Human Papillomavirus Impact on Sperm: History
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Contributor:
Arianna Sucato
,
Michela Buttà
,
Liana Bosco
,
Leonardo Di Gregorio
,
Antonio Perino
,
Giuseppina Capra

Increasing attention has been paid to understanding the causes of infertility, which is being recognized as a growing health problem affecting large numbers of couples worldwide. Male infertility is a contributing factor in approximately 30–40% of cases, and one of its etiological causes is sexually transmitted infections (STIs). Among sexually transmitted pathogens, human papillomavirus (HPV) can contribute in various ways to the failure of spontaneous and assisted reproduction, acting in the different phases of conception, especially in the early ones. In particular, HPV infection can affect sperm DNA integrity, sperm motility, count, viability, and morphology and can induce the production of anti-sperm antibodies (ASAs).

  • infertility
  • HPV infection
  • sperm parameters
  • HPV
  • DNA Fragmentation

1. Introduction

Infertility, which affects about 10–15% of couples worldwide, is a major public health concern, and male factors contribute substantially in approximately 30–40% of cases [1][2]. Male infertility is a multifactorial condition, and among the causes implicated with this status, it is possible to find genetic disorders, anatomical defects, systemic diseases, sexually transmitted infections, varicocele, oxidative stress, and erectile dysfunction as well as lifestyle factors, including smoking, diet, and radiation and xenobiotic exposure [1][3][4]. All these variables can negatively influence the processes involved in adequate sperm production, such as spermatogenesis, epididymal maturation, sperm storage, sperm transport, and accessory gland function [5]. Nevertheless, about 50% of infertile men are subject to idiopathic infertility, in which only oligospermia, asthenospermia, teratozoospermia, or other alterations are found in sperm [3].
There is considerable evidence that certain sexually transmitted infections (STI), including those caused by human immunodeficiency virus (HIV), Chlamydia trachomatis (CT), and human papillomavirus (HPV), can affect fertility [6].
HPV infection is the most common sexually transmitted infection, and almost all sexually active men and women are at risk of acquiring it during their lifetime [7][8]. The most common way in which these infections are spread is by direct contact of the skin or mucous membranes, particularly through vaginal or anal intercourse. In addition, non-penetrative sexual activities such as oral–genital, genital–genital, and hands-to-genital are potential routes of transmission [9][10].
More than 200 different types of HPV have been identified, including those acknowledged by the International Agency for Research on Cancer (IARC) as high-risk (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68), associated with cancers of the cervix, vagina, vulva, anus, head and neck, and penis; and those recognized as low-risk (HPV6 and 11) involved in the development of benign lesions, such as genital warts or condyloma acuminata [3][11][12].
Most of the time, the infection is completely asymptomatic and is cleared by the immune system within 12–24 months without any clinical sequelae [8]. When this does not occur, a persistent infection is settled, which is thought to be a prerequisite for the development of potential neoplastic hyperproliferative lesions [8].
In men, it has been discovered that HPV is present in semen as well as in several genital areas, including the penile shaft, glans, corona, scrotum, perianal, and anal regions [13][14]. HPV can affect every cellular component of the seminal fluid and could impair sperm parameters, including sperm count, motility, genomic integrity, morphology and concentration, leading to male infertility [10]. Notwithstanding, it is not known what the exact mechanism of HPV infection in spermatozoa is nor what role the infected cells play in the transmission of the virus [15]. For instance, recent studies have shown that HPV virions are able to bind to the equatorial segment of the sperm head through the interaction between L1 viral capsid protein and the proteoglycan syndecan-1 [16][17][18].
In addition, it has been speculated that infected sperm can transmit the infection to the cervix via fecundation, and as an ascending infection can even reach the placenta, causing miscarriages and infertility in couples [19][20]. Another way in which HPV could affect sperm quality is through the induction of the production of anti-sperm antibodies (ASAs), which would be responsible for sperm motility impairment [21].

2. HPV Impact on Sperm Parameters

The World Health Organization 2021 (WHO) manual defines the evaluation of sperm parameters, such as sperm count, viability, motility, morphology, and seminal fluid composition as the principal approach for semen quality assessment, as these are crucial to male fertility [22][23]. HPV infection has been linked in several studies to a decrease in progressive sperm motility and changes in immotile sperm rate, sperm morphology and concentration, although these correlations remain controversial [8][14][24][25]. The first work to report HPV-related alterations in sperm motility was conducted in 1997 by Lai et al. [26], who observed a lower curvilinear and straight-line velocity and a reduced mean amplitude of lateral head displacement of hrHPV-infected sperm cells (Table 1).
Table 1. Summary of the HPV-related effects on sperm.
Type of Infection Effect Reference
HPV positivity Increased risk of DFI > 30%, asthenozoospermia, ASAs production, and negative ART outcome (alteration in fertilization, implantation, and development of the embryo). [27][28][29]
hrHPV genotype Reduced sperm count and motility alterations. [26][30]
Multiple HPV
infections		 Hypospermia, abnormal viscosity, and increased seminal pH. [23]
HPV16 or HPV31 Sperm genomic DNA breaks and increased apoptotic events. [31]
HPV16 and
HPV18		 Exonic modification of p53 gene. [32]
In the following years, some studies confirmed these observations [18][31], whilst others [33][34] rejected these hypotheses, arguing that there is no association between HPV semen infection and impaired semen function. The detection of HPV-DNA in semen would therefore only be a secondary effect of the desquamation of penile-HPV-infected keratinocytes [35]. Damke et al. [23] conducted a study which demonstrated a correlation between HPV semen infection, mostly with multiple HPV types, and the detection of hypospermia, abnormal viscosity, and increased seminal pH (Table 1). In contrast, several works [24][33] found no clear relationship between HPV infection and alteration in seminal volume or concentration. Such disagreement could be related to the different sample sizes or methodologies used in the various studies. For instance, Damke et al. [23] based their study on 229 semen samples, whereas Rintala et al. [33] based theirs on 65 semen samples. From a methodological point of view, both studies based the semen analysis on the WHO criteria, but they used different genotyping techniques. Rintala et al. [33] used hybridization with digoxigenin-labeled high-risk HPV oligoprobes, identifying 12 genotypes; Damke et al. [23] used PCR-RFLP, which allowed the identification of a higher number of genotypes (39 genotypes). The lower number of samples and genotypes analyzed by Rintala et al. [33] compared to Damke et al. [23] may explain the lack of correlation found by the latter.
In terms of semen composition, semen generally has a pH of around 7.72 and must contain appropriate concentrations of citrate, potassium, sodium, calcium, magnesium, zinc, glucose, fructose, albumin, and proteins [36]. Since the volume of seminal vesicles and prostate secretions affects the concentration of sperm in the ejaculate, it also affects fertility and pregnancy rates [22]. Particularly, seminal vesicles produce fructose, the main sugar involved in the metabolic processes and motility of sperm, which has also a fundamental role in zinc chelation, fertilization, and sperm chromatin condensation. Meanwhile, the prostate gland is bound to the production of zinc and citric acid. The latter, whose levels are regulated by testosterone, is thought to be the main ligand of zinc, a key element in the regulation of sperm motility, germ cell maintenance, and spermatogenesis progression [37]. It has been suggested that in HPV-infected males, zinc production is not enough to condense sperm, which may be correlated with male infertility [10]. Indeed, Damke et al. [23] showed that men with HPV-positive semen may have altered proportions of prostate and seminal vesicle secretions, both associated with glandular dysfunction, which would have negative effects on fertility. Moreover, the detection in a 2013 study [38] of HPV-DNA in both epithelial and non-epithelial semen cells, as well as in semen leukocytes, supported the idea that HPV does not exclusively infect sperm cells. It can be concluded that the heterogeneous results regarding the relationship between seminal HPV-positivity and sperm quality could be due to the different targets of infection [39].

3. Correlation between HPV and Sperm DNA Fragmentation

Sperm DNA fragmentation (SDF) is a form of sperm nucleic acid damage that occurs before or after ejaculation and consists of double-stranded or single-stranded breaks [40]. At present, three main mechanisms are considered responsible for sperm DNA damage, namely impaired sperm chromatin maturation, unnatural sperm cell apoptosis, and oxidative stress [41][42].
The delivery of an undamaged paternal genome from the spermatozoa to the egg cell is essential for the correct development of the embryo [42][43]. Thus, there is a correlation between sperm DNA damage and impaired fertilization, lower embryo quality, decreased pregnancy rates, and high rates of pregnancy loss following in vitro fertilization (IVF) [40][44][45][46][47].
In light of this evidence, for the first time, the latest edition of the WHO laboratory manual for the examination/processing of human semen has included methods for evaluating the DNA fragmentation index (DFI) as an indicator of the measure of sperm DNA integrity [22]. Based on the data available in the literature, a DFI > 30% is considered predictive of infertility, while a value below 20% is considered physiological, although the WHO guidelines do not specify cut-off values [10][48]. Several techniques are considered suitable for assessing SDF, including terminal deoxynucleotidyl transferase (dUTP) nick-end-labeling (TUNEL) assay, single cell gel electrophoresis (Comet) assay, acridine orange flow cytometry (AO FCM) assay, and sperm chromatin dispersion (SCD) test (Figure 1) [22].
Ijms 24 17562 g001
Figure 1. Visualization of sperm DNA fragmentation using sperm chromatin dispersion test (SCD). (A) Normal sperms. (B) Sperms with fragmented DNA.
To the best of the knowledge, the integrity of sperm DNA is constantly affected by endogenous and exogenous elements. For example, double-strand breaks are physiologically induced during spermatogenesis to facilitate meiotic crossover and during spermiogenesis to facilitate histone-protamine replacement [48][49]. Nonetheless, other factors that are not always physiological, such as lifestyle (e.g., alcohol, smoking, drugs, diet), exposure to pollutants, diseases, aging, and infections can increase levels of SDF [8][42]. Specifically, infections of the genital tract in males lead to leukocytospermia and elevate oxidative stress in semen, resulting in DNA breakage in sperm [42]. Several studies have described the disruptive effect of infection with certain pathogens on sperm DNA integrity. These include mycoplasma, Chlamydia trachomatis, hepatitis B virus, and HPV, although for the latter, the literature’s data are not in agreement with each other [31][50][51]. Connelly and colleagues [31] showed that DNA fragmentation driven by fragments of the E6–E7 genes of HPV16 or 31 caused genomic DNA breaks and increased sperm apoptosis (Table 1). This finding was subsequently confirmed by Lee et al. [32], who demonstrated exonic modification of the p53 gene by the E6–E7 DNA fragments of HPV16 and 18, and Moreno-Sepulveda and Rajmil [27], who showed an increased risk of DFI > 30% in patients with HPV seminal infection (Table 1).
Despite this, some studies in the current literature have failed to find an association between a DFI value greater than 30% and the detection of HPV DNA in semen [17][52]. Furthermore, some years later, a correlation between the expression of an isoform of the E6 protein and the enhancement of oxidative stress-induced cellular DNA damage was highlighted [53]. In this context, Kato et al. [54] reported higher levels of superoxide dismutase (SOD), an antioxidant enzyme, in the seminal plasma of HPV-positive men compared to HPV-negative ones, suggesting the possible involvement of reactive oxygen species (ROS) in sperm DNA damage. ROS are physiologically produced in the cell microenvironment, and their correct production is crucial for different stages of fertilization [55]. However, the overproduction and imbalance of ROS causes oxidative stress, which is highly damaging to proteins, lipids, and DNA [54][55]. When the sperm cell fails to counteract effectively such effects, damaged DNA could promote HPV DNA integration [53][55]. Oxidative stress can be favored by genital tract infections, which induce an increase in seminal fluid leukocytes, capable of producing ROS [56]. Recently, it has been hypothesized to monitor the effect of various antioxidants based on SDF, but further studies are needed to propose it as a potential solution [55].

This entry is adapted from the peer-reviewed paper 10.3390/ijms242417562

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