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ToxSci Advance Access originally published online on December 29, 2004
Toxicological Sciences 2005 85(1):675-682; doi:10.1093/toxsci/kfi071
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Toxicological Sciences vol. 85 no. 1 © Society of Toxicology 2005; all rights reserved.

Effects of Sulfasalazine on Sperm Acrosome Reaction and Gene Expression in the Male Reproductive Organs of Rats

Tamio Fukushima*,{dagger},1, Masashi Kato*, Tetsuya Adachi{ddagger}, Yoshimasa Hamada*, Masao Horimoto*, Masatoshi Komiyama{dagger},§, Chisato Mori{dagger} and Ikuo Horii*

* Worldwide Safety Sciences, Nagoya Laboratories, Pfizer Japan Inc., 5-2, Taketoyo, Aichi 470-2393, Japan; {dagger} Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chiba 260-8670, Japan; {ddagger} Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan; and § Center for Environment, Health and Field Sciences, Chiba University, Kashiwa 227-0882, Japan

Received November 1, 2004; accepted December 20, 2004

Sulfasalazine (SASP) has been reported to depress the fertility in men and experimental male animals, but the fundamental mechanisms of infertility caused by SASP are still unknown. This study was designed to investigate the mechanisms of infertility in rats treated with SASP at a dose of 600 mg/kg for 28 days, including monitoring of sperm motility using computer associated sperm analysis system and acrosome reaction by FITC-concanavalin A lectin staining. The sperm motility and acrosome reaction, which are important for fertilization, were significantly reduced by SASP. Furthermore, to investigate the molecular mechanisms of infertility induced by SASP, mRNA expression analysis in the testes was performed using cDNA microarray as a first screening. It was revealed that CD59, which is located on the acrosomal membrane and is known to be important for the reproductive function of sperm, was affected in the testes; this was also confirmed by real-time PCR analysis, but the spermatogenesis-related genes examined in this study were not affected. Therefore, we focused on CD59 and two other acrosome membrane related-genes: MCP and DAF. CD59, MCP, and DAF in the epididymides of SASP-treated rats were significantly decreased as assessed by real-time RT-PCR analysis and additionally, the expression of CD59 protein was found to be decreased by Western blotting. These results allowed us to hypothesize that the suppression of epididymal acrosomal membrane proteins synthesis with their consequent reduced incorporation to the sperm membrane leads to a depressed sperm motility and acrosome reaction, and thereby leads to infertility in SASP treated male rats.

Key Words: sulfasalazine; acrosome reaction; CD59; mRNA expression.


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