Impaired Steroidogenesis and Implantation Failure in Bmal1-/- Mice

Evidence in humans and rodents suggests that normal circadian rhythmicity is important for supporting reproductive function. A molecular clock underlies circadian rhythmicity. Impaired fertility is observed in some genetically altered mice with deficiencies in genes of the molecular clock, suggesting a critical role for these genes in reproduction. Here we systematically characterize the reproductive phenotype of females deficient in the clock gene Bmal1. Bmal1(-/-) females are infertile. They exhibit progression through the estrous cycle, although these cycles are prolonged. Normal follicular development occurs in Bmal1(-/-) females, and healthy embryos of the expected developmental stage are found in the reproductive tract of Bmal1(-/-)females 3.5 d after mating to wild-type males. However, serum progesterone levels are significantly lower in Bmal1(-/-) vs. Bmal1(-/-) females on d 3.5 of gestation. Low progesterone levels in Bmal1(-/-) females are accompanied by decreased expression of steroidogenic acute regulatory protein in corpora lutea of Bmal1(-/-) vs. Bmal1(-/-)females. Whereas implantation of embryos is not observed in untreated or vehicle-treated Bmal1(-/-) females, exogenous administration of progesterone to Bmal1(-/-) females is able to reinstitute implantation. These data suggest that implantation failure due to impaired steroidogenesis causes infertility of Bmal1(-/-) females. (Endocrinology 150: 1879-1885, 2009)