title: MicroRNA profiling in ethylene glycol monomethyl ether-induced monkey testicular toxicity model.
abstract: To establish and characterize ethylene glycol monomethyl ether (EGME)-induced testicular toxicity model in cynomolgus monkeys, EGME at 0 or 300 mg/kg was administered orally to sexually mature male cynomolgus monkeys (n = 3/group) for 4 consecutive days. Circulating and testicular microRNA (miRNA) profiles in this model were investigated using miRNA microarray or real-time quantitative reverse transcription-PCR methods. EGME at 300 mg/kg induced testicular toxicity in all the monkeys, which was characterized histopathologically by decreases in pachytene spermatocytes and round spermatids, without any severe changes in general conditions or clinical pathology. In microarray analysis, 16 down-regulated and 347 up-regulated miRNAs were detected in the testis, and 326 down-regulated but no up-regulated miRNAs were detected in plasma. Interestingly, miR-1228 and miR-2861 were identified as abundant miRNAs in plasma and the testis of control animals, associated presumably with apoptosis and cell differentiation, respectively, and were prominently increased in the testis of EGME-treated animals, reflecting the recovery from EGME-induced testicular damages via stimulating cell proliferation and differentiation of sperm. Furthermore, down-regulation of miR-34b-5p and miR-449a, which are enriched in meiotic cells like pachytene spermatocytes, was obvious in the testis, suggesting that these spermatogenic cells were damaged by the EGME treatment. In conclusion, EGME-induced testicular toxicity in cynomolgus monkeys was shown, and this model would be useful for investigating the mechanism of EGME-induced testicular toxicity and identifying testicular biomarkers. Additionally, testicular miR-34b-5p and miR-449a were suggested to be involved in damage of pachytene spermatocytes.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
authors.forename: Ken
authors.initials: K
authors.lastname: Sakurai
authors.forename: Kei
authors.initials: K
authors.lastname: Mikamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Shirai
authors.forename: Takuma
authors.initials: T
authors.lastname: Iguchi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ito
authors.forename: Wataru
authors.initials: W
authors.lastname: Takasaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mori
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D046228:Microarray Analysis; D023421:Models, Animal; D060888:Real-Time Polymerase Chain Reaction; D013094:Spermatozoa / Q000166:cytology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D005026:Ethylene Glycols; D035683:MicroRNAs; C005219:methyl cellosolve