API

Relationship: 1498

Title

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7α-hydroxypregnenolone synthesis in the brain, decreased leads to Sexual behavior, decreased

Upstream event

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7α-hydroxypregnenolone synthesis in the brain, decreased

Downstream event

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Sexual behavior, decreased

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of CYP7B activity leads to decreased reproductive success via decreased sexual behavior non-adjacent

Taxonomic Applicability

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Term Scientific Term Evidence Link
Japanese quail Coturnix japonica NCBI
Cynops pyrrhogaster Cynops pyrrhogaster NCBI

Sex Applicability

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Sex Evidence
Male

Life Stage Applicability

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Term Evidence
Adult, reproductively mature

Key Event Relationship Description

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Gonadal steroid and prolactin are required to initiate a cascade of molecular events leading to sexual behavior. The cumulation of these reactions leads to the secretion of 7α-hydroxypregnenolone in the brain, a neurosteroid that acts as a trigger on sexual behavior.

7α-hydroxypregnenolone is synthesized by CYP7B in the telencephalon of both male and female. Its concentration fluctuates in the male brain according to season and light exposure, whereas it remains low in female. In agreement with the variation in 7α-hydroxypregnenolone concentration is the variation in sexual behavior frequency in male. Indeed, it was previously noted that 7α-hydroxypregnenolone peaked during the breeding period, increasing locomotor activity and frequency of tail-vibrating behavior (newt) or chasing, crowing, strutting, and mounting (bird).

Other components are required to induce sexual behavior since injection of 7α-hydroxypregnenolone in sexually immature newt has no effect on this specific parameter. However, no sexual behavior can be elicited in absence of 7α-hydroxypregnenolone.

Evidence Supporting this KER

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Biological Plausibility

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It is known that 7α-hydroxypregnenolone is secreted in the diencephalon. However, the fine-tuning mechanism of its regulation is still undetermined.

In newt, the neurosteroid secretion is driven by melatonin and prolactin, an important circadian and breeding regulator, respectively (Matsunaga et al., 2004; Tsutsui et al., 2008). Prolactin is synthetized in the hypophysis and is one of the molecules required to initiate the cascade of molecular events leading to sexual behavior in newt (Kikuyama et al., 1980). In male newt, it induces a dose-dependent activation of sexual behavior. Immunofluorescence experiments conducted on newt brain sections revealed the presence of prolactin receptors on neurons expressing CYP7B, which could explain the direct correlation between prolactin and 7α-hydroxypregnenolone secretion in relation to sexual behavior.

Quail are highly sensitive to light exposure and their behavior mostly relies on circadian rhythm. Melatonin secretion, high during the night, is known to inhibit CYP7B activity in male brain, which, in turn, decreases 7α-hydroxypregnenolone concentration. Following the same pattern, sexual behavior in male quail is high during the day and significiantly lower at night.

A decrease in sexual behavior can be induced by steroid hormones deregulation since their involvement in the regulation of sexual behavior is prominent. Indeed, castration of male bird induces a decrease/loss of reproductive behavior, which can be rescued by a testosterone therapy (Adkins and Adler, 1972). The same effect can be induced in bird by transferring them from a 16-hr.-light 8-hr.-dark cycle to an 8-hr.- light 16-hr.-dark cycle, which demonstrates the photoperiodic regulation of sexual behavior in bird (Sach, 1967). 

Empirical Evidence

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  • In male newt, 7α-hydroxypregnenolone concentration in the brain peaks in April and October, similarly to their sexual behavior (Haraguchi et al., 2010).
  • Intracranial injection of 7α-hydroxypregnenolone in male newt increased tail-vibration (the newt sexual behavior) incidence and frequency in a dose-dependent manner (Toyoda et al., 2012). In male quail, sexual behavior (frequency of chasing, pecking, head grabbing, mounting, and cloacal contact movement) was also increased in a dose-dependent manner following 7α-hydroxypregnenolone injection (Ogura et al., 2016).
  • Ketoconazole, a CYP7B inhibitor, prevented 7α-hydroxypregnenolone synthesis in vivo and abolished sexual behavior when given to male quail and newt. The behavior in ketoconazole-treated animals was successfully retrieved with 7α-hydroxypregnenolone supplementation or after ketoconazole treatment was stopped (Toyoda et al., 2012; Ogura et al., 2016).

A decrease in sexual behavior can be induced by steroid hormones deregulation since their involvement in the regulation of sexual behavior is prominent. Indeed, castration of male bird induces a decrease/loss of reproductive behavior, which can be rescued by a testosterone therapy (Adkins and Adler, 1972). The same effect can be induced in bird by transferring them from a 16-hr.-light 8-hr.-dark cycle to an 8-hr.- light 16-hr.-dark cycle, which demonstrates the photoperiodic regulation of sexual behavior in bird (Sach, 1967). 

Uncertainties and Inconsistencies

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Courtship and sexual behavior is due to the synergistic effect of multiple hormones (Iwata et al., 2000). 7α-hydroxypregnenolone is one of them and it was shown to be essential for sexual behavior, but it is not sufficient in itself to trigger sexual behavior in absence of prolactin (secreted in sexually mature animals during the breeding season).  

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Kikuyama, S., Yamamoto, K., Seki T. (1980). Prolactin and its role in growth, metamorphosis and reproduction in amphibians, Gunma Symp. Endocrinol., 17, 3–13

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.