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Subsequent suppression of gonadotropins and testosterone (T) restores differentiation to the spermatocyte stage; however, this process requires 6\u00a0weeks. We evaluated the role of Leydig cells (<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>s) in maintenance of the block in spermatogonial differentiation after exposure to radiation by specifically eliminating functional<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>s with ethane dimethane sulfonate (<jats:styled-content style=\"fixed-case\">EDS<\/jats:styled-content>).<jats:styled-content style=\"fixed-case\">EDS<\/jats:styled-content>(but not another alkylating agent), given at 10\u00a0weeks after irradiation, induced spermatogonial differentiation in 24% of seminiferous tubules 2\u00a0weeks later. However, differentiation became blocked again at 4\u00a0weeks as<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>s recovered. When<jats:styled-content style=\"fixed-case\">EDS<\/jats:styled-content>was followed by treatment with Gn<jats:styled-content style=\"fixed-case\">RH<\/jats:styled-content>antagonist and flutamide, sustained spermatogonial differentiation was induced in &gt;70% of tubules within 2\u00a0weeks. When<jats:styled-content style=\"fixed-case\">EDS<\/jats:styled-content>was followed by Gn<jats:styled-content style=\"fixed-case\">RH<\/jats:styled-content>antagonist plus exogenous T, which also inhibits<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>recovery but restores follicle stimulating hormone (<jats:styled-content style=\"fixed-case\">FSH<\/jats:styled-content>) levels, the spermatogonial differentiation was again rapid but transient. These results confirm that the factors that block spermatogonial differentiation are indirectly regulated by T, and probably<jats:styled-content style=\"fixed-case\">FSH<\/jats:styled-content>, and that adult and possibly immature<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>s contribute to the production of such inhibitory factors. We tested whether insulin\u2010like 3 (<jats:styled-content style=\"fixed-case\">INSL<\/jats:styled-content>3), a<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content>\u2010produced protein whose expression correlated with the block in spermatogonial differentiation, was indeed responsible for the block by injecting synthetic<jats:styled-content style=\"fixed-case\">INSL<\/jats:styled-content>3 into the testes and knocking down its expression in\u00a0vivo with si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>. Neither treatment had any effect on spermatogonial differentiation. The Leydig cell products that contribute to the inhibition of spermatogonial differentiation in irradiated rats remain to be elucidated.<\/jats:p>","DOI":"10.1111\/andr.12168","type":"journal-article","created":{"date-parts":[[2016,3,19]],"date-time":"2016-03-19T07:41:45Z","timestamp":1458373305000},"page":"412-424","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat"],"prefix":"10.1111","volume":"4","author":[{"given":"G.","family":"Shetty","sequence":"first","affiliation":[{"name":"Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer Center Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W.","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer Center Houston TX USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. 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