In C5-heterozygous intercrosses, the proportion of C5-homozygous-null female offspring exceeds the expected Mendelian...

The complement system has functions beyond host defense, including roles in development and reproduction. However, the role of complement C5 in fertilization and early embryonic development remains unclear. Here, we investigated the reproductive phenotype of C5-deficient mice on a BALB/c background. C5^-/- mice were fertile and showed no obvious reproductive abnormalities under standard laboratory housing conditions. However, offspring from C5^+/- × C5^+/- mating showed a significant deviation from the expected Mendelian distribution, with an increased proportion of female C5^-/- offspring, whereas male offspring showed no comparable distortion. In vitro fertilization reproduced this skewed ratio which was detectable at the blastocyst stage, suggesting that the underlying mechanism operates during fertilization or preimplantation development. Parent-of-origin analysis further suggested a contribution of maternal C5. During preimplantation development, C5, C5a receptor 1 (C5ar1), and C5a receptor 2 (C5ar2) mRNA levels showed distinct dynamic expression profiles. These findings revealed an unexpected sex- and genotype-dependent reproductive phenotype associated with C5 deficiency and suggest that C5-dependent signaling may contribute to genotype-dependent selection during fertilization or preimplantation development. The dynamic expression of C5a receptors further supports a potential role for C5a signaling in early embryonic development and expands the biological role of complement beyond immune defense to include regulation of mammalian reproduction.