Nanoparticulate TiO₂ Induced Suppression of Spermatogenesis is Involved in Regulatory Dysfunction of the cAMP-CREB/CREM Signaling Pathway in Mice.

Long-term exposure to nanoparticulate titanium dioxide (nano-TiO₂) is known to cause reductions of sperm numbers and quality in animals, and the cAMP-dependent signaling pathway has been demonstrated to play a key role in regulating spermatogenesis. However, whether the suppression of spermatogenesis induced by nano-TiO₂ is related to regulatory disturbances of the cAMP-CREB/CREM signaling pathway is not well investigated. In the current study, male mice were exposed to nano-TiO₂ at doses of 1.25, 2.5, or 5 mg/kgbw via gavage instillation for 90 consecutive days and the molecular mechanisms underlying suppression of spermatogenesis caused by nano-TiO₂ were investigated. Our findings showed that nano-TiO₂ could cross the blood-testis barrier, and accumulated in mouse testes, thus inducing obvious pathological changes and decreasing sperm concentrations and motility, as well as increasing rate of sperm malformation. Furthermore, nano-TiO₂ also induced significant reductions in protein expression including cyclic adenosine monophosphate content, protein kinase A, cAMP-responsive element modulator, p-cAMP-response element binding protein, lactate dehydrogenase-C, testis-specific protein kinase 1, and testicular specific CREM activator, and upregulation of protein expression including protein phosphatase, and transducer of regulated CREB 1, which may be associated with reductions of follicle stimulating hormone and luteinizing hormone levels. Together, the present study indicates that the reductions of FSH and LH concentrations and suppression of spermatogenesis in mice caused by nano-TiO₂ may be associated with the dysfunctions of the cAMP-CREB/CREM signaling pathway.