Pathophysiological effects of hypoxia on testis function and spermatogenesis

Multiple conditions can cause hypoxia in the testis, including exposure to high altitude, sleep apnoea, testicular torsion and varicocele. Varicocele accounts for up to 44% of instances of primary infertility, but the cumulative contribution of hypoxic conditions to male infertility is undefined. Results of controlled hypobaric hypoxia studies have demonstrated a substantial detrimental effect of short-term and long-term exposures on sperm; however, downstream effects on embryo development and offspring health are less well understood. Hypoxia can have direct and indirect effects on the molecular biology and biochemistry of germ cells, including changes to gene expression, metabolism, oxidative stress and to the endocrine environment. Hypoxia also has often-overlooked effects on the epididymis, such as altered composition and gene expression of epithelial cells, with knock-on effects on sperm maturation, including the capacity to acrosome react. Evidence from model species shows that paternal hypoxia exposure results in disrupted embryo development and transgenerational effects on male fertility and offspring physiology. Overall, hypoxia induces a complex, multifaceted subfertility phenotype that is reversible with resolution of the exposure, in part because of a resilient testis stem cell population that thrives in hypoxia. However, the potential for transgenerational effects deserves further exploration, particularly in considering the purported decline in sperm counts over the past 50 years.