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

Oyama, Yuki; Shimada, Kentaro; Miyata, Haruhiko; Iida-Norita, Rie; Emori, Chihiro; Kamoshita, Maki; Oura, Seiya; Katayama, Ryohei; Matzuk, Martin M.; Ikawa, Masahito

doi:https://doi.org/10.1111/andr.13808

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

Oyama, Yuki; Shimada, Kentaro; Miyata, Haruhiko et al.

Andrology, 2024

Number of Access:1,026（2025-08-14 12:35 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100184

Link to primary information

File	Format	Terms of use	Size	Views	Date.Available	Description	information
Andrology_andr.13808	pdf	None	5.77 MB	27	2025.02.03

Creative Commons : Attribution

Item Information

Output File Export EndNote Basic Export Mendeley

Title	Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice
Creator	ORCID 0000-0003-4579-5487 0000-0003-4579-5487 CreatorName Oyama, Yuki
	CreatorName Shimada, Kentaro
	NRID 1000050604732 1000050604732 ORCID 0000-0003-4758-5803 0000-0003-4758-5803 researchmap permalink hmiyata hmiyata Scopus Author ID 37161837000 37161837000 CreatorName Miyata, Haruhiko
	NRID 1000010816771 1000010816771 ORCID 0000-0003-0104-1974 0000-0003-0104-1974 researchmap permalink 7000029591 7000029591 CreatorName Iida-Norita, Rie
	NRID 1000010868136 1000010868136 researchmap permalink cemori cemori Scopus Author ID 55937469900 55937469900 CreatorName Emori, Chihiro
	NRID 1000070930288 1000070930288 researchmap permalink m.kamoshita m.kamoshita CreatorName Kamoshita, Maki
	CreatorName Oura, Seiya
	NRID 1000060435542 1000060435542 CreatorName Katayama, Ryohei
	CreatorName Matzuk, Martin M.
	NRID 1000020304066 1000020304066 ORCID 0000-0001-9859-6217 0000-0001-9859-6217 researchmap permalink read0054910 read0054910 Scopus Author ID 16689054500 16689054500 CreatorName Ikawa, Masahito
Subject	fertilization
	male contraceptive
	small molecule inhibitors
	sperm maturation
Description	Oyama Y., Shimada K., Miyata H., et al. Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice. Andrology , (2024); https://doi.org/10.1111/andr.13808.
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.
Publisher	John Wiley and Sons Inc
Source Title	Andrology
Date of Issued	2024-11-20
Language	English
Handle URL	https://hdl.handle.net/11094/100184
PISSN	20472919
eISSN	20472927
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1111/andr.13808
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Andrology. 2024
DC.title	Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice
DC.creator	Oyama, Yuki
	Shimada, Kentaro
	Miyata, Haruhiko
	Iida-Norita, Rie
	Emori, Chihiro
	Kamoshita, Maki
	Oura, Seiya
	Katayama, Ryohei
	Matzuk, Martin M.
	Ikawa, Masahito
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-11-20
DC.identifier	https://doi.org/10.1111/andr.13808
DC.subject	fertilization
	male contraceptive
	small molecule inhibitors
	sperm maturation
DC.description	Oyama Y., Shimada K., Miyata H., et al. Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice. Andrology , (2024); https://doi.org/10.1111/andr.13808.
DCTERMS.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.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100184
citation_title	Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice
citation_author	Oyama, Yuki
	Shimada, Kentaro
	Miyata, Haruhiko
	Iida-Norita, Rie
	Emori, Chihiro
	Kamoshita, Maki
	Oura, Seiya
	Katayama, Ryohei
	Matzuk, Martin M.
	Ikawa, Masahito
citation_publisher	John Wiley and Sons Inc
citation_language	English
citation_date	2024-11-20
citation_journal_title	Andrology
citation_doi	https://doi.org/10.1111/andr.13808
citation_public_url	https://hdl.handle.net/11094/100184

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

Link to primary information

Item Information

Show details