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Infertility, defined as the inability to achieve pregnancy after 12 months of sexual intercourse without the use of contraceptives , affects around 15% of couples of reproductive age, and male factor infertility is the cause in up to 50% of these cases [1,2]. Different aetiologies may be associated with male factor infertility, such as varicocele, cryptorchidism, genetic alterations, systemic diseases, hypogonadotropic hypogonadism, and altered semen analysis values [3,4]. Obesity was recently also included in this list [5–7].
The effects of excess body fat in female fertility are well documented [8,9], but results are still scarce and controversial with regard to male fertility [5,10,11]. Obesity can negatively affect fertility through various mechanisms, many not yet clarified. Higher body mass index (BMI) values result in an altered reproductive hormone profile, with lower testosterone and sex hormone-binding globulin levels, higher oestradiol levels and, in extreme cases, changes in gonadotrophin secretion . Levels of inhibin B, a marker of Sertoli cell function and spermatogenesis, may also be altered in these cases [5,13]. In addition, the accumulation of suprapubic and inner thigh fat may lead to an increase in scrotal temperatures (hyperthermia) in obese men. This affects spermatogenesis by causing testicular oxidative stress [14,15].
Most reports describe the relationship between obesity and altered standard semen analysis parameters [5,16,17], but lack information regarding sperm functional analysis. It is important to evaluate the consequences of obesity with regard to sperm function in men. The aim of the present study was to assess the impact of higher BMI values on sperm mitochondrial activity and DNA integrity.
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Overweight and obesity, defined as abnormal or excessive fat accumulation, are associated with an increased risk of many health problems, including type II diabetes, cardiovascular disease, hypertension, dyslipidaemia, cancers and infertility . The currently high rates of obesity are attributable to the increase in sedentary lifestyles and, in particular, to changes in diet .
Recently, the association of BMI with standard semen analysis parameters has been examined in several studies. Sallmen et al. observed that a three-unit increase in male BMI was associated with infertility. In another study, Jensen et al. observed that high (>25 kg/m2) or low (<20 kg/m2) BMI were associated with reduced semen quality (e.g. sperm concentration and total sperm count). Percentages of normal spermatozoa were lower, although not significantly, among men with high or low BMI. Semen volume and percentage of motile spermatozoa were not affected by BMI in their study. Similarly, in the present study, we did not observe significant differences among the groups in ejaculated volume and sperm morphology; however, sperm concentration was not different and a lower total motile count was observed in overweight and obese groups.
The impact of obesity on fertility can be attributed primarily to endocrine mechanisms [12,24]. It has been reported that higher BMI values are related to lower inhibin B levels [5,13] and that hyperthermia, resulting from accumulation of fatty tissue around the scrotum, causes oxidative stress to the testicles .
Reactive oxygen species (ROS) play an important role in modulating the essential functions of sperm, e.g. capacitation, hyperactivation and acrosomal reaction; however, imbalances between ROS production and semen antioxidant capacity will result in oxidation of membrane polyunsaturated fatty acids [25,26], loss of mitochondrial membrane potential , and single and double-strand DNA fragmentation .
There is a strong association between decreased sperm motility and oxidative stress [29,30]. Sperm motility is generated through constant ATP production by mitochondria localized in the sperm midpiece. To produce ATP through oxidative phosphorylation, the mitochondrial membrane must have selective permeability, which maintains an electrolytical gradient between the inner and outer mitochondrial environments. Excessive ROS will alter phospholipid membranes, and thus disrupt membrane selectivity, and will also inhibit oxidative phosphorylation, ultimately leading to decreased ATP production [31,32]. In the present study, men in the obese group had lower sperm mitochondrial activity than those in the eutrophic group.
Excessive production of ROS may also lead to increased DNA damage, through the production of lypid degradation by-products which bind to DNA, through oxidation of DNA bases (mainly guanosine), or through direct interaction with the DNA strand, leading to non-specific single- and double-strand breaks [28,29]. Sperm DNA integrity has been extensively researched recently as a marker of male factor infertility. Initially, ROS usually alter the sperm lipid bilayer by oxidation of methylene groups in polyunsaturated fatty acids. The process ultimately leads to the production of lipid degradation by-products, of which malonaldehyde is one of the most common. Malonaldehyde is an alkylating agent with the ability to covalently bind to nucleophilic groups of DNA, peptides and proteins, modifying their molecular function . In the second stage of excessive ROS production, guanosine is oxidized to 8′-OH guanosine, a promutagenic effect that leads to altered pairing of DNA bases . In the third stage, excess ROS will directly interact with DNA and cause single- and double-strand non-specific breaks in the DNA molecule .
In their study on 483 men, Chavarro et al. observed that sperm with high DNA damage were significantly more numerous in obese men than in normal-weight men. In a study by Kort et al. increasing BMI was positively correlated with the DNA fragmentation index calculated using the sperm chromatin structure assay. Obese and overweight men had a higher DNA fragmentation index (27% and 25.8%, respectively) than normal-weight men (19.9%). In the present study, we found that men in the obese group had a higher percentage of sperm with DNA damage than those in the eutrophic and overweight groups.
We conclude that higher BMI values are associated with decreased mitochondrial activity, progressive motility and increased DNA fragmentation.