Testicular toxicity induced by a triple neurokinin receptor antagonist in male dogs

• Published in: Reproductive toxicology (Elmsford, N.Y.) N.Y.), 2011-05, Vol.31 (4), p.440-446
• Main Authors: Noritake, Ken-Ichi, Suzuki, Junko, Matsuoka, Toshiki, Makino, Toshihiko, Ohnishi, Hitoshi, Shimomura, Kazuhiro, Uenoyama, Yoshihisa, Tsukamura, Hiroko, Maeda, Kei-Ichiro, Sanbuissho, Atsushi
• Format: Article
• Language: English
• Subjects: Animals; Antagonist; Biological and medical sciences; Cyclic S-Oxides - toxicity; Dog; Dogs; Embryology: invertebrates and vertebrates. Teratology; Follicle Stimulating Hormone - blood; Fundamental and applied biological sciences. Psychology; Hypothalamus - drug effects; Hypothalamus - metabolism; Luteinizing hormone; Luteinizing Hormone - blood; Male; Medical sciences; Morpholines - toxicity; Neurokinin; Neurokinin B - metabolism; Orchiectomy; Organ Size - drug effects; Prostate - drug effects; Prostate - pathology; Quinolines - toxicity; Receptors, Neurokinin-3 - antagonists & inhibitors; Receptors, Neurokinin-3 - metabolism; Receptors, Tachykinin - antagonists & inhibitors; Receptors, Tachykinin - metabolism; Sperm Count; Sperm Motility - drug effects; Spermatogenesis - drug effects; Spermatozoa - drug effects; Spermatozoa - metabolism; Spermatozoa - pathology; Teratology. Teratogens; Testicular toxicity; Testis - drug effects; Testis - metabolism; Testis - pathology; Testosterone - blood; Time Factors; Toxicology
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2010.12.007

Mechanism mediating the testicular toxicity induced by CS-003, a triple neurokinin receptor antagonist, was investigated in male dogs. Daily CS-003 administrations showed testicular toxicity, such as a decrease in the sperm number, motility and prostate weight; and an increase in sperm abnormality, accompanying histopathological changes in the testis, epididymis and prostate. A single CS-003 administration suppressed plasma testosterone and LH levels in intact and castrated males. The suppressed LH release was restored by GnRH agonist injection, suggesting that pituitary sensitivity to GnRH is not impaired by CS-003. Treatment with SB223412, a neurokinin 3 receptor antagonist, caused a similar effect to CS-003, such as toxicity in the testis, prostate and epididymis and decreased plasma level of LH and testosterone. In conclusion, CS-003-induced testicular toxicity is caused by the inhibition of neurokinin B/neurokinin 3 receptor signaling probably at the hypothalamic level in male dogs.