Superoxide dismutase 2 haplodeficiency alters spermatogenesis and early development in mice

Elevated levels of ROS are closely associated with impaired male fertility. Although spermatogenesis involves high mitochondrial oxygen consumption and consequent ROS generation, the precise mechanism by which oxidative stress contributes to sperm dysfunction remain poorly understood. Here we demonstrate for the first time that haplodeficiency of mitochondrial antioxidant enzyme SOD2/MnSOD show alterations in reproductive physiology. Colonies of Sod2^+/- mice exhibited reduced litter size and prolonged breeding-to-parturition period, effects observed exclusively when males carried the transgene. Sod2 expression increased progressively along the spermatogenic lineage from spermatogonia to spermatozoa. Using transgenic mice expressing the mitochondrial biosensor mito-roGFP2-Orp1, we identified an inverse gradient of H₂O₂ consistent with expression of the mitochondrial antioxidant enzyme expression. Both, Sod2^+/- haplodeficient and Sod2^+/++ overexpressing mice displayed alterations in the spermatogenic series and in the seminiferous tubules stage distribution relative to wild type animals, but this was not correlated with a reduction in sperm count, motility, or viability. Notably, sperm from Sod2^+/- mice exhibited reduced fertilization rate and significantly decreased early pre-embryonic viability during first stages following in vitro fertilization. Collectively, these findings indicate that impaired mitochondrial redox homeostasis due to Sod2 haplodeficiency compromises early embryonic development, leading to reduced reproductive success, and identify SOD2 as a potential marker of sperm functional quality.