{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T01:33:29Z","timestamp":1767922409971,"version":"3.49.0"},"reference-count":40,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,1,2]],"date-time":"2013-01-02T00:00:00Z","timestamp":1357084800000},"content-version":"vor","delay-in-days":1765,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Andrology"],"published-print":{"date-parts":[[2008,3,4]]},"abstract":"<jats:p><jats:bold>ABSTRACT: <\/jats:bold> Experimental cryptorchidism has been shown to induce germ cell apoptosis. Nitric oxide (NO), a ubiquitous free radical produced by NO synthases (NOSs), has been associated with apoptosis in a number of cell types. However, the regulation of NOSs in experimental cryptorchid testes remains unknown. Tetrahydrobiopterin (BH4), an essential cofactor of NOS, plays an important role in the generation of NO. It has been reported that activation of the immune system stimulates an increase in endogenous BH4 rate\u2010limiting enzyme GTP cyclohydrolase I (GTPCH I) activity, resulting in an increase in intracellular BH4 levels and BH4\u2010dependent NO synthesis in various cells. We examined the effect of dietary treatment with BH4 on GTPCH I, BH4 synthesis, NO production, and testicular damage in cryptorchid model mice. Male mice were treated with oral BH4 starting from age 4 weeks or received standard diet only, and right cryptorchid testes were created surgically at age 10 weeks. The testes were evaluated 0, 3, 5, 7, and 10 days after surgery by assays of testicular weight, BH4 and dihydrobiopterin (oxidized BH4) levels, <jats:italic>GTPCH I<\/jats:italic> mRNA levels, NOS protein expression levels, NO concentration, and nitrotyrosine (product of ONOO<jats:sup>\u2212<\/jats:sup>; determinant of NO\u2010dependent damage) levels. In untreated mice, <jats:italic>GTPCH I<\/jats:italic> mRNA and BH4 levels increased and eNOS protein expression, NO concentration, and nitrotyrosine levels increased gradually. BH4 treatment decreased <jats:italic>GTPCH I<\/jats:italic> mRNA and BH4 levels, with concomitant reduction of eNOS protein levels, nitrotyrosine levels, and NO concentration, resulting in reduced testicular damage. Our findings demonstrate that supplementation with BH4 could provide a new therapeutic intervention for heat stress\u2014based testicular dysfunction.<\/jats:p>","DOI":"10.2164\/jandrol.107.002758","type":"journal-article","created":{"date-parts":[[2008,2,28]],"date-time":"2008-02-28T02:47:25Z","timestamp":1204166845000},"page":"153-163","source":"Crossref","is-referenced-by-count":5,"title":["Oral Administration of Tetrahydrobiopterin Attenuates Testicular Damage by Reducing Nitric Oxide Synthase Activity in a Cryptorchid Mouse Model"],"prefix":"10.1002","volume":"29","author":[{"given":"Yutaka","family":"Kondo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomomoto","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Yamaguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toyotaka","family":"Yada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,1,2]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod46.6.1114"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000110785.96039.f6"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(94)91154-1"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2004.10.003"},{"key":"e_1_2_5_6_1","doi-asserted-by":"crossref","first-page":"5337","DOI":"10.1210\/endo.137.12.8940355","article-title":"Nitric oxide inhibits Leydig cell steroidogenesis","volume":"137","author":"Punta K.","year":"1996","journal-title":"Endocrinology"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.3.347"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1464-410x.2001.00986.x"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(98)00298-1"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8502995"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.2.e36"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(98)00601-6"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1939-4640.2005.tb01096.x"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000190000.98707.6d"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302227200"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2002-0142"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4165(85)90124-2"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.82.12.4154"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00967976"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.33.19743"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.6.12.1381691"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod53.5.1146"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.139.3.922"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117221"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.humrep.a136174"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1996.0418"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041560103"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.2388"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(01)01382-1"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2004.11.003"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(03)00172-2"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod65.2.514"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.18.2172"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000029122.79665.D9"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64380-5"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(95)90271-6"},{"key":"e_1_2_5_37_1","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1016\/S0021-9258(19)39752-2","article-title":"Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP\u20101, and T 24 cells. 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