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There is mounting evidence that the adverse progeny outcome associated with increased paternal age is due to increased DNA damage and mutation rates as well as altered epigenetic marks in sperm chromatin. In this chapter, we first provide an overview of the dramatic changes that take place in sperm chromatin composition and organization during the complex process of spermatogenesis. We then present existing evidence demonstrating the effects of paternal age on sperm chromatin, on the dynamics of age-dependent DNA damage and repair, and on epigenetic marks as well as the potential role played by oxidative damage during spermatogenesis

Over the past few years, couples have tended to delay parenthood for a variety of reasons. While a large amount of information has been gathered about the consequences of advanced maternal age on fertility and on the health of their offspring, much less is known about the effects of paternal aging. In this article, we highlight what is known about male reproductive senescence. The gradual declining functions of the male reproductive organs and dysregulation of the hypothalamic-pituitary–gonadal axis with aging are described, as well as their consequences on semen parameters. The loss of sperm DNA integrity and the increased risks of genetic diseases in the offspring of older men are also discussed.

Oxidative stress (OS) associated with direct contact with the environment and light exposure is a very potent and continuous stressor of the ocular surface and internal structures of the eye that are required to manage its effects. Constant replenishment of tears together with the superficial lipid layer produced by the meibomian glands (MG) is one protective mechanism. The lipid-rich fraction of the tears coats the deeper aqueous fraction, preventing its evaporation. However, lipids are particularly sensitive to oxidative damage that could alter tear film quality. To counteract oxidative damage, MG along with other structures of the ocular surface use primary antioxidant (AO) systems to limit OS damage such as lipid peroxidation. Limited information concerning the primary enzymatic AO system of the human MG prompted this investigation. Using different approaches (RT-PCR, enzymatic activity assays and immuno-fluorescent microscopy), we determined the presence, distribution and subcellular locations of the major AO enzymes belonging to the classical catalytic triad (superoxide dismutase, catalase and glutathione peroxidases) in adult human MG and conjunctiva (Conj). We showed that both tissues exhibit glutathione peroxidase expression. In addition to the ubiquitous cytosolic GPx1 protein, there was significant expression of GPx2, GPx4 and GPx7. These isoforms are known to preferentially scavenge phospholipid-hydroperoxide compounds. This characterization of the primary AO system of human MG and Conj may help pave the way for the development of diagnostic procedures and have implications for treatment of common MG dysfunction (MGD) and dry eye syndrome (DES).

Gamete DNA integrity is one key parameter conditioning reproductive success as well as the quality of life for the offspring. In particular, damage to the male nucleus can have profound negative effects on the outcome of fertilization. Because of the absence of repair activity of the quiescent mature spermatozoa it is easily subjected to nuclear damage, of which oxidative damage is by far the most prominent. In relation to the organization of the mammalian sperm nucleus we show here that one can correlate the nuclear regions of lower compaction with areas preferentially showing oxidative damage. More precisely, we show that oxidative DNA damage targets primarily histone-rich and nuclear matrix-attached domains located in the peripheral and basal regions of the mouse sperm nucleus. These particular sperm DNA domains were recently shown to be enriched in genes of paramount importance in postfertilization DNA replication events and in the onset of the embryonic developmental program. We propose that monitoring of sperm DNA oxidation using the type of assay presented here should be considered in clinical practice when one wants to estimate the integrity of the paternal nucleus along with more classical assays that essentially analyze DNA fragmentation and nucleus compaction.

Spermatozoa leave the testis in an immature functional state and are devoid of self defense mechanisms. They will become motile and ready to fertilize only after their descent and their progressive maturation within the epididymal tubule. The epididymis also ensures the survival and the protection of male gametes while they go through the epididymis and during their storage in between two ejaculations. Amongst common stresses that concern spermatozoa, oxidative stress occupies a peculiar and dual position. While the events of epididymal sperm maturation necessitate a given level of oxidation, spermatozoa are particularly sensitive to oxidative damage. A fine balance between beneficial oxidation versus detrimental oxidative damage has to be maintained in the epididymal environment. Antioxidant enzymes of the glutathione peroxidase family play a key role in controling such a situation in the epididymis.

Spermatozoa are the smallest and most cyto-differentiated mammalian cells. From a somatic cell-like appearance at the beginning of spermatogenesis, the male germ cell goes through a highly sophisticated process to reach its final organization entirely devoted to its mission which is to deliver the paternal genome to the oocyte. In order to fit the paternal DNA into the tiny spermatozoa head, complete chromatin remodeling is necessary. This review essentially focuses on present knowledge of this mammalian sperm nucleus compaction program. Particular attention is given to most recent advances that concern the specific organization of mammalian sperm chromatin and its potential weaknesses. Emphasis is placed on sperm DNA oxidative damage that may have dramatic consequences including infertility, abnormal embryonic development and the risk of transmission to descendants of an altered paternal genome.Le spermatozoïde est la cellule la plus petite et la plus cytologiquement différenciée chez les mammifères. D’une apparence proche de celle d’une cellule somatique au début de la spermatogenèse, la cellule germinale mâle va, au travers d’un processus hautement sophistiqué, atteindre une organisation finale entièrement dédiée à sa mission qui est de conduire le lot chromosomique paternel au sein de l’ovule. Afin de pouvoir accommoder l’ADN paternel dans la minuscule tête du spermatozoïde, un remodelage complet de la chromatine est nécessaire. Cette revue est essentiellement concentrée sur les aspects connus à ce jour de ce programme de condensation nucléaire spermatique. Une attention particulière est donnée aux avancées les plus récentes concernant l’organisation très spécifique du noyau spermatique et sur ses points de fragilité, en particulier face aux dommages radicalaires. Ces derniers peuvent avoir des conséquences dramatiques qui se posent en termes d’infertilité, de développements embryonnaires anormaux et de risque de transmission à la descendance d’un patrimoine génétique paternel altéré.

Spermatozoa leave the testis in an immature functional state and are devoid of self defense mechanisms. They will become motile and ready to fertilize only after their descent and their progressive maturation within the epididymal tubule. The epididymis also ensures the survival and the protection of male gametes while they go through the epididymis and during their storage in between two ejaculations. Amongst common stresses that concern spermatozoa, oxidative stress occupies a peculiar and dual position. While the events of epididymal sperm maturation necessitate a given level of oxidation, spermatozoa are particularly sensitive to oxidative damage. A fine balance between beneficial oxidation versus detrimental oxidative damage has to be maintained in the epididymal environment. Antioxidant enzymes of the glutathione peroxidase family play a key role in controling such a situation in the epididymis.

International audience; The mammalian glutathione peroxidase (GPx) gene family encodes bifunctional enzymes that can work either as classical reactive oxygen species (ROS) scavengers or as thiol peroxidases, thereby introducing disulfide bridges in thiol-containing proteins. These dual effects are nowhere better demonstrated than in epididymal maturing spermatozoa, where the concomitant actions of several GPx ensure the achievement of the structural maturation of sperm cells as well as their protection against ROS-induced damage. We review here the roles played by the sperm-associated forms of GPx4 (mitochondrial GPx4 and nuclear GPx4), the secreted GPx5 protein, and the epithelial proteins GPx1, GPx3, and cellular GPx4, all functioning in the mammalian epididymis at different stages of the sperm's epididymal journey, and in different epididymis compartments.