Testosterone biosynthesis and spermatogenesis disruption by PM exposure: The hidden role of bitter taste transduction

Male infertility, a major global reproductive health concern, has been linked to increased particulate air pollution and inflammatory response. Bitter taste transduction, involved in sensing bitterness, inflammation, and immune regulation, remains understudied in male reproductive damage. This research investigated how particulate matter (PM) impacts male reproductive health and the involvement of bitter taste transduction in reproductive toxicity. A PM exposure mouse model was established via aerosol inhalation of ovalbumin (OVA) following intraperitoneal injection of OVA. Results showed that PM exposure reduced sperm count, increased sperm malformation rate, decreased seminiferous epithelium height and tubular diameter, and caused disordered spermatogenic cell arrangement, along with decreased Johnsen scores, suggesting testicular structural damage and spermatogenesis disorders. Furthermore, PM exposure reduced serum testosterone levels and diminished the mRNA expression of genes involved in testosterone synthesis, transport, and spermatogenesis, including luteinizing hormone receptor (LHR), steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage enzyme (P450scc), 17-beta-hydroxysteroid dehydrogenase (17(1-HSD), androgen-binding protein (ABP), and DEAD-box helicase 3 Y-linked (Ddx3y). Meanwhile, pro-inflammatory cytokine gene TNF-alpha and inflammatory genes IL-4R alpha, JAK1, JAK2, JAK3, STAT3, and STAT6 were significantly upregulated in testes of PMexposed mice. This was accompanied by inhibited expression of Th1 cytokine gene IFN-gamma and enhanced expression of Th2 cytokine genes IL-4, IL-5, and IL-13. Twenty-four out of thirty-five bitter taste receptor (T2R) genes, along with their downstream signaling molecules alpha-gustducin and transient receptor potential cation channel subfamily M member 5 (TRPM5) genes exhibited transcriptional repression in testes of PM-treated mice. The bitter compound baicalin alleviated PM-induced male reproductive damage accompanied with activating testis-specific T2R cluster (T2R102, T2R109, T2R113, T2R117, T2R119, T2R124, T2R135, T2R136), alpha-gustducin and Trpm5. In conclusion, PM inhalation affects testosterone biosynthesis and spermatogenesis, induces inflammatory response and immune imbalance, and causes testicular injury, all of which are associated with the inhibition of bitter taste transduction. The results indicate that bitter signaling molecules could serve as potential targets for preventing and managing infertility in men.