Association study of telomere length with idiopathic male infertility

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Telomeres are evolutionary conserved, multifunctional DNA-protein complexes located at the ends of eukaryotic chromosomes. Telomeres maintain chromosome stability and genome integrity and also play an important role in meiosis which aid in synapsis, homologous recombination, and segregation. Sperm telomere has been reported to play an important role in fertilization and embryo development. Nowadays, the association between telomere and reproduction is one of the major areas of interest, however whether sperm telomere associated with male infertility is not clear. In this study, in order to find out the association between Chinese idiopathic infertility and sperm telomere length, we analyzed the difference of sperm telomere length between idiopathic infertile men and normal fertile men, as well as the correlations between sperm telomere length and human semen characteristics. We analyzed 126 Chinese idiopathic infertile men and 138 normal fertile men for sperm telomere length by using quantitative PCR. We found that the relative sperm mean telomere length of infertile men was significantly shorter than that of fertile men (2.894±0.115 vs. 4.016±0.603, P=5.097×10(-5)). Both sperm count and semen progressive motility are related with telomere length. Our results suggest that sperm telomere length is associated with idiopathic male infertility of China and we proposed the possibility that shorter telomeres in sperm chromosome will reduce spermatogenesis and sperm functions, which finally affected the fertility of male.

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... A positive association between male infertility factors and TL was observed in 19 studies (68-86) and a negative association in 2 studies (39,87) (Table II). In total, 15 of the positively associated studies detected a sperm TL (sTL) association (68)(69)(70)72,(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84), while 3 studies detected an LTL association (73,85,86), and one study detected both STL and LTL (71). In several studies, shorter sTL was reported in association to infertility (72,76,78,80) while Vecoli et al reported an increase in sTL in areas of high environmental exposure (77). ...
... In patients with decreased sperm motility, a shorter sTL has been found and has also been associated with a lower sperm count, vitality and protamination (81,82), but negatively associated with DNA fragmentation in normozoospermic individuals (81). Abnormal semen quality, according to the WHO criteria, has been associated with a shorter TL than that of semen with normal parameters. ...
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Telomere length (TL) has long been associated with aging, as telomeres serve as protective caps of chromosomes, and are thus deeply involved in the preservation of genome integrity and are vital to cellular functions. Traditionally, a strong link connects aging and infertility in both sexes, with an earlier onset in females. Over the past decade, telomeres have attracted increasing attention due to the role they play in fertility. In this review, we investigated the potential positive or negative association between relative TL and different factors of female and male infertility. A systematic search of the PubMed database was conducted. Out of the 206 studies identified, 45 were reviewed as they fulfilled the criteria of validity and relevance. Following an analysis and a comparison of the study outcomes, several clear trends were observed. The majority of female infertility factors were associated with a shorter TL, with the exception of endometriosis, premature ovarian failure and clear cell carcinoma that were associated with a longer TL and polycystic ovary syndrome (PCOS), which revealed conflicting results among several studies, leading to ambiguous conclusions. Male infertility factors were associated with a shorter TL. Although this review can provide an outline of general trends in the association of TL with infertility factors, further epidemiological and original research studies are required to focus on investigating the basis of these varying lengths of telomeres.
... In this regard, some research works reported that men with idiopathic infertility have significant shorter sperm telomeres and loss of telomere homeostasis (evidenced in lower levels of TERRA and telomerase) than healthy controls. [43][44][45] Similarly, Biron-Shental et al found that sub- fertile men presented more sperm cells with shorter TL and less telomerase reverse transcriptase-positive sperm cells than controls. 46 This has been attributed to a negative influ- ence of telomere reduction over sperm function and indicates that an altered telomere dynamic in sperm may be one expla- nation for reduction in male fertility potential, especially in the idiopathic cases (Figure 3). ...
... In this respect, several studies have found a positive correlation of sperm TL and conventional good quality sperm parameters like motility, vitality, and sperm count. 44,[47][48][49][50][51][52] This has also been reported with other character- istic related to DNA integrity, finding that a decrease in sperm TL is related to an increase in DNA fragmentation and reduc- tion in protamination. 51,52 Due to the impact over sperm qual- ity, the attrition of telomeres (principally associated with oxidative stress condition) can lead to detrimental effect of fertility potential and increase in DNA instability. ...
In modern society, fertility problems and demand of treatment seem to be on the rise, which led to an increased interest in research regarding human reproduction. Among these efforts, the study of the molecular senescence process has gain notorious popularity as aging is one of the most important variables involved in reproductive capacity and since the comprehension of telomere dynamics has become an important and influential theme. This new knowledge regarding the reproductive aging process is expected to offer new tools to understand the acquisition, maintenance, and loss of fertility potential. Therefore, this review seeks to clarify the relevance of molecular aging (evaluated by telomere shortening) in human reproduction, showing that it is a dynamic and variable process modulated according to the specific tissue and stage of development. As well, it is discussed how telomere status influence the development and progression of some fertility pathologies, the outcome of assisted reproductive treatments, and programming of aging in the offspring.
... respectively). 31,32 The qPCR method can however, only provide the mean telomere length values per cell sample and not per cell or individual telomere. In comparison to the gold standard TRF analysis, qPCR measures relative telomere length and cannot provide absolute telomere length values in kilobases. ...
To study the relevance of sperm telomere length and infertility in men. : Our case-control study included twenty-five males in couple with sub-fertility/infertility (test group) and twenty five healthy males (control group) with proven paternity in the age group 25 to 35 years. The Absolute Sperm Telomere length (aSTL) was measured by real-time PCR. We investigated whether any significant difference in the aSTL value existed between the groups and analysed the relationship between aSTL and other sperm parameters. The mean (SE) aSTL recorded in the infertile cases was significantly shorter than for the control group being 140.60 (6.66) Kb/genome and 239.63 (12.32) Kb/genome respectively (p <0.001) A weak correlation was eminent between aSTL kb/genome and the total sperm count mil/ml (rho= 0.04, p - 0.86), progressive sperm motility (rho= - 0.02, p=0.934) and sperm viability (rho= - 0.07 p=0.741) in the infertile group. The measurement of aSTL by real-time PCR is a simple and rapid method that offers further paramount information with respective to the quality of sperm. It is befitted for epidemiological studies, hence opening new perspectives in the evaluation of male infertility. Limitations - Our study was confined to men aged between 25 and 35 years. Further comparative studies are needed to explore the significance of STL and infertility in older males. Additional studies will help illumine the significance of aSTL as a prognostic biomarker in assisted reproduction.
... Negative correlation between STL and vitality and sperm concentration was observed in donors with abnormal semen parameters. Unlike the latter study, we found no correlation between STL and age, as in other [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. However, for the present study, we selected men with normozoospermia as control and men with astenozoospermia, teratozoospermia, astenoteratozoospermia and oligoastenoteratozoospermia in the same age range. ...
... Turner & Hartshorne (2013) also showed no relationship between the length of sperm telomeres and semen quantity, sperm morphology and motility. Additionally, a study by Shuyuan et al. (2015), in a group of 126 men with idiopathic infertility, showed that men not only had short sperm telomeres compared to 136 fertile patients, but also that there was a relationship between the length of sperm telomeres and sperm quantity and motility. These authors suggest that shorter sperm telomeres could indicate reduced spermatogenesis, and consequently reduced fertility. ...
In recent years, male infertility has become a growing social problem. Standard diagnostic procedures, based on assessing seminological parameters, are often insufficient to explain the causes of male infertility. Because of this, new markers with better clinical application are being sought. One of the promising markers seems to be an assessment of telomere length of sperm. Sperm telomeres, in contrast to somatic cells, are elongated as men age. The results of some studies suggest that telomere length may be relevant in the case of fertilization and normal embryo development. Literature reports indicate that there is a correlation between telomere length of sperm and abnormal sperm parameters. The measurement of telomere length using the method of quantitative PCR could become a new marker of spermatogenesis, which can be useful for evaluating male reproductive age.
... Critically short telomeres in sperm have been shown to be predictive of an increased risk of male infertility. Studies in India (Thilagavathi et al., 2013a) and China (Shuyuan et al., 2015) have analyzed STL in men with idiopathic infertility and have found that the STL was relatively shorter in infertile men than in controls (p b 0.005). These findings suggest that short STL is a possible contributor to male infertility. ...
It has been well demonstrated that polycyclic aromatic hydrocarbons (PAHs) can cause reproductive toxicity, and shorter telomere length in sperm may be one of the factors causing male infertility. However, whether exposure to PAHs is associated with sperm telomere length (STL) has never been evaluated. The present study aimed to assess the potential association between PAHs exposure and STL, and to explore potential biomarkers that may predict the effects of low-level exposure to PAHs on human sperm. Questionnaires and biological samples were collected from 666 volunteers participating in the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study in 2014. Semen parameters were measured for 656 participants, while urinary PAH metabolites, STL and sperm apoptosis were successfully measured for 492, 444 and 628 participants, respectively. The linear regression analysis revealed that increased levels of urinary 1-hydroxypyrene (1-OHPyr) and 1-hydroxynapthalene (1-OHNap) were associated with decreased STL (− 0.385; 95% CI, − 0.749, − 0.021 for 1-OHPyr; and − 0.079; 95% CI, − 0.146, − 0.011 for 1-OHNap). The significant negative associations remained after adjusting for potential confounders. However, no significant associations were observed between urinary PAH metabolites and semen quality or sperm apoptosis. We also administrated rats with benzo[a]pyrene (B[a]P; 0, 1, 5, and 10 mg/kg) for 4 weeks and found shorter STL and decreased telomerase expression in germ cells in a dose-dependent manner. In conclusion, environmental exposure to some PAHs may be associated with decreased human STL, and the in vivo animal results also demonstrate the adverse effects of B[a]P on telomere of male germ cells.
Study question: Can differences in DNA isolation alter assessment of sperm telomere length (spTL) and do they account for conflicting results in the literature on spTL and male fertility? Summary answer: DNA isolation methods preferentially include or exclude short, extrachromosomal (EC) telomere-specific sequences that alter spTL measurements, and are responsible for a proportion of the disparity observed between investigations. What is known already: The relationship between spTL and male fertility has become an active area of research. The results across investigations, however, have been discordant, generating a need to critically evaluate the existing body of knowledge to guide future investigations. Study design, size, duration: Quantitative experiments determined the effect of DNA isolation on the integrity of sperm DNA and measures of spTL, while a systematic analysis of the current literature evaluated the effect of DNA isolation and study design on experimental outcomes. Participants/materials, setting, methods: Two DNA isolation methods were compared: Genomic Tips which isolate 'High Molecular Weight' (HMW) DNA exclusively, and QIAamp® DNA Mini which isolates 'Total' genomic DNA irrespective of size. DNA quality was assessed via field inversion gel electrophoresis (FIGE) and spTL was measured via terminal restriction fragment analysis. In addition, major databases in medicine, health and the life sciences were subject to a targeted search, and results were independently screened according to defined exclusion/inclusion criterion. Findings from primary articles were analyzed for concordance and study designs were compared across six moderator variables (sample size, participant age, fertility status, semen fraction, telomere population and type of analysis). Main results and the role of chance: HMW DNA spTL was significantly longer than spTL measured from total DNA (P < 0.01), indicating that Total DNA contained short, EC telomeric repeats that shifted downstream assessment towards shorter spTL. HMW DNA spTL reflected the length of intact, chromosomal telomeres. Major findings on spTL showed the greatest concordance amongst studies that implemented HMW DNA isolation prior to spTL assessment. Studies that utilized Total DNA varied in concordance, but outcomes were similar if (i) a comparative analysis was applied or (ii) a sample size threshold of 81 was achieved for correlative analysis. Limitations, reasons for caution: Chromosomal and EC telomeric DNA were distinguished based on outcomes of HMW DNA isolation and size. Further experiments are required to determine the nature and function of these two types of telomeric sequences. Wider implications of the findings: This study reveals a dramatic impact of upstream DNA processing and study design on measurements of spTL, which accounts for conflicting results in the literature. Future assessments of spTL should incorporate independent detection of chromosomal and EC telomeric DNA and specific experimental planning. Study funding/competing interests: This study was funded by CReATe Fertility Centre, Toronto, Ontario, Canada. The authors have declared no conflict of interest. Registration number: N/A.
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