Experimental cryptorchidism has been shown to induce germ cell apoptosis. Nitric oxide (NO), a ubiquitous free radical produced by nitric oxide 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-limiting enzyme GTP cyclohydrolase I (GTPCH I) activity, resulting in an increase in intracellular BH4 levels and BH4-dependent 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 4-weeks-old or received standard diet only, and right cryptorchid testes were created surgically at 10 weeks of age. The testes were evaluated 0, 3, 5, 7, and 10 days after surgery by assays of testicular weight, BH4 and dihydrobiopterin (BH2: oxidized BH4) levels, GTPCH I mRNA, NOSs protein expression, NO concentration, and nitrotyrosine (product of ONOO-; determinant of NO-dependent damage ) levels. In untreated mice, GTPCH I mRNA, and BH4 levels increased and eNOS protein expression, NO concentration, and nitrotyrosine levels elevated gradually. BH4 treatment decreased GTPCH I mRNA and BH4 levels, with concomitant reduction of eNOS protein, 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-based testicular dysfunction

Written by
Kondo Y, Ishikawa T, Yamaguchi K, Yada T, Fujisawa M.

Reference
J Androl. 2007 Oct 31; [Epub ahead of print]

PubMed Abstract
PMID:17978343

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