A unique urinary constituent, 6-hydroxy-6-methyl-3-heptanone, is a pheromone that accelerates puberty in female mice

Background: Olfactorily mediated puberty acceleration in female mice (measu red by an increase in uterine weight) has been observed since the 1960s wit hout the active chemosignal being structurally identified. There are many c ontroversies in the literature as to whether this male-originated pheromone is a volatile substance. We investigated the chemical nature of the urinar y fractions that are responsible for the characteristic uterine weight incr eases. Results: The active pheromone was identified as 5,5-dimethyl-2-ethyltetrahy drofuran-2-ol and/or its open-chain tautomer (6-hydroxy-6-methyl-3-heptanon e). A series of cyclic vinyl ethers were isolated from chromatographically active fractions of the urine. Because these compounds did not accelerate p uberty, we postulated that these ethers were degradation products of a lact ol (5,5 -dimethyl-2-ethyltetrahydrofuran-2-ol). The lactol was then detecte d directly in the mouse urine extract using a silylation agent. Synthetic 6 -hydroxy-6-methyl-3-heptanone had strong biological activity, whereas its c lose structural analogs did not. Conclusions: The male house mouse excretes into its urine a large quantity of a volatile substance that has a unique lactol/hydroxyketone structure. T his substance is capable of binding to the less volatile urinary constituen ts, such as proteins or peptides, and is active in puberty-acceleration bio assays. The controversies regarding the volatility of the puberty-accelerat ing pheromones can now be explained by considering a complex of volatile la ctol/hydroxyketone and urinary proteins.