**5. Conclusions**

In conclusion, the importance of oxidative stress as a major modulator of mammalian sperm function is incontrovertible. ROS have a positive role to play in driving the cascade of biochemical changes associated with sperm capacitation through their ability to control tyrosine phosphatase activity, stimulate cAMP generation and mediate the oxidation and ultimate release of cholesterol from the sperm plasma membrane. However, for obvious structural reasons these cells have very little defense against oxidative stress and are, thus, highly dependent on the powerful antioxidant properties of the fluids that surround them following their release from the germinal epithelium (seminiferous and epididymal tubule fluid and, for a short while at the moment of insemination, seminal plasma). If this extracellular antioxidant protection should be compromised for genetic, environmental or lifestyle reasons then the male germ line comes under oxidative attack. Oxidative stress may also be exacerbated by a variety of conditions that promote ROS generation by cells in the immediate vicinity (e.g., leukocyte infiltration secondary to infection) or by the spermatozoa themselves (exposure to RF-EMR, the stresses associated with cryopreservation, heat and exposure to a wide range of xenobiotics including bisphenol A, phthalate esters, parabens, etc). The complex combination of factors responsible for creating oxidative stress in the male germ line may well vary from patient to patient and is still not fully explored. Understanding the nature of these factors is significant because it will help guide the preconception care of such patients. Ensuring the functionality and genetic integrity of spermatozoa prior to conception is important, not just because it may promote the chances of conception but because

it will minimize the genetic and epigenetic mutational load carried by the o ffspring and in so doing promote their long-term health trajectory.

**Author Contributions:** R.J.A. conceived the article and prepared an initial draft which was then reviewed, edited and revised by J.R.D. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
