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

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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.

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