Bitter taste signaling pathway is required for spermatogenesis and maintenance of male fertility in mice.

Recently, the expression of bitter taste receptors and their downstream taste signaling cascade has been widely found outside the gustatory system, indicating important physiological functions of bitter taste receptors in various extraoral organs, including testis, but little is known about their functions in spermatogenesis. Here, we describe the localization and expression pattern of taste signaling transduction molecules in the testis. Genetic mutation of bitter signaling transduction molecules decreased the litter size, the IVF rate, and the diameter of seminiferous tubules and even resulted in empty seminiferous tubules. Transmission electron microscopy observations further revealed that overdeveloped acrosomes adhered to atrophic round spermatids in double-mutant mice. Mutant mice lacking bitter taste receptor signaling exhibited a dysfunction of adenosine 5'-monophosphate-activated protein kinase and inducible nitric oxide synthase signaling pathways, and a decreased expression of zonula occludens-1 and β-catenin in testis, indicating a disruption for the structure and functions of the blood-testis barrier. Transcriptome analysis further showed that bitter taste signaling deficiency can alter the expression profile of transcripts related to signal pathways, hormone synthesis, cell adhesion molecules, the chemokine signaling pathway, and cell metabolism in the testis, which finally contribute to impaired male fertility. In short, our work provides previously unidentified in vivo evidence that bitter taste signaling plays a critical role in the maintenance of normal spermatogenesis. These data further support the concept that bitter taste receptors exert functions outside the gustatory system and may have implications for the diagnosis and management of human male infertility.