypregnenolone concentration in the brain.

In the quail brain, the precise localization of CYP7B protein was explored and the results were as followed: nucleus preopticus medialis (POM), the nucleus paraventricularis magnocellularis (PVN), the nucleus ventrodedialis hypothalami (VMN), the nucleus dorsolateralis anterior thalami (DLA) and the nucleus lateralis anterior thalami (LA) (Tsutsui et al., 2008).

In the salmon, cells expressing CYP7B are mainly localized in the magnocellular preoptic nucleus, oculomotor nucleus, nucleus lateralis valvulae, and nucleus lateralis valvulae (Haraguchi et al., 2015). 

In the newt brain, CYP7B cells are mainly localized in the anterior preoptic area, the magnocellular preoptic nucleus, and the tegmental area. It was also detected in the lateral and dorsal pallium, the suprachiasmatic nucleus, the ventral hypothalamic nucleus, and the tectum mesencephali (Haraguchi et al., 2010).

Empirical Support for Linkage

• CYP7B inhibitor (ketoconazole, 10^-4 M) decreased the synthesis of 7α-hydroxypregnenolone in vitro (Tsutsui et al., 2008; Matsunaga et al., 2008; Toyoda et al., 2012).
• CYP7B inhibitor (intracerebroventricular injection of ketoconazole, 5 μg, from 5 AM to 6 AM) decreased the synthesis of 7α-hydroxypregnenolone in the brain (quail) in vivo (Tsutsui et al., 2008).
• CYP7B activity is regulated (inhibited) by melatonin in male quail. When male quail brains were injected (intracerebroventricular) with a melatonin receptor antagonist (luzindole), the production of 7α-hydroxypregnenolone significantly increased (Tsutsui et al., 2008). The opposite effect was observed on newt where melatonin stimulated 7α-hydroxypregnenolone synthesis (Koyama et al., 2009). 
• Similarly, orbital enucleation and pinealectomy performed on male quail, which abolished melatonin synthesis, induces a significant increase in 7α-hydroxypregnenolone concentration (Tsutsui et al., 2008).  

Uncertainties or Inconsistencies

 

 

 

Quantitative Understanding of the Linkage

Little is known about the dose-response of CYP7B inhibitors. This information is lacking in the literature. 

One experiment conducted in vitro with mouse recombinant enzyme showed that 1 µM clotriconazole significantly decreased CYP7B activity while 10 µM abolished it (Rose et al., 1997). However, the subtrate used in the experiment was DHEA meaning that the measured product was 7α-hydroxyDHEA. It is highly plausible that the same result would have been observed with pregnenolone as a substrate for CYP7B and 7α-hydroxypregnenolone as a product. 

 

References

do Rego, J.L., and Vaudry, H. (2016). Comparative aspects of neurosteroidogenesis: From fish to mammals. Gen Comp Endocrinol 227, 120-129.

Haraguchi, S., Matsunaga, M., Koyama, T., Do Rego, J.L., and Tsutsui, K. (2009). Seasonal changes in the synthesis of the neurosteroid 7alpha-hydroxypregnenolone stimulating locomotor activity in newts. Ann N Y Acad Sci 1163, 410-413.

Haraguchi, S., Koyama, T., Hasunuma, I., Vaudry, H., and Tsutsui, K. (2010). Prolactin increases the synthesis of 7α-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.

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.

Paul, S.M., and Purdy, R.H. (1992). Neuroactive steroids. FASEB J 6, 2311-2322.

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., Ukena, K., Takase, M., Kohchi, C., and Lea, R.W. (1999). Neurosteroid biosynthesis in vertebrate brains. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 124, 121-129.

Tsutsui, K., and Yamazaki, T. (1995). Avian neurosteroids. I. Pregnenolone biosynthesis in the quail brain. Brain Res 678, 1-9.

Yantsevich, A.V., Dichenko, Y.V., Mackenzie, F., Mukha, D.V., Baranovsky, A.V., Gilep, A.A., Usanov, S.A., and Strushkevich, N.V. (2014). Human steroid and oxysterol 7alpha-hydroxylase CYP7B1: substrate specificity, azole binding and misfolding of clinically relevant mutants. FEBS J 281, 1700-1713.

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.

CYP7B activity, inhibition leads to Locomotor activity, decreased

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

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. 

How Does This Key Event Relationship Work

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.

Weight of Evidence

Biological Plausibility

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). 

Empirical Support for Linkage

• 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 or 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.

Quantitative Understanding of the Linkage

No information is available at this moment. 

 

References

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.

7α-hydroxypregnenolone synthesis in the brain, decreased leads to Locomotor activity, decreased

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

How Does This Key Event Relationship Work

The presence of 7α-hydroxypregnenolone in the brain is associated with locomotor activity in the salmon and in the male bird and newt. 7α-hydroxypregnenolone is a neurosteroid synthesized from pregnenolone by CYP7B in vertebrates including bird, newt, and fish. When 7α-hydroxypregnenolone concentration increases in the brain (endogenous or exogenous), these animals become active. Oppositely, decreased synthesis of 7α-hydroxypregnenolone limits locomotor activity (Matsunaga et al., 2004).  

The importance of 7α-hydroxypregnenolone synthesis is sex dependent in bird and newt. In these species, only male locomotor activity is influenced by the neurosteroid (Matsunaga et al., 2004, Tsutsui et al., 2008). However, both male and female are affected by 7α-hydroxypregnenolone in salmon (haraguchi et al., 2015). 

It was known before that locomotor activity in vertebrates fluctuated over a circadian and/or seasonal cycle, although the full mechanism was elusive (Saper et al., 2005). The discovery of 7α-hydroxypregnenolone activity in the brain allowed a better understanding of the locomotor activity regulation in the context of cyclic variations of the environment.

Weight of Evidence

Biological Plausibility

The relationship between 7α-hydroxypregnenolone and locomotor activity is clearly established in quail, newt and salmon. However, the regulation of its synthesis differs in these species.

In diurnal bird such as quail, melatonin secretion during nighttime inhibits 7α-hydroxypregnenolone synthesis which is reflected by the decreased locomotor activity. Under daylight condition, melatonin secretion is abolished which induces an increase in 7α-hydroxypregnenolone and stimulates locomotor activity (Tsutsui et al., 2008). 

Oppositely, newt is a nocturnal animal and melatonin secretion acts as an inducer of 7α-hydroxypregnenolone synthesis. Consequently, 7α-hydroxypregnenolone is elevated at night and drives locomotor activity (Koyama et al., 2009). 

7α-hydroxypregnenolone concentration 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). 

Empirical Support for Linkage

• Intracranial injection of 7α-hydroxypregnenolone induced a significant increase in salmon, male quail and newt locomotor activity. The same injection had no effect on female quail and newt (Haraguchi et al., 2015). 
• Intracranial injection of ketoconazole, an inhibitor of 7α-hydroxypregnenolone synthesis, in male quail and newt decreases locomotor activity. The same injection had no effect on female quail and newt (Matsunaga et al., 2004, Tsutsui et al., 2008). 
• Intracranial delivery of melatonin, an inhibitor of 7α-hydroxypregnenolone synthesis, decreases locomotor activity in male quail (Tsutsui et al., 2008). 
• The concentration of 7α-hydroxypregnenolone in the male quail diencephalon is high between 7 AM and 1 PM and peaks at 11 AM. The locomotor activity follows the same pattern. However, the concentration of 7α-hydroxypregnenolone in the female brain is constantly low which correlates with their low locomotor activity.
• Decreased 7α-hydroxypregnenolone in the salmon brain induced by aminoglutethimide (an inhibitor of CYP11A which induces a depletion of pregnenolone and a concurrent decline in 7α-hydroxypregnenolone concentration) abolishes salmon homing migration (Haraguchi et al., 2015). 

Uncertainties or Inconsistencies

No inconsistency was reported so far. 

Quantitative Understanding of the Linkage

• 7α-hydroxypregnenolone injected in the quail brain (0, 10, or 100 ng) induced a dose-dependent increase of locomotor activity (Tsutsui et al., 2008). 
• The same experiment was conducted in the newt using 0.1, 0.5, or 1 ng. A dose-dependent increase of locomotor activity was observed (Matsunaga et al., 2004).  
• The same experiment was conducted in the chicken using 0.10, or 200 ng. A dose-dependent increase of locomotor activity was observed (Hatori et al., 2011). 

 

References

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.

Hatori M, Hirota T, Iitsuka M, et al. Light-dependent and circadian clock-regulated activation of sterol regulatory element-binding protein, X-box-binding protein 1, and heat shock factor pathways. Proc Natl Acad Sci U S A. 2011;108:4864–9

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.

Saper, C.B., Lu, J., Chou, T.C., and Gooley, J. (2005). The hypothalamic integrator for circadian rhythms. Trends Neurosci 28, 152-157.

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.

 

7α-hydroxypregnenolone synthesis in the brain, decreased leads to Dopamine release in the brain, decreased

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

How Does This Key Event Relationship Work

7α-hydroxypregnenolone is synthesized in the diencephalon and the rhombencephalon (newt only) and has a paracrine effect on dopaminergic neurons that project into the telencephalon including the striatum. 

 

Weight of Evidence

Biological Plausibility

7α-hydroxypregnenolone cannot be directly related to dopamine release since it has no known receptor and the cells that synthesize it are not in direct contact with the dopaminergic neurons. However, it was shown that 7α-hydroxypregnenolone release induces dopamine secretion in the brain.

 

Empirical Support for Linkage

• 7α-hydroxypregnenolone concentration in the brain of salmon prior to upstream migration was decreased using aminoglutethimide (AG) injection (CYP11A inhibitor) and lead to a decreased dopamine concentration in the telencephalon compared to control. This effect was rescued with intracerebroventricular injection of 7α-hydroxypregnenolone. Simultaneous measurements of hypothalamic dopamine concentration showed an absence of variation after AG-injection or AG+7 PREG (Haraguchi et al., 2015)

• Tyrosine hydroxylase (TH) is a marker of dopamine neurons. Immunolabelling of CYP7B and TH revealed that these enzymes are  expressed in two different cell populations in the salmon magnocellular preoptic nucleus and that they are in close proximity to each other (Haraguchi et al., 2015).

• 7α-hydroxypregnenolone (1 ng) was injected in non-breeding male newt and several monoamines concentration were measured using HPLC-electrochemical detection. 7α-hydroxypregnenolone increased dopamine concentration in the rostral brain region including striatum. No change was observed in the concentration of any other monoamine (Matsunaga et al., 2004).

• Newt brain incubated in vitro with 7α-hydroxypregnenolone (0, 10⁻⁸, 10⁻⁷, or 10⁻⁶ M) induced a dose-dependent increase of dopamine concentration after 10 minutes (Matsunaga et al., 2004).

Uncertainties or Inconsistencies

Since the neurosteroid receptor has yet to be identified, no direct interaction between 7α-hydroxypregnenolone and dopaminergic neuron has been demonstrated. It is thus possible that an intermediate event takes place in between to indirectly connect the neurosteroid to dopamine release.

Quantitative Understanding of the Linkage

One study specifically performed a dose-reponse experiment for 7α-hydroxypregnenolone in relation to dopamine concentration.

• Newt brain incubated with 7α-hydroxypregnenolone (0, 10⁻⁸, 10⁻⁷, or 10⁻⁶ M) induced a dose-dependent increase of dopamine concentration after 10 minutes (Matsunaga et al., 2004). 

References

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.

 

Dopamine release in the brain, decreased leads to Locomotor activity, decreased

AOPs Referencing Relationship

Locomotor activity, decreased leads to Decreased, Reproductive Success

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

How Does This Key Event Relationship Work

A decrease in locomotor activity can be detrimental for the animal since it can limit exploration of territory, search for mating partner, and food consumption. It can also increase vulnerability to predation. Thus, a decrease in locomotor activity can have multiple effects that synergetically contribute to decreasing reproductive success. 

 

Weight of Evidence

Biological Plausibility

Locomotor performance measured in the laboratory has frequently been used as a surrogate for fitness in animals (Bennett and Huey, 1990). In an environment with easily accessible food, the impact of a decreased locomotor activity are minimal. However, in a hostile environment that requires extensive foraging, insufficient locomotor activity can limit food intake and induce energetic deficit which, in turn, affects the energy available for reproduction. Similarly, a decreased locomotor activity is likely to limit the ability to escape predation and, consequently, to impair reproduction. 

In a context of high competition between males for sexually-matured females, a decreased locomotor activity can limit the reproductive success. 

Empirical Support for Linkage

In nature, locomotion, feeding and mate searching are interrelated behaviors.

• In a behavioral experiment, it was concluded that locomotor activity was correlated with the chemo-investigative behavior of nose tapping, a behavior used in both foraging and mate searching in the plethodontid salamanders (Schubert et al., 2006).

• It is predicted that suppression of locomotor activity by an acute stressor likely incurs costs to foraging and reproduction in salamender (Desmognathus ochrophaeus) (Ricciardella et al., 2010). 

• In lizards, male behaviour (including social interactions and general locomotion) had a positive correlation that explained 81% of fertilization success. More active males sired offspring from more clutches (R2=0.9, F _1,7 = 56.12; P = 0.002). This correlation could be the result of an increased probability of encountering receptive female and thus reproductive success when male are active and traverse their territory (Keogh et al., 2012).

• The same observation was made in bird and newt. Indeed, increased locomotory activity in breeding male is believed to contribute to the rapid encounter of the male with a sexually mature female (Jones et al., 2001; Tsutsui et al., 2013).

• Lizards exposed to pesticides had decreased fitness caused by a decrease in locomotor performance. This sublethal effect is believed to decrease individual’s ability to avoid predators, capture prey, and defend territories (DuRant et al., 2007).

 

Quantitative Understanding of the Linkage

It is reasonnable to believe that all mobile animals using sexual reproduction could experience a decline in reproductive success following a decreased locomotor activity. 

References

Bennett A.F., Huey R.B., Studying the evolution of physiological performance, Oxford Surv. Evol. Biol., 7 (1990), pp. 251-284

DuRant S.E., Hopkins W.A., Talent L.G., Impaired terrestrial and arboreal locomotor performance in the western fence lizard after exposure to an AChE-inhibiting pesticide, Environmental Pollution, Volume 149, Issue 1, 2007, Pages 18-24,

E.K.M. Jones , N.B. Prescott , P. Cook , R.P. White & C.M. Wathes (2001) Ultraviolet light and mating behaviour in domestic broiler breeders, British Poultry Science, 42:1, 23-32

Gavrilov V.V., Veselovskaya E.O., Gavrilov V.M., Goretskaya M.Y, and Morgunova G.V. (2013). Diurnal Rhythms of Locomotor Activity, Changes in Body Mass and Fat Reserves, Standard Metabolic Rate, and Respiratory Quotient in the FreeLiving Coal Tit (Parus ater) in the Autumn–Winter Period. Biology Bulletin, Vol. 40-8, pp. 678–683.

 Keogh JS, Noble DWA, Wilson EE, Whiting MJ (2012) Activity Predicts Male Reproductive Success in a Polygynous Lizard. PLoS ONE 7(7): e38856

Ricciardella L.F., Bliley J.M., Feth C.C., Woodley S.K. (2010). Acute stressors increase plasma corticosterone and decrease locomotor activity in a terrestrial salamander (Desmognathus ochrophaeus), Physiology & Behavior, Vol.101-1, pp. 81-86

Schubert S.N., Houck L.D., Feldhoff P.W., Feldhoff R.C., Woodley S.K. (2006). Effects of androgens on behavioral and vomeronasal responses to chemosensory cues in male terrestrial salamanders (Plethodon shermani). Horm Behav, 50, pp. 469–476

Tsutsui, Kazuyoshi et al. “New Biosynthesis and Biological Actions of Avian Neurosteroids.” Journal of Experimental Neuroscience 7 (2013): 15–29. PMC. Web. 26 June 2017.

Decreased, Reproductive Success leads to Decreased, Population trajectory

AOPs Referencing Relationship