Ejaculation is a complex biphasic process involving a series of neurophysiological activities, such as the contraction of a large number of muscle groups and the ejaculation of the semen from the anterior urethra (Alwaal et al., 2015). Three consecutive stages (including emission, expulsion, and orgasm) might constitute the process of ejaculation, and any problem in these stages would lead to ejaculation dysfunction (Forbes et al., 2018), such as premature ejaculation (PE) and delayed ejaculation. PE is a prevalent male ejaculation dysfunction with epidemic data showing that 20–30% of adult men are affected (Rowland, 2011; El-Hamd et al., 2019). Based on the recent definition of the International Society of Sexual Medicine (ISSM), PE is divided into two categories: lifelong PE (LPE) and acquired PE (APE) (Serefoglu et al., 2014). LPE has the following three characteristics: a) ejaculation has always occurred prior to or within about 1 min of vaginal penetration; b) those who are always or almost unable to control delayed ejaculation; and c) those who have negative personal consequences, such as distress, bother, and/or the avoidance of sexual intimacy (Parnham and Serefoglu, 2016).

Because many of the factors associated with sexual function and dysfunction are of genetic basis, this field has become a focus of attention for behavioral geneticists (Ciocanel et al., 2019). In the 1940s, Schapiro et al., have found that the incidences of PE in the male family members (fathers or brothers) of PE patients are higher than those without PE patients (Schapiro, 1943), which suggests that PE seems to be familial. This conclusion has also been confirmed by Waldinger et al. (1998). Additionally, Jern et al. (2007) conducted twin model-fitting analyses with different indicator variables of ejaculatory function based on a population sample of 3,946 twins and their siblings to investigate the genetic effects on PE and found a significant moderate genetic effect (28%) in PE, which provide a convincing proof for the above conclusion (Jern et al., 2007).

Notably, gene polymorphisms might play an important role in the etiology of LPE (Wang et al., 2021). From the recent study by Waldinger et al. (2011), we know that genetic factors might be associated with the pathogenesis of LPE. In other words, LPE might be related to some genetic factors, such as weakened central serotonin (5-HT) neurotransmission, hyperfunction of 5-HT1A receptors, and decreased 5-HT2C receptor function (Giuliano and Clément, 2006). Janssen et al. (2014) have found that 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) polymorphism is associated with the duration of the intravaginal ejaculatory latency times (IELTs) by using a stopwatch in 89 Dutchmen with LPE. Among men who ejaculate within 1 min after vaginal penetration, men with LL genotype ejaculated 100% faster than men with SS genotype and 90% faster than men with SL genotype. In addition, findings from another study have shown that Cys23Ser 5-HT2C receptor gene polymorphism might be associated with the IELTs in the Dutch Caucasian men with LPE. Moreover, men with Cys/Cys genotypes are more likely to report shorter IELTs than men with Ser/Ser genotypes (Janssen et al., 2009).

However, the quest for identifying the actual genetic loci that contribute to LPE etiology has not been successful. Jannini et al. (2015) thought that candidate gene studies of PE are much like the candidate gene studies in other fields of research (Jannini et al., 2015), which is disappointing. Due to discrepancies in the design and methods of research, the correlation of most reports was not obtained in subjective replication experiments, and the conclusions may be inconsistent. In our study, three groups of ejaculation rats, namely, “rapid, normal, and delayed,” were selected based on the animal model of PE in rats and the theory of ejaculation. Among them, the rats in the “rapid” ejaculation group can be used to stimulate humans with PE. Subsequently, we used the rat brain tissue for whole-transcriptome sequencing to screen the differential genes among the three groups and provide a theoretical basis for the targeted therapy of PE.

For human beings, ejaculation is considered one of the most amazing living phenomena in the world of biology (Giuliano, 2011). PE, ejaculation retardation, and other ejaculation dysfunction not only affect fertility but also affect the quality of sexual life (Burri et al., 2018). Therefore, the study on the molecular mechanism of brain neuroregulation during animal ejaculation will not only open up new ideas for understanding the physiological rules of animal ejaculation but also provide a new scientific basis for clinical research.

In this study, differential expression was noted using statistical analysis for a total of 12 genes (10 upregulated and 2 downregulated) in the “normal vs. PE” group, 143 genes (123 upregulated and 20 downregulated) in the “normal vs. sluggish” group, and 9 genes (6 upregulated and 3 downregulated) in the “PE vs. sluggish” group by sequencing the brain tissue of male rats in three different ejaculatory states. Further analysis showed that three genes (i.e., BGIG10116_34868, BAG3, and C7) differed between the three groups (P < 0.05). Notably, BGIG10116-34868 had significant differences among the 3 groups (P < 0.01), which has not been found earlier. To verify the accuracy of sequencing, we repeated experiments using Q-PCR, and the result was consistent with sequencing.

Further analysis of the association between lncRNA (BGIG10116_34868) and ejaculation showed that BGIG10116-34868 was correlated with EF and EL, which suggested that genetic changes may affect the ejaculation behavior.

In other animal experiments, studies have shown that after 8-OH-DPAT and dapoxetine were administered to rats in three different ejaculatory states, a large number of genes in the central nervous system could be found upregulated or downregulated, and their ejaculatory parameters also changed (Qin et al., 2017b). Santtila et al. (2010) found that carriers of the 10R10R genotype had lower scores compared with the combined 9R9R/9R10R carrier group by analyzing dopamine (DA)-transporter gene (DAT1) and four indicators (i.e., anteportal ejaculation, number of penile thrusts, ejaculation latency time, and feeling of control over ejaculation) associated with PE function, for anteportal ejaculation, number of thrusts, and feeling of control over ejaculation had a significant difference, except for ejaculation latency time.

To explore the mechanism of BGIG10116-34868, we carried out targeted predictions and found that genes, such as miR-506 and miR-105, were related. According to previous studies, miR-506 and miR-105 played a certain role in regulating the 5-HT system and the DA system. MiR-506 was a component of a cluster of X-chromosomes linked with miRNA (Yoshida et al., 2021), which had been reported to function as an important tumor suppressor in many human cancers. Peng et al. (2016) found that miR-506 acts as a tumor-suppressive agent by targeting signal transducer and activator of transcription 3 (STAT3), indicating that STAT3 was a direct target of miR-506. In addition, a study found that pharmacological inhibition of STAT3 increased the serotonin transporter (SERT) expression (also known as 5-HT transporter (5-HTT)), thus reducing depression-like behavior in wild-type rats in a depressed mouse model (Kong et al., 2015). The neurobiology of ejaculation was complex with the 5-HT transporter system playing a central role (Xia et al., 2020). Polymorphism in SLC6A4 encodes a 5-HT transporter (5-HTT) which is a major regulator of serotonin neurotransmission and is involved in the pathogenesis of PE. 5-HTT is responsible for clearing 5-HT from synapses and thus acts as a regulator of presynaptic and postsynaptic 5-HT receptor stimulation. Obviously, the change in SERT/5-HTT also has a certain effect on PE (Ye et al., 2020). As a result of all the above factors combined, we can speculate that miR-506 can regulate ejaculation function by STAT targeting SERT/5-HTT.

MiR-105 belongs to the GABRA3A gene region on the X chromosome. LncRNA has been shown to modulate the expression of DA, which is another major central neurotransmitter in psychiatric disorders. Zhao et al. (2017) reported that chronic morphine can induce a sustained increase in the expression of the D1 receptor at the glutamic-ergic terminal of projection neurons from the medial prefrontal cortex (mPFC) to the basolateral amygdala (BLA), due to downregulation of miR-105. Evidence of DA hinting to regulate male sexual behavior has been reported since the early 1970s. Studies have shown that systemic injection of selective D1-like antagonist SCH23390 can reduce the number of ejaculations before ejaculation and during the mating test in male rats (Domínguez-Salazar et al., 2014). In recent years, studies have shown that DA promotes semen excretion/ejaculation through the D2 receptor (Hyun et al., 2002). Therefore, both the DA and 5-HT systems are indispensable during ejaculation and appear to regulate sexual behavior in both men and women. DA seems to be the “trigger” for sex, while 5-HT acts as the “brake” (Qin et al., 2017a).

The etiology and pathogenesis of ejaculation dysfunction disorder are still not clear, and the genetic factors are considered to be closely related (Mostafa et al., 2020). In this context, we identified a novel gene, namely, BGIG10116-34868, by sequencing rat brain tissue, which may be a therapeutic target for PE. As a new gene, the study of this gene is still in the primary stage and there are many subsequent studies that should be needed, such as knocking out the BGIG gene of rats to observe their sexual behavior.

By sequencing rat brain tissue, we first discovered that only one unknown candidate gene, namely, BGIG10116-34868 has significant differences among the 3 groups (“rapid,” “normal,” and “sluggish”). BGIG10116-34868 is also linearly correlated with EF and EL. As a new gene, BGIG10116-34868 may be a potential target gene for PE, which provides a new direction for future research on ejaculation dysfunction.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA760464.

The animal study was reviewed and approved by Anhui Medical University LLSC20211063.

JG, HJ, and XZ conceived and designed the study, and revised the article for intellectual content. JG, RG, HL, XL, and PG acquired the data and analyzed and interpreted the data. JG, RG, PG, HL, XL, and JD drafted the article. All authors contributed to the study’s conception and design, read, and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.