Male Germ Cell Telomeres and Chemical Pollutants: Comparison
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Telomerase activity in male germ cells ensures that the telomere length is maintained at maximum levels during spermatogenesis, despite telomere shortening due to DNA replication or other genotoxic factors such as environmental pollutants. An emerging body of evidence has associated an exposure to pollutants with male infertility. Although telomeric DNA may be one of the important targets of environmental pollutants, only a few authors have considered it as a conventional parameter for sperm function.

  • telomere
  • male germ cells
  • sperm
  • pollutants

1. Germ Cell Telomere and Environmental Pollutants

The effects of environmental pollution on sperm quality has been the subject of numerous epidemiological investigations, and several reviews have recently been published on the topic [44,45,46,47][1][2][3][4]. Although numerous authors have identified excessive telomere shortening in the somatic cells of subjects exposed to air pollutants [48[5][6][7],49,50], to date, studies analyzing the influence of environmental pollutants on telomere structure/function in germ cells are very limited. Indeed, the sperm parameters considered in the research are predominantly on sperm volume, sperm concentration, sperm count, motility and morphology, DNA fragmentation and chromatin integrity.
Studies that have focused on gaseous air pollutants or particulate matter (PM) (PM2.5, PM10, SO2, NO2, CO and O3) have highlighted their negative correlations with sperm quality [46,51,52,53,54,55][3][8][9][10][11][12]. Significant alterations in at least one of the sperm parameters in association with at least one of the pollutants studied were detected. In particular, the sperm volume and total sperm count were found to be significantly negatively associated with smoking, carbon disulfide and traffic pollution [47][4]. Traffic pollution included common gaseous pollutants such as nitrogen oxides, sulfur compounds, and sulfur oxides. However, the sperm volume and total sperm count were not significantly influenced by lead exposure and environmental pollution. The latter included sulfur dioxide, nitric anhydride, nitrogen oxides and sulfur oxides, sulfur dioxide, nitrogen oxides, carbon monoxide, ozone, methane, non-methane hydrocarbons and volatile organic compounds [47][4].
Huang and collaborators [46][3], investigating a cohort of approximately 1100 men, provided evidence that exposure to PM2.5 and its constituents (antimony, cadmium, lead, manganese and nickel) may contribute to decreased semen quality. The daily average concentrations of PM2.5 constituents were continuously collected at fixed monitoring stations that were away from industrial sources, traffic, buildings, or residential resources of emissions, such as the burning of coal, waste or oil. The authors used three different statistical models to estimate the associations between PM2.5 constituent exposures and semen quality. The restudyearch demonstrated that each increase in the interquartile range (36.5 μg/m3) of PM2.5 exposure was significantly associated with an approximately 8% decrease in sperm concentration (95% CI: 2.3%, 14.4%) and in total sperm count (95% CI: 0.7%, 15.0%). Exposure to antimony, cadmium, lead, manganese and nickel was significantly associated with a decrease in sperm concentration, while exposure to manganese was also significantly associated with a decrease in total motility. Non-smokers were more sensitive to exposure to PM2.5 constituents, particularly antimony and cadmium. However, although the restudyearch was carried out on relatively large population, it presents several limitations. Firstly, the monitoring data came from only two fixed stations and did not take into account spatial variations; secondly, other air pollutants, including ozone, carbon monoxide, etc., were not considered; thirdly, most subjects underwent only one semen examination; and lastly, the association between PM2.5 constituents and sperm morphology were not analyzed. It was also demonstrated that cadmium, a major constituent of PM2.5, could also induce altered spermatogenesis [56][13]. These metals can induce lipid peroxidation and testicular necrosis and apoptosis, which have been related to altered circulating androgen levels and fertility [46][3]. In conclusion, these studies suggest that gaseous air pollutants and PM may negatively affect sperm quality, particularly the sperm concentration.
Another recent review provides a solid summary of the existing works that correlate exposure to polycyclic aromatic hydrocarbons (PAHs) with male infertility [57][14]. PAHs are a large family that contain the most widespread environmental contaminants in the world. Usually, they attach to the surface of PM and can be absorbed through the skin, respiratory tract and gastrointestinal tract. The biomonitoring of levels of urinary PAH metabolites is an important approach used to measure human exposure and the burden of PAHs on the body [58][15]. The data showed that there is a significant negative relationship between PAH metabolites and sperm volume, concentration, motility, morphology, as well as an observed DNA degeneration. It is of note that the review emphasizes that the CYP1A1 genotype polymorphisms are more common in infertile men.
Endocrine disruptors (EDCs) in the environment are responsible for a decline in semen quality that has been most notable in the last few decades. A recent review provides results from epidemiological investigations over the last 30 years concerning the association between exposure to environmental and occupational pesticides (organophosphate, organochlorine, pyrethroid, carbamate, and other pesticide chemical groups) and semen quality [59][16]. The studies show that exposure to non-persistent EDCs, such as bisphenol A, triclosan, parabens, synthetic pyrethroids, organophosphate pesticides and phthalates, may decrease semen quality by affecting semen quality parameters such as sperm volume, total sperm count, motility, total motile count, sperm motion, sperm DNA damage (comet extent, tail length, tail distributed moment, percent of DNA located in the tail, DNA fragmentation index, high DNA stainability), the X:Y ratio and aneuploidy [45,59][2][16].
Finally, there has been a recent interest in electronic-waste-recycling-associated chemical exposure and intermediate health outcomes, including DNA damage. Significantly higher levels of DNA damage in spermatozoa, resulting in an increased risk of infertility, has been found in workers exposed to e-waste that contains harmful substances, including clastogens and aneugens [60][17].

2. Germ Cell Telomere and Oxidative Stress

It has well known that reactive oxygen species (ROS) are required for the maintenance of mammalian spermatogonial stem cells (SSCs) and that a high glycolysis level favors the long-term self-renewal of SSCs [71,72][18][19]. In these cells, ROS were produced mainly by the ROS–BCL6B–NOX1 pathway and minimally by mitochondrial OXPHOS activity, which is much lower in SSCs compared to differentiating spermatogonia [72,73][19][20]. Unlike SSC self-renewal or spermatogonial proliferation, spermatogonial differentiation relies more on mitochondrial respiration. In fact, energy production is shifted from glycolysis to OXPHOS in spermatocytes and spermatids [73][20]. Spermatozoa utilize glycolysis for survival but require both glycolysis and OXPHOS for motility and fertilization. However, cellular ROS levels must be tightly regulated to maintain normal cell functions since excessive ROS production can cause oxidative damage, overwhelm the cellular antioxidant capacity and trigger apoptosis [74][21]. Indeed, the attachment of ROS to sperm DNA is believed to be a step in the cascade reaction that leads to DNA fragmentation and, ultimately, apoptosis [75,76,77][22][23][24]. Therefore, a delicate balance needs to be established in order to maximize the beneficial effects of ROS and prevent the detrimental effects of over-physiological levels.
It has been largely demonstrated that one of the toxic effects of pollutants is an increase in oxidative stress caused by an increase in the production of ROS [63,64][25][26]. ROS-induced oxidative stress is now recognized as the most common underlying mechanism that accelerates telomere shortening and dysfunction in somatic cells [78][27]. With regard to this, there is evidence that an increase in ROS can lead to alterations in the bases of DNA, such as the oxidation of guanine to 8-oxoguanine (8-oxoG), which ends up as an excised base [28,79][28][29]. The telomeric TTAGGG repeats show a high susceptibility to oxidative radicals and are sensitive to the accumulation of 8-oxoG, resulting in the alteration of telomeric proteins and the inhibition of telomerase, which in turn, results in the shortening, dysfunction and instability of telomeres [80][30]. ROS also induce single-strand breaks (SSB) in telomeres directly, leading to replication fork collapse and telomere loss [81][31]. Furthermore, the presence of the shelterin complex in telomeres prevents the recruitment of DNA damage response (DDR) proteins; therefore, damage to telomeres caused by ROS may not efficiently activate the DDR and hampers the DNA repair process downstream of the initial DDR [82][32]. ROS can also induce the disruption of the proteins that regulate telomere length, including telomeric repeat binding factor 1 and 2 (TRF1 and TRF2) binding [83,84][33][34]. Finally, evidence has indicated that the correspondence of oxidative adducts with the end of telomeric DNA prevents telomere lengthening [85][35].
Several enzymatic pathways are known to counter such oxidative insults. PRDX1 (peroxiredoxin 1, a ROS-scavenger) is highly enriched in telomeres during replication and reduces hydrogen peroxide to water and protects against oxidative attack [86][36]. In addition, 8-oxodG must be resolved by the base excision repair (BER) pathway. This starts with recognition and excision by 8-oxoG DNA glycosylase (OGG1), thus yielding an AP site, which must be cleaved by AP endonuclease 1 (APE1) and processed by downstream BER to restore the original G:C bp.
Therefore, it cannot be rejected that spermatozoa from a single individual could exhibit different telomere lengths not only due to specific telomerase activity during the early stages of spermatogenesis, but also due to their exposure to ROS and to the efficiency of the systems that counteract oxidative damage [29][37]. Spermatozoa have OGG1 and the capacity to excise 8-oxodG residues, and do not contain APE1 [87][38]. Furthermore, spermatozoa, due to their extremely reduced cytoplasm, have low amounts of antioxidant enzymes and consequently use the high antioxidant capacity of seminal plasma [88,89,90][39][40][41]. In the male urogenital tract, ROS mainly originate from leucocytes and abnormal immature spermatozoa. In moderate concentrations, ROS play an important role in post-testicular sperm maturation. They are involved in the formation of interprotamine disulphide bridges during epididymal transit, thus enhancing the nuclear condensation of spermatozoa [90][41]. ROS also participate in membrane tyrosine phosphorylation, which enables flagellar capacitation and hyperactivation [76,90][23][41]. In this regard, Mishra and collaborators [91][42] found longer telomeres in infertile men experiencing mild oxidative stress. Thus, although severe oxidative stress leads to extensive damage to biomolecules, a moderate oxidative stress level could be necessary for STL maintenance and beneficial to cellular homeostasis [37,90,91][41][42][43].

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