Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice

Granulocyte-macrophage colony-stimulating factor (GMCSF) has been identifie d as a potentially important mediator of intercellular communication in the female reproductive tract, with principal target cells being the large pop ulations of myeloid leukocytes in the cycling and pregnant uterus, the prei mplantation embryo, and trophoblast cells of the developing placenta. To de termine the physiological significance of this cytokine in reproduction, th e fertility of genetically GM-CSF-deficient (GM-/-) mice was examined. Impl antation rates were normal in GM-/- mice, and viable pups were produced. Ho wever, the mean litter sizes of GM-/- x GM-/- breeding pairs were 25% small er at weaning than those of GM+/- x GM+/- pairs, due to fetal death late in gestation and early in postnatal life, with a disproportionate loss of mal e pups. On Day 17 of pregnancy, the mean number of resorbing and malformed fetuses was twice as high in pregnant GM-/- females (21%, vs. 11% in GM+/- females); the mean fetal weight and the mean fetal:placental ratio in survi ving conceptuses were diminished by 7% and 6%, respectively; and the number of very small fetuses (< 500 mg) was 9-times as high (23% vs. 2.5%). Morta lity during the first 3 wk of life was 4.5-times as high in pups born to GM -/- mothers (9%, vs. 2% in GM+/- females), and diminished size persisted in GM-/- pups, particularly males, into adulthood. The detrimental effect of maternal GM-CSF deficiency was less apparent when GM-/- females were mated with GM+/+ males; litter sizes at birth and at weaning were not significant ly smaller than in GM+/- matings, and fetal weights and fetal:placental rat ios were also comparable. When polymerase chain reaction was used to genoty pe embryonic tissue in heterozygote matings, GM-/- fetuses from GM-/- femal es were found to be smaller than their GM+/- littermates and smaller than G M-/- fetuses gestated in GM+/- females. The size and distribution of uterin e granulocyte and macrophage populations were normal during the estrous cyc le, during early pregnancy, and in midgestation. Analysis of placental stru cture revealed that the ratio of labyrinthine to spongiotrophoblast areas w as reduced by approximately 28% in GM-/- placentae, and the proportion of v acuolated trophoblast "glycogen cells" in the spongiotrophoblast layer was diminished. Compromised placental function as a result of subtle developmen tal aberrations may therefore partially account for embryonic growth retard ation in GM-CSF-deficient mice. Collectively, these studies show that fetal growth and viability are jeopardized in the absence of maternal GM-CSF. Th e detrimental effects are most clearly evident when the conceptus is also G M-CSF deficient, suggesting that GM-CSF of either maternal or fetal origin is required for optimal growth and survival of the fetus in mice.