Sezgin Gunes1, 2 and Mehmet Alper Arslan2, 3
Department of Medical Biology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
Department of Multidisciplinary Molecular Medicine, Health Sciences Institute, Ondokuz Mayis University, Samsun, Turkey
Department of Medical Biology, Faculty of Medicine, Health Sciences Institute, Samsun, Turkey
Environmental factorsEpigeneticsGametogenesisDNA methylationHistone tail modificationsShort noncoding RNAsProtaminationmiRNA
Puberty is initiated by secretion of gonadotropin-releasing hormone (GnRH) and reactivation of hypothalamic-pituitary-gonadal (HPG) axis. The age of onset of puberty varies greatly from one person to another and between the genders [1, 2]. This variability can be determined by both genetics and environmental exposure of individuals. Twin studies indicated alterations in pubertal timing of even monozygotic twins though it is much more common in dizygotic twins . This finding demonstrated the role of environmental factors in the timing of puberty , including nutrition and chemicals .
Environmental factors can involve a large variety of exposures, such as occupational exposures (workplace exposures), environmental exposures (ultraviolet light, radon gas, infectious agents, pesticides, traffic pollution), and exposures resulting from lifestyle choices (nutrition, smoking, cosmetics, physical activity) or medical treatments (radiation and medicines including chemotherapy, hormone drugs, drugs that suppress the immune system) . Dioxin-like chemicals, metals, phytoestrogens, polychlorinated biphenyls, polycyclic aromatic hydrocarbons, phthalates, and several classes of pesticides are certain types of environmental pollutants that may interact with epigenetic mechanisms . There is common belief that exposure to environmental factors can impair development, onset of puberty, and gametogenesis (both spermatogenesis and oogenesis) in adults and reduce fertility.
Several studies have demonstrated detrimental effects of occupational exposures on gametogenesis. In a study, dibromochloropropane (DBCP) , an active ingredient in nematicides, was shown to cause severe impairment of spermatogenesis and mostly irreversible fertility in highly exposed men [6, 7]. Persistent organic pollutants (POP) such as organic compounds including dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) are widely used around the world for industrial and agricultural processes and accumulate in adipose tissues. Bjerregaard and colleagues have found high PCB concentration in plasma lipid levels (67 %) of women at reproductive age and concluded that substantial portion of Greenlandic fetuses is prenatally exposed to harmful concentrations of PCBs . However, other studies found no major link between occupational exposures and the impairment of gametogenesis [9, 10].
Endocrine-disrupting chemicals (EDC) are exogenous agents that interfere with the hormone action or aid in the elimination of hormones in the body that are responsible for the maintenance of development, behavior, and reproduction [11, 12]. Skincare products and basic toiletries contain some chemicals such as parabens and phthalates . In addition, phthalates and bisphenol A (BPA) are monomers of plastics. The EDCs and phthalates are antiandrogenic chemicals and therefore affect males greatly, compared to females. However, BPA and cadmium are estrogenic [13–15]. The potential adverse effects of parabens and phthalates on testosterone metabolism and spermatogenesis have been reported in a number of animal studies [16–18]. A few studies have found a significant relationship between urinary levels of monobutyl phthalates and poor semen parameters [19, 20].
Published studies on the reproductive toxicity of the pesticides and associated with semen parameter or oocyte quality are limited. Recent studies have demonstrated a link between impairment of gametogenesis and some environmental chemicals . Two studies have reported an association between nonpersistent insecticides and alterations in steroid hormone levels and sperm concentration, motility, and DNA integrity [21, 22]. Nevertheless, Swan and colleagues have shown a sufficiently significant correlation between urinary metabolite levels of the currently used pesticides (alachlor, atrazine, diazinon) and low sperm counts in males living in mid-Missouri, Colombia . In this chapter, we have reviewed and discussed current evidence indicating that environmental factors may have a detrimental role in gametogenesis.
Epigenetics and Gametogenesis
Epigenetic modifications are heritable and reversible processes to regulate gene activity and expression, without any alteration of DNA sequences. These modifications include DNA methylation, histone tail modifications, and short noncoding RNAs and can be inherited through both mitotic and meiotic divisions. Epigenetic modifications can be altered by internal and external factors, including environmental chemicals, nutrition, and stress .
DNA methylation is the addition of a methyl group from S-adenosylmethionine to the fifth position of the cytosine ring (5meC) in the CpG islands (CGIs) . CGIs are short interspersed C+G-rich DNA sequences and are localized in the promoters or regulatory regions of almost all housekeeping genes, developmental genes, and some tissue-specific genes [25, 26]. Methylation of these cytosines is correlated with inactivation or silencing of the associated promoter, whereas hypomethylation usually leads to activation of gene expression [26, 27]. Silencing of gene expression is either due to inhibition of transcription factor binding to methylated cytosines or repression mediated by methyl-CpG-binding proteins [26, 28].
DNA methylation is catalyzed by maintenance DNA methyltransferases (DNMTs) (DNMT1) and de novo DNMTs (DNMT3A, DNMT3B, DNMT3L) . DNMT1 is responsible for maintenance of DNA methylation during DNA replication and termed as maintenance methyltransferase. DNMT3A, DNMT3B, and DNMT3L mediate de novo methylation of genomic DNA during early phase of embryonic development specifically in germ cells.
Sertoli cells proliferate in fetal life, postnatal/neonatal period, and prior to puberty. Sertoli cell number can be influenced by environmental factors during any of these periods. Sertoli cells can support only a limited number of mature germ cells; therefore, Sertoli cell proliferation during fetal life is critical for the number of sperms produced in adulthood. This proliferation is controlled by testosterone during fetal life and postnatal/neonatal period and by follicle-stimulating hormone (FSH) during puberty. Environmental factors may affect the proliferation of Sertoli cells during any one of these three periods, which may have an impact on sperm counts. Maternal lifestyle choices during pregnancy may be a determining factor for sperm count of the son during adulthood through the subsequent decrease in the number of Sertoli cells in testes [4, 30]. DNMT1 maintains DNA methylation patterns during mammalian oogenesis , and DNMT1 gene homozygous mutations in mice cause severe genomic imprinting defects and X inactivation abnormalities .
Reprogramming of Non-imprinted Genes
The methylation marks of primordial germ cells (PGCs) are erased in a number of sequential reactions during the development of embryo between 8 and 13.5 days post coitum (dpc) in both sexes [33–35]. By 12.5 dpc, methylation marks of some single-copy genes including alpha actin and myosin light chain (mylc) are erased. Furthermore, some repetitive elements undergo substantial demethylation of their methylation marks, while other repetitive sequences are not completely erased [36, 37]. By 13.5 dpc, PGCs enter mitotic/meiotic arrest [34, 36]. The second demethylation mechanism removes methyl groups from CGIs within the inactive X chromosome, imprinted loci, and some genes expressed in germ cells . After this demethylation process, a specific remethylation program starts to reestablish parental genomic imprints in germ cells. Remethylation program begins at around 15.5 dpc in spermatogonia and type I spermatocytes; hence, spermatozoa transmit the paternal imprint [39, 40]. In the mouse female germline, DNA remethylation takes place in oocytes that have entered meiosis and been arrested in diplotene of meiotic prophase I .
The methylation sequences of the oocyte and the sperm are both inside the genes and between the genes . On the other hand, repeat methylation level in oocyte is lower than in spermatozoa and somatic cells .
Reprogramming of Imprinted Genes
Spermatozoa have unique DNA methylation patterns that are formed during early stages of development and are essential for proper sperm production and spermatogenesis . Some genes are imprinted differentially by DNA methylation depending on which parent they are inherited from, which causes alterations in gene expression depending on the allele transmitted from the father or the mother . Igf2/H19, Rasgrf1, Dlk1-Gtl2, and Zdbf2 loci of sperm genome are methylated only in male germ cells . Many imprinted genes are involved in the regulation of growth and development . Several studies have demonstrated a significant association between methylation statuses of both maternally and paternally imprinted genes and sperm abnormalities [42, 45–51]. During mammalian oogenesis, the reprogramming process takes place for histone modification and short noncoding RNAs changed by both internal and external causes [52, 53]. DNA methylation pattern of imprinted genes in oocytes of mice and murine is altered by diabetes and obesity [54, 55]. Epigenetic alterations can occur at any time of life and can be transmitted to the future generations . DNA methylation is the most common epigenetic aberration induced by environmental agents. These epimutations can be transgenerational or non-transgenerational in germline cells .
Environmental toxicants influence gene expression by epigenetic mechanisms and by directly binding to promoter regions of target genes. Additionally, in animal models, epigenetic modifications during oogenesis are effected by maternal diets .
Histones are basic proteins rich in lysine and arginine located in nucleus and are subject to posttranslational modifications on their N- and C-terminal tails via acetylation, methylation, phosphorylation, and ubiquitination . These chemical modifications change binding capacity of regulatory factors to DNA and thus lead to alterations in gene activity and expression during development and in response to the environmental factors. Generally, acetylation of lysine (K) residues of histone 3 (H3) and histone 4 (H4) leads to active transcription by inducing open chromatin configuration and facilitating transcription factor binding in spermatogonial stem cells [60, 61]. On the contrary, deacetylation causes inactivation of transcription and generally correlates with methylation of histones .
During spermatogenesis, methylation of H3K and H4K histone tails is regulated by histone methyltransferases (HTM) and histone demethylases (HDM) [63, 64]. Acetylation of H2A, H2B, H3, and H4 were shown to be high in mouse spermatogonia, and these histones were deacetylated throughout meiosis in round spermatids and reacetylated in elongating spermatids . Hyperacetylation of H4K has been shown to be responsible for the conversion of histone to protamines in elongating spermatids . Recently, a few studies have investigated the role of histone tail modification in spermatogenesis. La Spina and colleagues evaluated the methylation of H3K4Me, H3K4Me3, H3K9Me2, H3K79Me2, and H3K36Me3 and acetylation of H3K4Ac and H4K5Ac in normal and abnormal human sperm. They reported the presence of unexpected and unexplained heterogeneous histone modifications, and the presence of H3K4Me1, H3K9Me2, H3K4Me3, H3K79Me2, and H3K36Me3 marks in poorly functional human sperm . Further studies are required to evaluate the impact of histone tail modifications induced by environmental exposures.
Sperm chromatin packaging is a critical process that serves to accommodate enormous amounts of DNA into a small sperm cell. Fertilization requires many physiological events including movement of sperm cells along the entire female reproductive system, attachment to zona pellucida, and penetration into the oocyte. For accomplishment of all these phases, a regulatory mechanism controlling the replacement of 85–95 % of histones by protamines becomes effective . Protamines are small proteins rich in arginine. They are located in sperm nucleus and synthesized during later stages of spermatogenesis. Protamination of sperm chromatin facilitates compaction of nucleus required for sperm motility and also protects sperm genome from oxidation and harmful molecules within the female reproductive system .
Replacement of histones by protamines involves translocation of histones by selected histone variants which are expressed during spermatogenesis. Hyperacetylation of histone tails causes the unwinding of chromatin structure and stimulates DNA strand breaks by topoisomerase enzyme that, in turn, facilitates separation of histones and replacement by transition proteins (TPs) [67, 68]. TP1 and TP2 bind to DNA and are completely replaced by protamines. Transition proteins play a critical role in separation of histones and facilitate the condensation of sperm DNA by protamines at later stages . Despite controversial publications, it is abundantly clear that deviations in protamine ratio might be associated with various phenotypic features including decreased sperm counts and function and poor embryonic quality [69, 70].
The Role of miRNAs in Gametogenesis
Spermatogenesis is a complex differentiation process that consists of at least three major phases starting with diploid spermatogonial stem cells and ending with haploid mature spermatozoa. The process requires prompt and timely transitions between mitotic, meiotic, and postmeiotic stages, which, as expected, are tightly regulated at both transcriptional and posttranscriptional levels . Growing evidence has indicated that a specialized group of short noncoding RNAs termed microRNAs (miRNAs) exert an essential posttranscriptional control on each step of male germ cell differentiation .
miRNAs are 21–25 nucleotide long, endogenous noncoding RNAs that inhibit gene expression by binding to their target mRNAs, leading to either mRNA cleavage/degradation or translational repression. The biogenesis of miRNAs is a multistep process starting with RNA polymerase II-driven transcription of large precursor RNA molecules called pri-miRNAs . Pri-miRNAs are processed in the nucleus by a type III RNase termed Drosha and its cofactor Pasha/DGCR8 to become pre-miRNAs. Pre-miRNAs are then exported from the nucleus into the cytoplasm by exportin 5. In the cytoplasm, cleavage of pre-miRNAs by another type III RNase called Dicer results in the generation of mature duplex miRNA molecules . Either strand of the duplex may be incorporated into the so-called RNA-induced silencing complex (RISC) to downregulate its target mRNA via complementary base pairing at its 3′ untranslated region (3′UTR) . The degree of miRNA-mRNA complementarity is considered to be the key factor in the choice of posttranscriptional mechanism employed by miRNAs . Perfect base pairing results in mRNA cleavage and its subsequent degradation, whereas imperfect pairing leads to translational repression.
Recent studies have indicated that miRNAs are expressed in all phases of male germ cell differentiation and are required for spermatogenesis in mammalians . The absolute requirement for miRNAs for spermatogenesis has been shown by two initial studies where Dicer1 gene was knocked out in two different mouse models [76, 77]. Germ cell-specific deletion of Dicer1 in these models led to complete male infertility due to alterations in meiotic progression, increased spermatocyte apoptosis, and failure of haploid male germ cell differentiation. Since Dicer processes both miRNAs and endogenous siRNAs (endo-siRNAs) while Drosha is only limited to miRNA biogenesis, to dissect between the specific effects of miRNAs and endo-siRNAs, a following study has utilized Drosha and Dicer conditional knockout mouse models. In this study, it has been reported that both knockout males were infertile due to impaired spermatogenesis characterized by depletion of spermatocytes and spermatids leading to oligoteratozoospermia or azoospermia . Interestingly, when compared to ones from Dicer knockouts, testes from Droshaknockouts were more severely disrupted in terms of spermatogenesis, which further highlights the significance of miRNAs for normal spermatogenesis and male fertility .
There have been several studies investigating the role of miRNAs in human spermatogenesis, and results have so far supported the abovementioned observations obtained from animal models. Next-generation sequencing analysis of short RNA transcriptome from three normal human testes has identified a total of 770 known and five novel human miRNAs, indicating the abundance and complexity of miRNAs in the human testis . The most abundant miRNAs detected in this study were let-7 family members, miR-34c-5p, miR-103a-3p (meaning from the 3′arm), miR-202-5p, miR-508-3p, and miR-509-3-5p, which target gene transcripts involved in regulation of meiosis, spermatogenesis, germ cell apoptosis, testicular development, p53-related pathways, and homologous recombination pathways . In a more recent study where the expression levels of 736 miRNAs were tested in spermatozoa from ten normozoospermic fertile men, 221 miRNAs were found to be consistently present in all individuals . Potential targets of these miRNAs were found to be enriched in processes involved in development, morphogenesis, spermatogenesis, and embryogenesis. In the same study, three most stably expressed miRNAs, namely, miR-532-5p (meaning from the 5′arm), miR-374b-5p, and miR-564, have also been proposed by the authors to be used as fertility biomarkers .
Although cell stage-specific expression of miRNAs during spermatogenesis and their genuine and potential targets are relatively well defined in rodents, such studies are largely missing in humans [72, 74, 81]. Recently, one such study has isolated human spermatogenic cell populations from different stages of spermatogenesis and identified their miRNA expression profiles by microarray analysis . A total of 559 miRNAs were found to be distinctively expressed by human spermatogonia, pachytene spermatocytes, and round spermatids. Comparative analyses revealed 32 miRNAs to be significantly upregulated and 78 miRNAs to be downregulated between human spermatogonia and pachytene spermatocytes, suggesting that these miRNAs have a role in meiotic and mitotic phases of spermatogenesis, respectively. In addition, 144 miRNAs were found to be upregulated, while 29 miRNAs were downregulated between pachytene spermatocytes and round spermatids, indicating a potential role for these miRNAs in the regulation of spermiogenesis . Taken together, it has become more evident that in humans, as well as in rodents, miRNAs play essential roles in spatial and temporal control of gene expression, driving precise transitions between the major stages of spermatogenesis.
Finally, it is noteworthy to mention here the contribution of environmental factors to the epigenetic regulation of spermatogenesis . As is widely acknowledged, the male epigenome is subject to change due to certain environmental stressors, and these environmentally induced epigenetic changes can be transmitted to the next generations even though they are not exposed to the stressors themselves . A miRNA microarray study performed with spermatozoa from adult men living in an environmentally polluted region in China has revealed 73 significantly upregulated and 109 downregulated miRNAs compared to the control group . Since environmental pollution is one of the well-known factors accounting for decreased sperm quality in humans , these results suggest that differentially expressed miRNAs under such in men exposed to electronic waste pollution conditions might help explain the detrimental impact of environmental pollution on sperm quality and count .
Compared to spermatogenesis , investigating the connection between miRNA activity and oocyte development and oogenesis in humans has remained a poorly studied area. This may in part be due to the finding that despite their presence, gene regulation by miRNAs is kept in an inactive state in both mouse oocytes and early embryos [85, 86]. Although endo-siRNAs are thought to replace miRNAs in regulating gene expression and mRNA degradation at these stages , further studies are required to address the mechanism of action of endo-siRNAs and miRNAs in human oogenesis.
For several environmental exposures, it has been shown that these chemicals can alter the epigenetic profiles and subsequently lead to various diseases . Epigenetic aberrations caused by environmental factors can be transmitted from oocyte and spermatozoan to the offspring. Germline cells undergo developmental epigenetic alterations during both spermatogenesis and oogenesis. Spermatogenesis does not start before puberty; however, the foundations of spermatogenesis begin during the fetal life, and abnormalities during this period may have subsequent effects on the quality of spermatogenesis in adulthood more than in adolescence period . Environmentally induced germ cell differentiation and regulation in puberty is poorly understood. More work is necessary to understand the extent of epigenetic aberrations induced by environmental exposures during puberty. Epigenetic factors known to cause aberrant changes in epigenetic pathways are well documented; however, their exact mechanism in puberty has not been properly clarified. Further studies are required to elucidate the mechanisms relating to the origin of these alterations and to determine their significance and functional consequences for gametogenesis in puberty.
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