Environmental and External Factors Related to Mitochondrial ROS

2.2.4.1 Environmental

The generation of ROS in all cell types can be exacerbated by a multitude of external and environmental factors. Industrial development is exposing men and women to an increasing number of different chemicals and by-products of manufacturing in their environment. Many of these toxic compounds are found to induce oxidative stress and have been suggested to pose a serious threat towards the normal and reproductive health of humans around the world and especially in developing nations [105], Some environmental compounds that are known to induce mitochondrial ROS generation include phthalates [106], estrogens [107], and EMR [53].

One of the most heavily investigated compounds for effects on reproductive function are phthalates. Phthalates are most commonly found in plastic food packaging and can be released into foods upon contact, increasing human exposure levels of these compounds [108]. Phthalate exposure in rats has shown to induce significant levels of DNA damage in spermatozoa as well as impairing normal sper-matogenesis [109], Additional studies have shown that exposure of germ cells to phthalates in vitro results in oxidative stress, mitochondrial dysfunction, cytochrome c release, and apoptosis [110, 111].

An in-depth mouse study investigating the in vivo effects of exposure to various phthalates found treatment resulted in higher concentration in semen and this negatively correlated with semen quality. Increased ROS generation was also observed in spermatozoa as well as other markers of oxidative stress including lipid peroxidation and DNA damage. Although the source of ROS was not investigated, bis(2-ethylhexyl) phthalate DEHP treatment also resulted in mitochondrial dysfunction, a major cause of mitochondrial ROS as discussed [112].

2.2.4.2 Paternal Age

The consequences of paternal age on human fertility have come to the fore due to changes in human reproductive patterns, a combination of social changes, prolonged life expectancy, and a reliance on Assisted reproductive technology (ART) [113]. The association between increased paternal age and decreased sperm parameters has been well documented. Jung et al. [114] reported that older subjects (>50 years) showed a 27% decrease in progressive motility compared to younger men (21-25 years). Another study also found that older subjects (>55 years) exhibited approximately 25% lower total sperm count, semen volume, and sperm concentration compared to the younger age group (30-35 years) [115]. Furthermore, recent studies have also shown that ROS production and oxidative stress are increased in human spermatozoa during aging, suggesting a possible role for the decline in fertility [116],

Although the source of ROS in the study by Cocuzza et al. [116] was not investigated, other evidence related to aging suggests that it may be of mitochondrial origin. Many hallmarks of reduced fertility including oxidative DNA damage and lipid peroxidation have been shown to be increased in various tissues during aging [117-119].

Increased age in humans has also shown to be linked to increased levels of mutation in mtDNA [120]; this is a direct result of the constant mitochondria ROS generation in combination with the lack of protection to mtDNA in comparison to that provided to nuclear DNA by histones or protamines [121]. Subsequently, mutations or deletions in mtDNA lead to defects in oxidative phosphorylation, calcium homeostasis, and other related mtDNA diseases [122]. With increased paternal age associated with decreased fertility, it is likely that the two are linked by the associating factor of mitochondrial ROS.

2.2.4.3 Smoking

The carcinogenic and toxic effects of cigarette smoking on the health of an individual are well documented. Smoking has also been shown to result in an increased likelihood of male infertility, with significantly higher levels of seminal ROS generation [123] and DNA damage [124] found in these men. Previous research has shown a significant elevation in the activity of MnSOD (mitochondrial isozyme) in cigarette smokers [125], indicating that cigarette smoking may cause increased mitochondrial ROS generation, rather than via a cytosolic or membrane oxidase system.

In smokers, the overall mitochondrial ETC function is significantly decreased which also correlates with increased peroxidative damage to lymphocyte membranes [126]. An extremely large Danish study of 2,542 healthy men, without bias towards reproductive history, discovered that compared with nonsmokers, smokers exhibited significantly decreased sperm concentration, semen volume, motility, and total sperm count [127]. Although the changes observed were only minor (20-30% decrease), such effects may further compound an already-existing minor reproductive condition or combine with other xenobiotics to further reduce fertility. Overall, the smokers presented in the study exhibited increased seminal ROS production and decreased antioxidant levels. A number of independent studies have also shown that smoking results in higher levels of DNA damage in the human spermatozoa in comparison to nonsmokers [124, 128, 129]. Also, a higher rate of smoking observed in men is associated with corresponding increases in the rate of aneuploidy in spermatozoa [130, 131][ Overall, the results on smoking in men provide further evidence for the role that oxidative stress and DNA damage play in male infertility. Although only suggestive evidence exists, these data also provide a rationale for further investigation into the role of mitochondria in smoking-related oxidative stress in the male germ line.

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