Maternal hyperhomocysteinemia compromises female offspring fertility through overactivation of primordial follicles.

Hyperhomocysteinemia (HHcy), characterized by plasma homocysteine concentrations exceeding 15 μmol/L, has been associated with various issues that impact personal health and offspring well-being. This study examines the effect of maternal HHcy induced by a high-methionine diet on the fertility of female offspring mice. The results showed that maternal HHcy caused the overactivation of primordial follicles in female offspring mice by promoting the phosphorylation of key factors, including RPS6, mTOR, FOXO3a, and AKT. Moreover, the number of mitochondria in mature oocytes decreases, and mitochondrial function decreases, further leading to increased reactive oxygen species (ROS) levels, a higher degree of DNA damage, and spindle abnormalities, ultimately impairing the quality of oocytes. These findings demonstrate that maternal HHcy decreases offspring fertility by inducing primordial follicle overactivation and impairing oocyte quality, providing new insights into the pathological mechanisms through which HHcy affects the reproductive potential of offspring.