Sakurai Ken, Mikamoto Kei, Shirai Makoto, Iguchi Takuma, Ito Kazumi, Takasaki Wataru, Mori Kazuhiko
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
J Toxicol Sci. 2015 Jun;40(3):375-82. doi: 10.2131/jts.40.375.
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.
为了建立并表征乙二醇单甲醚（EGME）诱导的食蟹猴睾丸毒性模型，将0或300mg/kg的EGME口服给予性成熟的雄性食蟹猴（每组n = 3），连续给药4天。使用miRNA微阵列或实时定量逆转录PCR方法研究该模型中的循环和睾丸微小RNA（miRNA）谱。300mg/kg的EGME在所有猴子中均诱导了睾丸毒性，其组织病理学特征为粗线期精母细胞和圆形精子细胞减少，一般状况或临床病理学无任何严重变化。在微阵列分析中，在睾丸中检测到16个下调的miRNA和347个上调的miRNA，在血浆中检测到326个下调的miRNA但未检测到上调的miRNA。有趣的是，miR-1228和miR-2861被鉴定为对照动物血浆和睾丸中丰富的miRNA，分别可能与细胞凋亡和细胞分化相关，并且在EGME处理的动物睾丸中显著增加，反映了通过刺激精子的细胞增殖和分化从EGME诱导的睾丸损伤中恢复。此外，在睾丸中，富含减数分裂细胞如粗线期精母细胞的miR-34b-5p和miR-449a明显下调，表明这些生精细胞受到EGME处理的损伤。总之，显示了EGME诱导的食蟹猴睾丸毒性，该模型将有助于研究EGME诱导的睾丸毒性机制并鉴定睾丸生物标志物。此外，提示睾丸miR-34b-5p和miR-449a参与粗线期精母细胞的损伤。
