Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice.

IF 3.2 2区 医学 Q1 ANDROLOGY
Andrology Pub Date : 2024-11-20 DOI:10.1111/andr.13808
Yuki Oyama, Kentaro Shimada, Haruhiko Miyata, Rie Iida-Norita, Chihiro Emori, Maki Kamoshita, Seiya Oura, Ryohei Katayama, Martin M Matzuk, Masahito Ikawa
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Abstract

Background: Inhibition of sperm maturation in the epididymis is a promising post-testicular strategy for short-acting male contraceptives. It has been shown that ROS1, a receptor tyrosine kinase expressed in the epididymis, is essential for epididymal differentiation, sperm maturation, and male fertility in mice. However, it is unknown if inhibition of ROS1 suppresses male fertility reversibly.

Objectives: Our study aimed to investigate the effects of ROS1 inhibitor administration in male mice on sperm function and fertility.

Materials and methods: We used lorlatinib, an anti-cancer drug that inhibits ROS1. We treated 10-week-old sexually mature male mice with lorlatinib for 3 weeks and performed fertility tests, histological staining, in vitro fertilization, sperm motility analyses, and immunoblot analyses. We also performed the same analyses 3 weeks after discontinuing the lorlatinib treatment.

Results: Inhibition of ROS1 for 3 weeks suppressed male fertility. Lorlatinib-treated mice showed no overt abnormalities in testicular sections, but epithelium maintenance of the epididymal initial segment was impaired. Accordingly, the levels of OVCH2, RNASE10, and ADAM28, which are expressed in the epididymis, decreased. Spermatozoa from the lorlatinib-treated mice lost their ability to bind to the zona pellucida, and ADAM3 processing was abnormal. Sperm motility was also impaired in the lorlatinib-treated mice. These impairments were recovered 3 weeks after discontinuing the drug treatment.

Discussion and conclusion: Inhibition of ROS1 with lorlatinib suppressed sperm maturation and male fertility reversibly. Future exploration of molecules that specifically target ROS1 and the ROS1 pathway in the epididymis may lead to the development of safe and reversible male contraceptives.

用罗拉替尼抑制 ROS1 的活性会可逆地抑制雄性小鼠的生育能力。
背景:抑制附睾中的精子成熟是短效男性避孕药的一种很有前途的睾丸后策略。研究表明,ROS1 是一种在附睾中表达的受体酪氨酸激酶,对小鼠附睾分化、精子成熟和雄性生育能力至关重要。然而,抑制 ROS1 是否会可逆地抑制雄性生育能力尚不清楚:我们的研究旨在探讨雄性小鼠服用 ROS1 抑制剂对精子功能和生育能力的影响:材料和方法:我们使用了抑制ROS1的抗癌药物lorlatinib。我们用洛拉尼布治疗10周大的性成熟雄性小鼠3周,并进行了生育力测试、组织学染色、体外受精、精子活力分析和免疫印迹分析。我们还在停止洛拉替尼治疗3周后进行了同样的分析:结果:抑制ROS1 3周会抑制雄性生育能力。洛拉替尼处理的小鼠睾丸切片未显示明显异常,但附睾初段上皮的维持能力受损。附睾中表达的OVCH2、RNASE10和ADAM28的水平也相应下降。经洛拉尼布处理的小鼠精子失去了与透明带结合的能力,ADAM3处理也出现异常。经洛拉尼布治疗的小鼠精子运动能力也受到影响。这些损伤在停药3周后恢复:讨论与结论:用lorlatinib抑制ROS1可逆地抑制精子成熟和男性生育能力。未来对专门靶向附睾中ROS1和ROS1通路的分子进行探索,可能会开发出安全、可逆的男性避孕药。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Andrology
Andrology ANDROLOGY-
CiteScore
9.10
自引率
6.70%
发文量
200
期刊介绍: Andrology is the study of the male reproductive system and other male gender related health issues. Andrology deals with basic and clinical aspects of the male reproductive system (gonads, endocrine and accessory organs) in all species, including the diagnosis and treatment of medical problems associated with sexual development, infertility, sexual dysfunction, sex hormone action and other urological problems. In medicine, Andrology as a specialty is a recent development, as it had previously been considered a subspecialty of urology or endocrinology
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