Seminal Fluid Signalling in the Female Reproductive Tract: Implications for Reproductive Success and Offspring Health

Abstract

Carriage of sperm is not the only function of seminal fluid in mammals. Studies in mice show that at conception, seminal fluid interacts with the female reproductive tract to induce responses which influence whether or not pregnancy will occur, and to set in train effects that help shape subsequent fetal development. In particular, seminal fluid initiates female immune adaptation processes required to tolerate male transplantation antigens present in seminal fluid and inherited by the conceptus. A tolerogenic immune environment to facilitate pregnancy depends on regulatory T cells (Treg cells), which recognise male antigens and function to suppress inflammation and immune rejection responses. The female response to seminal fluid stimulates the generation of Treg cells that protect the conceptus from inflammatory damage, to support implantation and placental development. Seminal fluid also elicits molecular and cellular changes in the oviduct and endometrium that directly promote embryo development and implantation competence. The plasma fraction of seminal fluid plays a key role in this process with soluble factors, including TGFB, prostaglandin-E, and TLR4 ligands, demonstrated to contribute to the peri-conception immune environment. Recent studies show that conception in the absence of seminal plasma in mice impairs embryo development and alters fetal development to impact the phenotype of offspring, with adverse effects on adult metabolic function particularly in males. This review summarises our current understanding of the molecular responses to seminal fluid and how this contributes to the establishment of pregnancy, generation of an immune-regulatory environment and programming long-term offspring health.

Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

“…The inflammatory regulators interleukin (IL)-1α, IL-6, tumor necrosis factor α (TNF), transforming growth factor (TGF)-β1 and IL-10, and the chemokines C-C motif chemokine (CCL) 5 (RANTES), CCL20 (MIP-3α), C-X-C motif chemokine (CXCL) 1 (GRO-α) and CXCL8 (IL-8) were screened based on previously reported data on cytokine responses elicited by semen in vivo and in vitro [7,13]. …”

“…In particular, IL1A was significantly increased, whereas CCL5 was unaffected by SP treatment for both treatment time lengths. After a 12 h-incubation with SP, we detected a significant increase in the expression of additional factors of interest, namely colony stimulating factor 2 ( CSF2 ) and prostaglandin-endoperoxide synthase 2 ( PTGS2 ), that were included in the analysis because of their implication in the response to semen in vivo [7,21], and IL7 , a lymphotropic cytokine that was previously shown to promote HIV-1 replication in the FGM ex vivo [22] (Fig 2 and S2 Table). As for cytokine levels in ECM, indomethacin treatment did not significantly affect the basal expression levels of all measured factors, except for a reduction (median) of CCL5 (0.7-fold), CCL20 (0.5-fold), and IL10 (0.7-fold) after a 4 h-incubation (n = 7, p<0.05) (Fig 2 and S2 Table).…”

“…Semen is a complex mixture of cells and molecules with immunoregulatory function [6]. An inflammatory response characterized by leukocyte infiltration and upregulation of proinflammatory and growth factors occurs in the FGM soon after exposure to semen, in a highly conserved fashion among mammals [7]. This response, also called leukocytic reaction, was originally described in humans by analyzing cervical smears collected after artificial insemination, showing a significant amount of neutrophils that egressed the mucosa as early as 20 min after treatment [8,9].…”

Characterisation of mouse epididymosomes reveals a complex profile of microRNAs and a potential mechanism for modification of the sperm epigenome

“…Despite this, an analysis of the key biological pathways potentially targeted by differentially accumulating miRNAs revealed a majority centred on regulation of cellular growth and proliferation, cellular development, and cell death and survival, as might be expected of molecules involved in the maintenance of epididymal homeostasis. Given that epididymosomes also feature among the constituents of seminal fluid that are delivered to the female tract at the time of ejaculation, it must also be considered that they could exert similar regulatory control within the female reproductive with potential implications for conditioning of the periconceptual environment5051.…”

Transcriptional signatures throughout development: the effects of mouse embryo manipulation in vitro

“…Indeed, transfer of mouse zygotes following in vitro exposure to different nutritional milieu during the pronuclear stage alters birth weight in a condition-specific manner (Banrezes, et al 2011). A notable physiological feature that separates the IVC group is that these in vivo -generated embryos are exposed to seminal fluid, which can elicit unique gene expression changes (Schjenken and Robertson 2015). In addition to gene expression, protocol-specific effects have also been described for blastocyst cell number and lineage ratio, implantation efficiency, fetal and placental growth, postnatal growth and adult glucose metabolism (Kohda, et al 2011, Schwarzer, et al 2012, Scott, et al 2010).…”