Mechanisms of environmental reproductive toxicity: Sperm DNA damage

The spermatogenetic process in the human produces a heterogeneous cell population showing different degrees of maturation, variable morphological features and fertilizing capacity. There is a large body of evidence that some of the ejaculated spermatozoa possess a variety of abnormalities at the nuclear, cytoskeletal, and organelle levels and that these anomalies impact fertility. Damage of sperm DNA or its chromatin structure can occur at any step of whole spermatogenesis and could have endogenous (i. e. pathological altered germ cell maturation) or exogenous origin (i. e. exposure to xenobiotic substances). Three main theories have been proposed to explain DNA anomalies in the ejaculated human spermatozoa (Sakkas and Alavarez, 2010). The first theory supports that DNA damage in mature spermatozoa is associated with poor chromatin packaging or abnormal packing due to underprotamination and/or alteration of Topisomerase II activity which results in the presence of endogenous nicks in DNA (Manicardi et al., 1995). The second theory proposes that sperm DNA damage could be related to a process called \u201cabortive apoptosis\u201d whereby sperm cells are earmarked for apoptosis during spermatogenesis but survive to be present in the ejaculate (Sakkas et al., 2002). A major factor affecting sperm is also their vulnerability to oxidative stress, because they are deficient in both antioxidant and DNA-repair systems and rich in targets for oxidative attack (Aitken et al., 1998). The correct DNA packaging and stability appears to be fundamental for the protection against both endogenous and exogenous DNA damage. Transmission of damaged DNA to the offspring, particularly at levels that exceed the DNA repair capacity of the oocyte, has been shown to have serious consequences in animal models and is also being more and more implicated in the human. Normal sexual development, differentiation and function in the human has been shown to be altered by the presence of synthetic chemicals in the environment acting as endocrine disruptors or mutation agents. Moreover, exposure to physical agents or chemicals, including therapeutic drugs and environmental toxicants, either individually or together, can affect the integrity of sperm chromatin (Stronati et al., 2006). The observation that ejaculated human spermatozoa possess DNA damage raises numerous problems relating to why and how these spermatozoa arise in the ejaculate of some men and what consequences they have if they succeed in their genetic project. Understanding the mechanisms responsible will improve our knowledge about certain causes of male infertility