Male infertility, female fertility and extrapair copulations

Females that are socially bonded to a single male, either in a social monogamy or in a social polygyny, are often sexually polyandrous. Extrapair copulations (EPC) have often been suggested or rejected, on both empirical and theoretical grounds, as an important mechanism that enables females to avoid fertility risks in case their socially bonded male is infertile. Here, we explore this possibility in two steps. First, we present a mathematical model that assumes that females have no precopulatory information about male fertility, and shows that a female EPC strategy increases female reproductive success only if certain specific conditions are upheld in the nature of male infertility. In particular, these conditions require both (i) that fertile sperm precedence (FSP) is absent or incomplete within ejaculates of the same male (i.e. that an infertile male is, at least partly, truly infertile), and (ii) the existence of FSP among ejaculates of different males (such that infertile spermatozoa of the infertile male are at a disadvantage when competing against spermatozoa of a fertile male). Second, to evaluate their potential role in the evolution of female EPC, we review the abundance and FSP patterns of the different male infertility types. The conclusion is drawn that some common infertility types, such as poor sperm count or motility, contribute to the evolution of female EPC, whereas other common infertility types, such as sperm depletion or allocation in a social monogamy (but not in a social polygyny), and in particular male driven polyspermy, do not. Also, a deeper look at the arms race between sperm fertilization efficiency and female barriers to sperm may answer the non‐trivial question: “why are some types of infertility so common?”     

Immunodominant semen proteins I: New patterns of sperm proteins related to female immune infertility

Infertility affects approximately 10% of couples at reproductive age. Semen constituents may be potential immunogenic structures for women. The aim of our work is to detect and identify sperm proteins interacting with serum IgG antibodies from women with fertility disorders. The biochemical characterization of sperm antigens was performed using one and two dimensional gel electrophoresis, both of which were followed by immunoblotting. The IgG-binding proteins of interest were identified using mass spectrometry. From the serum pool of 30 infertile women, we detected sperm antigens within a relative molecular mass range between 30–80 kDa with an isoelectric point of 4–7. No antigens were detected using the serum pool from 10 fertile women (control group). Heat shock proteins (HSP 70) were identified as major sperm antigens associated with female immune infertility. Additionally, we report for the first time that alpha-enolase is a significant sperm antigen from the serum pool of infertile women. We suggest that the IgG-binding proteins identified in our study are related to immune infertility in the case of certain women with abnormally high levels of IgG antibodies linked to sperm proteins. Our results might be useful in the diagnoses of female immune infertility and may provide potential targets for further therapeutic treatment.     

Male genital tract chlamydial infection: implications for pathology and infertility

Chlamydia trachomatis infections are prevalent worldwide, but current research, screening, and treatment are focused on females, with the burden of disease and infertility sequelae considered to be a predominantly female problem. The prevalence of chlamydial infection, however, is similar in males and females. Furthermore, a role for this pathogen in the development of male urethritis, epididymitis, and orchitis is widely accepted. The role of Chlamydia in the development of prostatitis is controversial, but we suggest that Chlamydia is an etiological agent, with incidences of up to 39.5% reported in patients with prostatitis. Infection of the testis and prostate is implicated in a deterioration of sperm, possibly affecting fertility. Chlamydia infections also may affect male fertility by directly damaging the sperm, because sperm parameters, proportion of DNA fragmentation, and acrosome reaction capacity are impaired with chlamydial infection. Furthermore, the proportion of male partners of infertile couples with evidence of a Chlamydia infection is greater than that documented in the general population. An effect of male chlamydial infection on the fertility of the female partner also has been reported. Thus, the need for a vaccine to protect both males and females is proposed. The difficulty arises because the male reproductive tract is an immune-privileged site that can be disrupted, potentially affecting spermatogenesis, if inappropriate inflammatory responses are provoked. Examination of responses to infection in humans and in experimental animal models suggest that an immunoglobulin A-inducing vaccine will be able to target the male reproductive tract effectively while avoiding harmful inflammatory responses that may impair fertility.     

Calsperin is a testis-specific chaperone required for sperm fertility

Calnexin (CANX) and calreticulin (CALR) are homologous lectin chaperones located in the endoplasmic reticulum and cooperate to mediate nascent glycoprotein folding. In the testis, calmegin (CLGN) and calsperin (CALR3) are expressed as germ cell-specific counterparts of CANX and CALR, respectively. Here, we show that Calr3(-/-) males produced apparently normal sperm but were infertile because of defective sperm migration from the uterus into the oviduct and defective binding to the zona pellucida. Whereas CLGN was required for ADAM1A/ADAM2 dimerization and subsequent maturation of ADAM3, a sperm membrane protein required for fertilization, we show that CALR3 is a lectin-deficient chaperone directly required for ADAM3 maturation. Our results establish the client specificity of CALR3 and demonstrate that the germ cell-specific CALR-like endoplasmic reticulum chaperones have contrasting functions in the development of male fertility. The identification and understanding of the maturation mechanisms of key sperm proteins will pave the way toward novel approaches for both contraception and treatment of unexplained male infertility.     

Does immunity regulate ejaculate quality and fertility in humans?

The production of high-quality ejaculates may represent significantcosts during male reproduction. Spermatozoa are perceived asnonself by the immune system and are exposed to immunologicalattacks in the male reproductive tract. Autoimmunity to spermatozoaresults in the production of antisperm antibodies that reducesperm quality and hence fertility. Thus, males are dependenton the testis being an immunoprivileged site to reduce immunologicalreactions against their own sperm, and immunoprivilege is obtainedby the blood-testis barrier and by hormonal immunosuppression.A meta-analysis on the effects of immunosuppressive corticosteroidtreatment of male infertility revealed that treatment reducedthe level of antisperm antibodies, improved sperm motility andsperm count, and increased conception rate. These results emphasizethe importance of immunosuppression and the associated pathogenicityfrom infectious organisms as important costs for the productionof high-quality ejaculates.     

The testis‐specific gene 1700102P08Rik is essential for male fertility

Male infertility is a rising problem around the world. Often the cause of male infertility is unclear, and this hampers diagnosis and treatment. Spermatogenesis is a complex process under sophisticated regulation by many testis‐specific genes. Here, we report the testis‐specific gene 1700102P08Rik is conserved in both the human and mouse and highly expressed in spermatocytes. To investigate the role of 1700102P08Rik in male fertility, knockout mice were generated by CRISPR‐Cas9. 1700102P08Rik knockout male mice were infertile with smaller testis and epididymis, but female knockout mice retained normal fertility. Spermatogenesis in the 1700102P08Rik knockout male mouse was arrested at the spermatocyte stage, and no sperm were found in the epididymis. The deletion of 1700102P08Rik causes apoptosis in the testis but did not affect the serum concentration of testosterone, luteinizing hormone, and follicle‐stimulating hormone or the synapsis and recombination of homologous chromosomes. We also found that 1700102P08Rik is downregulated in spermatocyte arrest in men. Together, these results indicate that the 1700102P08Rik gene is essential for spermatogenesis and its dysfunction leads to male infertility.     

Inbreeding in three‐spined sticklebacks (Gasterosteus aculeatus L.): effects on testis and sperm traits

Mating between relatives often results in inbreeding depression, and is assumed to have a strong effect on fitness traits such as fertility and gonad/gamete quality. However, data concerning this topic are contradictory and particularly scarce in fishes. Three‐spined sticklebacks (Gasterosteus aculeatus L.) show inbreeding depression in fertilization and hatching success, survival rates, body symmetry and behavioural traits. To date, any knowledge of the impact of inbreeding on males' gonads and gametes is lacking in this species. In the present study, testis and sperm traits were quantified in outbred and inbred males. Overall, these traits were not generally impaired by inbreeding, and this result was not changed by a second/third generation of brother–sister matings. However, testes brightness, a potential measure of oxidative stress, was negatively correlated with sperm number. Additionally, inbred males with higher body condition had significantly brighter testes, whereas their sperm number was significantly negatively correlated with sperm quality (as estimated by head volume). Such a trade‐off did not appear in outbred males. The comparatively small impact of inbreeding on testis and sperm traits might be explained by the low number of inbred individuals that reached the reproductive phase. © 2012 The Linnean Society of London, Biological Journal of the Linnean Society, 2012, 107 , 510–520.     

Infertile matings and sperm competition: the effect of "nonsperm representation" on intraspecific variation in sperm precedence patterns

In theoretical and experimental approaches to the study of sperm competition, it is often assumed that ejaculates always contain enough sperm of good quality and that they are successfully transferred and used for fertilization. However, this view neglects the potential effects of infertility and sperm limitation. Permanent or temporal male infertility due to male sterility, insemination failures, or failures to fertilize the ova implies that some males do not achieve sperm representation in the female reproductive tract after mating. A review of the literature suggests that rates of nonsperm representation may be high; values for the proportion of infertile matings across 30 insect species vary between 0% and 63%, with the median being 22%. I simulated P2 (the proportion of offspring fathered by the second male to copulate with a female in a double-mating trial) distributions under a mechanism of random sperm mixing when sample sizes and rates of male infertility varied. The results show that nonsperm representation can be responsible for high intraspecific variance in sperm precedence patterns and that it can generate misleading interpretations about the mechanism of sperm competition. Nonsperm representation might be a common obstacle in the studies of sperm competition and postcopulatory female choice.     

Infertility induced in rats by immunization with synthetic peptide segments of a sperm protein.

Three peptide segments (YAL-198, YAL-201 and YAL-212) corresponding to the extracellular domain of a human sperm protein designated as YWK-II antigen were synthesized as multiple antigen peptide (MAP). Male and female rats were immunized with the YWK-II-MAPs and fertility determined. In a group of 12 female rats immunized with YAL-198, seven animals were infertile and two animals were subfertile. When immunized with YAL-201 and YAL-212, 4 and 2 animals were infertile, respectively. In a group of 15 males immunized with YAL-198, 2 animals were infertile and 6 were subfertile. Two animals immunized with YAL-201 were subfertile. All control male and female rats immunized with bovine serum albumin and adjuvant were fertile. Sera obtained from infertile rats immunized with YAL-198 contained higher titers of antibodies compared to those obtained from fertile animals. The present study shows that immunization with synthetic peptide segments of a sperm protein can effectively reduce fertility.     

度他雄胺对大鼠附睾精子成熟和生育的影响

目的通过度他雄胺对大鼠附睾精子和生育的影响,探索调节雄性生育的睾丸后作用靶点。方法使用度他雄胺20和40 mg/(kg.d)大鼠灌胃给药,连续2周。给药结束后雄雌鼠按1∶2合笼,计算生殖指数;采用计算机辅助精子分析系统分析精子活力和形态;采用SYBR-14和PI双重荧光染色计算精子存活率;采用Elisa法测定大鼠睾酮(T)和双氢睾酮(DHT)血清浓度;采用HE染色法对各组睾丸、附睾进行组织学分析。结果度他雄胺低、高剂量组双氢睾酮浓度均显著下降,分别为0.54和0.28 nmol/L(P<0.01),精子活力明显降低,分别为39.0%和28.7%(P<0.01),畸形率分别增加为10.3%和15.6%(P<0.05),最后受孕率分别降为62.5%和38.4%。而睾酮水平和交配指数均无明显变化(P>0.05),睾丸和附睾亦无明显病理学改变。结论度他雄胺通过抑制DHT生成,影响附睾精子成熟而导致大鼠不育,为今后男性避孕和不育药物研发提供了新思路。     

Coevolution of sperm and female reproductive tract morphology in stalk-eyed flies

Sperm and female reproductive tract morphology are among the most rapidly evolving characters known in insects. To investigate whether interspecific variation in these traits results from divergent coevolution we examined testis size, sperm length and female reproductive tract morphology for evidence of correlated evolution using 13 species of diopsid stalk-eyed flies. We found that sperm dimorphism (the simultaneous production of two size classes of sperm by individual males) is ancestral and occurs in four genera while sperm monomorphism evolved once and persists in one genus. The length of ''long-sperm'' types, though unrelated to male body or testis size, exhibits correlated evolution with two regions of the female reproductive tract, the spermathecae and ventral receptacle, where sperm are typically stored and used for fertilization, respectively. Two lines of evidence indicate that ''short sperm'', which are probably incapable of fertilization, coevolve with spermathecae. First, loss of sperm dimorphism coincides phylogenetically with reduction or loss of spermathecae. Second, evolutionary change in short-sperm length correlates with change in spermathecal size but not spermathecal duct length or ventral receptacle length. Morphological coevolution between sperm and female reproductive tracts is consistent with a history of female-mediated selection on sperm length.     

Characteristics of infertility and the improvement of fertility by thyroxine treatment in adult male hypothyroid rdw rats

We previously reported that rdw rats were infertile in both sexes. The present study was conducted to determine whether hypothyroidism in adult male rdw rats induced infertility by impairing sexual behavior or testicular function, whether the infertility could be reversed by thyroxine (T(4)) treatment, and whether the mutant could be produced by infertile rdw rats via in vitro fertilization. The sexual behavior was analyzed by pairing with normal female rats. The fertility of epididymal sperm was determined by in vitro fertilization. The results indicated that the infertility resulted from both defective sexual behavior and testicular function. No untreated rdw rats mated. The weights of epididymides were significantly low, whereas those of testes were not different from those of untreated normal rats. Epididymal sperm with cytoplasmic droplets were observed at a significantly high frequency. No fertilization was detected either in vivo or in vitro. Thyroxine treatment markedly increased serum T(4) levels and the weights of both epididymides and testes. Partial reversion of the impaired sexual behavior was observed, and the percentage of epididymal sperm with cytoplasmic droplets was markedly decreased after T(4) treatment. Fertility of epididymal sperm was completely reversed when determined both in vivo and in vitro, and homozygous embryos developed to term after transfer without loss of viability.     

Counteracting effects of heavy metals and antioxidants on male fertility

Infertility is regarded as a global health problem affecting 8–12% of couples. Male factors are regarded as the main cause of infertility in 40% of infertile couples and contribute to this condition in combination with female factors in another 20% of cases. Abnormal sperm parameters such as oligospermia, asthenospermia, and teratozoospermia result in male factor infertility. Several studies have shown the deteriorative impact of heavy metals on sperm parameters and fertility in human subjects or animal models. Other studies have pointed to the role of antioxidants in counteracting the detrimental effects of heavy metals. In the currents study, we summarize the main outcomes of studies that assessed the counteracting impacts of heavy metal and antioxidants on male fertility. Based on the provided data from animal studies, it seems rational to administrate appropriate antioxidants in persons who suffer from abnormal sperm parameters and infertility due to exposure to toxic elements. Yet, further human studies are needed to approve the beneficial effects of these antioxidants.

     

An update of the regulatory factors of sperm migration from the uterus into the oviduct by genetically manipulated mice

Mammalian reproductive processes involve spermatogenesis, which occurs in the testis, and fertilization, which takes place in the female genital tract. Fertilization is a successive, multistep, and extremely complicated event that usually includes sperm survival in the uterus, sperm migration through the uterotubal junction (UTJ) and the oviduct, sperm penetration through the cumulus cell layer and the zona pellucida, and sperm–egg fusion. There may be a complex molecular mechanism to ensure that the above processes run smoothly. Previous studies have discovered essential factors for these fertilization steps through in vitro fertilization experiments. However, recent gene disruption approaches in mice have revealed that many of the factors previously described as important for fertilization are largely dispensable in gene‐knockout animals, and some previously unknown factors are emerging. As a result, the molecular mechanisms of fertilization, especially sperm migration from the uterus into the oviduct, have recently been revised by the emergence of genetically modified animals. In this review, we only focus on and update the essential genes for sperm migration through the UTJ and describe recent advances in our knowledge of the basis of mammalian sperm migration.     

PACAP ameliorates fertility in obese male mice via PKA/CREB pathway-dependent Sirt1 activation and p53 deacetylation

Obesity is strongly linked to male infertility. Testicular spermatogenic cell apoptosis plays an important role in obesity-related male infertility. Pituitary adenylate cyclase-activating peptide (PACAP) has been recently shown to exhibit antiapoptotic and antidiabetic effects. However, the effects of PACAP on obesity-related male infertility remain unknown. The purpose of the current study is to explore the role of PACAP in obesity-related male infertility. Here, C57BL/6 male mice were fed with a high-fat diet to induce obesity and then treated with PACAP. PACAP treatment ameliorated obesity characteristics, including body weight, epididymal adipose weight, testes/body weight, serum lipids levels, and reproductive hormone levels in vivo. Additionally, PACAP was shown to improve the reproductive function of the obese mice, which was characterized by improved testis morphology, sperm parameters, acrosome reaction, and embryo quality after in vitro fertilization via silent information regulator 1 (Sirt1) activation and p53 deacetylation. These beneficial effects of PACAP were abolished in obese mice with testis-specific knockdown of Sirt1. The mechanism studies showed that PACAP selectively binds to the PAC1 receptor to attenuate palmitic acid-induced mouse spermatogenic cell (GC-1) apoptosis via the PKA/CREB/Sirt1/p53 pathway. However, this mechanism was inhibited in GC-1 cells lacking Sirt1. Finally, human semen studies showed that the decline in sperm quality in obese infertile men was partly due to Sirt1 downregulation and p53 acetylation. Our data suggest that PACAP could ameliorate fertility in obese male mice and may be a promising candidate drug for obesity-induced male infertility.     

Idiopathic infertility in married couples in the light of cytogenetic analysis and sperm penetration assay

We have selected 47 couples with unexplained infertility in order to analyse a possible link between sperm dysfunction studied in males in in vitro conditions and karyotype analysis of somatic cells. In order to identify so called "idiopathically infertile" couples we had to exclude any change in reproductive organs in both partners or in spermiogram which would qualify any of spouses into known category of infertility. We have revealed chromosome aberrations (translocations and marker chromosomes) in 19% of infertile males and in 6% of infertile females. Idiopathically infertile males had an overall decreased ability of sperm function (measured by proportion of penetrated hamster oocytes by human sperm) in comparison to fertile controls, however, still well placed within physiological range of values. Only sperm from a patient with identified translocation was clearly below the normal level of penetration (20% of penetrated oocytes), however, also the patients with revealed chromosome variant polymorphisms presented statistically lower values of penetration in comparison to fertile controls (39% vs 57%, p<0.05). On the contrary, patients with marker chromosomes did not exhibit affected sperm function. It can be speculated that only particular chromosome aberration in group of idiopathically infertile males may affect sperm functional capability (measured in vitro), however, the intragonadal genetic analysis has to be recommended in order to confirm such a causative link.     

Reconstructing paternal genotypes to infer patterns of sperm storage and sexual selection in the hawksbill turtle

Postcopulatory sperm storage can serve a range of functions, including ensuring fertility, allowing delayed fertilization and facilitating sexual selection. Sperm storage is likely to be particularly important in wide‐ranging animals with low population densities, but its prevalence and importance in such taxa, and its role in promoting sexual selection, are poorly known. Here, we use a powerful microsatellite array and paternal genotype reconstruction to assess the prevalence of sperm storage and test sexual selection hypotheses of genetic biases to paternity in one such species, the critically endangered hawksbill turtle, Eretmochelys imbricata. In the majority of females (90.7%, N = 43), all offspring were sired by a single male. In the few cases of multiple paternity (9.3%), two males fertilized each female. Importantly, the identity and proportional fertilization success of males were consistent across all sequential nests laid by individual females over the breeding season (up to five nests over 75 days). No males were identified as having fertilized more than one female, suggesting that a large number of males are available to females. No evidence for biases to paternity based on heterozygosity or relatedness was found. These results indicate that female hawksbill turtles are predominantly monogamous within a season, store sperm for the duration of the nesting season and do not re‐mate between nests. Furthermore, females do not appear to be using sperm storage to facilitate sexual selection. Consequently, the primary value of storing sperm in marine turtles may be to uncouple mating and fertilization in time and avoid costly re‐mating.     

ENU‐induced mutant allele of Dnah1, ferf1, causes abnormal sperm behavior and fertilization failure in mice

Given attention to both contraception and treatment of infertility, there is a need to identify genes and sequence variants required for mammalian fertility. Recent unbiased mutagenesis strategies have expanded horizons of genetic control of reproduction. Here we show that male mice homozygous for the ethyl‐nitroso‐urea‐induced ferf1 (fertilization failure 1) mutation are infertile, producing apparently normal sperm that does not fertilize oocytes in standard fertilization in vitro fertilization assays. The ferf1 mutation is a single‐base change in the Dnah1 gene, encoding an axoneme‐associated dynein heavy chain, and previously associated with male infertility in both mice and humans. This missense mutation causes a single‐amino‐acid change in the DNAH1 protein in ferf1 mutant mice that leads to abnormal sperm clumping, aberrant sperm motility, and the inability of sperm to penetrate the oocyte's zona pellucida; however, the ferf1 mutant sperm is competent to fertilize zona‐free oocytes. Taken together, the various mutations affecting the DNAH1 protein in both mouse and human produce a diversity of phenotypes with both subtle and considerable differences. Thus, future identification of the interacting partners of DNAH1 might lead to understanding its unique function among the sperm dyneins.     

The influence of nuptial feeding and sperm transfer on the immunological cost of reproduction in the ground cricket Allonemobius socius

Mating is often accompanied by decreased female immune function across numerous animals systems, suggesting that immune suppression is a widespread reproductive cost. However, the trade‐off between immunity and reproduction can be minimized when females have access to abundant nutrient resources. This observation suggests that the nuptial gifts provided by males in many insect systems may help to offset the common immunological cost to reproduction. In the present study, this hypothesis is tested in the ground cricket Allonemobius socius (Scudder), whose females receive a sizeable haemolymph‐based gift. Accordingly, male gift donation is controlled by covering the tibial spur (the source of the gift) of randomly chosen males with clear nail polish. The influence of sperm transfer on female immunity is disentangled from that of the nuptial gift by also examining females who fail to receive sperm during mating (spermatophore transfer has a 40% failure rate in virgin males). It is predicted that females who receive a nuptial gift will exhibit superior immune function compared with those who receive no gift. The results show that sperm transfer reduces female immune function, which is an expected immunological cost of reproduction. By contrast to the prediction, nuptial gifts do not minimize the immunological cost of reproduction in this system. Unexpectedly, the receipt of a gift appears to decrease female immune function independent of sperm transfer. The findings suggest that the nuptial gift, similar to sperm, signals the female to begin her reproductive investment, causing limited resources to be reallocated from immune function.