**3. Upcoming issue for paternal epigenetic inheritance**

(lncRNA), and tRNA fragments (tRFs) [8], and lastly they acquire progressive motility. After epididymal maturation, SPZ are still incapable to fertilize eggs; they have to spend some time in the female reproductive tract before they acquire this competence (fertilizing ability) through the capacitation process [9]. During this phase, SPZ undergo other important biochemical modifications in terms of steroid removal or protein modifications [10]; after that, they interact with cumulus-cell oocyte complex to penetrate the matrix of the cumulus oophorus [11]. Capacitated SPZ are subjected to acrosome reaction, a prerequisite event for spermegg fusion [12], then they penetrate the zona pellucida, to meet and fuse with the egg plasma membrane [13]. After this fusion, finely controlled by a large body of proteins, SPZ deliver to the oocyte their haploid genome. **Figure 1** summarizes the main features of spermatogenesis

**Figure 1.** Schematic view of the main events characterizing spermatogenesis in testis, followed by spermatozoa (SPZ) maturation in male reproductive tracts and capacitation/fertilizing ability in female reproductive tracts. SPG: spermatogonia; ISPC: primary spermatocytes; IISPC: secondary spermatocytes; rSPT: round spermatids; eSPT:

Intricate neuronal circuitries, mainly governed by hypothalamic kisspeptin and gonadotropin releasing hormone (GnRH) reciprocal communications, centrally orchestrate reproduction [1] and lead to pituitary gonadotropin discharge and sex steroid biosynthesis in order to sustain spermatogenesis and sperm release. In addition to hormonal milieu, a complex network of intratesticular cell-to-cell communications regulates germ cell progression, coordinating mitosis, meiosis, differentiation, and maturation [2, 3]. Thus, SPZ morphological feature is

**2. The control of spermatogenesis and sperm quality**

critical to ensure proper physiological activity.

and SPZ maturation.

elongating spermatids; SPZ: spermatozoa.

2 Spermatozoa - Facts and Perspectives

Once considered just a "carrier" for male haploid genome at fertilization, nowadays, the functional role of SPZ has been revised. In fact, a part haploid genome, SPZ, preserve some spermspecific RNA components, absent in the oocyte, such as fragments of longer transcripts, able to control early embryogenesis [22–24]. Mature SPZ also contain a rich repertoire of ncRNAs, such as miRNAs, tRFs, lncRNAs, and PIWI-interacting RNAs (piRNAs). Their deregulation not only alters SPZ physiology but may affect SPZ contribution to a regular embryo development, through epigenetic dynamics [25], since there is a need to focus more attention on SPZ as carrier of transgenerational epigenetic inheritance.

The specific epigenetic signatures of SPZ include DNA methylation status, chromatin remodeling, and ncRNA pools. Unlike somatic cells, germ cells have hypomethylated DNA [26], and genome-wide hypermethylation of sperm DNA status is associated with pregnancy failure [27]. As reported in the previous paragraph, chromatin remodeling, made possible through histone replacement by protamines, is a key step of spermiogenesis and does not occur in ovogenesis [5, 28]. Interestingly, a deregulated histone-protamine exchange induces DNA damage and male subfertility [29]. A small percentage of paternal genome retains histones and reveals a nucleosome organization, in not random distribution, thus affecting transcription factor accessibility to DNA at specific gene loci [30]. Furthermore, together with a well-known histone code, a protamine code has been suggested in SPZ [31]. Lastly, sperm RNA cargo plays an important role in SPZ epigenetic landscape. Several classes of RNAs have been identified in SPZ [32] and their possible contribution in the regulation of gene expression in embryo is currently under investigation. Surely these small RNAs take part in the sperm epigenetic transgenerational pattern of inheritance because they are vulnerable to paternal exposure to various forms of stress and they are able to regulate developmental trajectories of the offspring. In fact, a high-fat diet (HFD) in male mice alters sperm miRNA content and, thus, glucose tolerance in both male and female offspring [33]. Similarly, sperm tRNA fragments injected from HFD males or from male mice with a protein restriction status to normal zygotes are vehicles of transgenerational transmission of metabolic disorders in the offspring [34, 35].

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Introductory Chapter: Spermatozoa - Facts and Perspectives

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Therefore, DNA methylation, posttranslational histone modifications, chromatin remodeling, and ncRNA activity are plastic epigenetic mechanisms, modifiable in response to environmental and behavioral events and heritable from father to the offspring as an acquired mark [36]. This also means that paternal lifestyle or experiences, including physical activity, nutrition, and exposure to pollutants, can alter SPZ epigenome, with male infertility, embryo development failure, abnormal embryonic molecular makeup, and disease susceptibility of the offspring as a result [37].
