Effects of male reproductive toxicants on gene expression in rat testes.
Predictive biomarkers of testicular toxicity are needed for an efficient development of drugs. The purpose of the present study was to obtain further insight into the toxicity mechanisms of various male reproductive toxicants and to detect genomic biomarkers for rapid screening of testicular toxicity. Four reproductive toxicants, 2,5-hexanedione (Sertoli cells toxicant), ethylene glycol monomethyl ether (EGME; spermatocytes toxicant), cyclophosphamide (spermatogonia toxicant) and sulfasalazine, were orally administered to male rats once. Six hours after the single dosing, gene expression in the testes was monitored by cDNA microarray and real-time RT-PCR and the testes were histopathologically examined. No histopathological abnormality was detected except for slight degeneration of spermatocytes in the EGME-treated testes. cDNA microarray analysis revealed differential gene expression profiles, and it was possible based on the profiles to characterize the action of the compounds in the testes. Interestingly, 3 spermatogenesis-related genes -- heat shock protein 70-2, insulin growth factor binding protein 3 and glutathione S transferase pi -- were affected by all the compounds. The above changes of gene expression were detectable within a short period after the dosing prior to the appearance of obvious pathological changes. These data suggest that cDNA microarray is a useful technique for evaluation of primary testicular toxicity. Furthermore, we propose the above 3 spermatogenesis-related genes as potential biomarkers of testicular toxicity.
Fukushima
Tamio
T
Worldwide Safety Sciences, Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., Aichi.
Yamamoto
Toshinori
T
Kikkawa
Rie
R
Hamada
Yoshimasa
Y
Komiyama
Masatoshi
M
Mori
Chisato
C
Horii
Ikuo
I
D000284:Administration, Oral; D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D004822:Epididymis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects*; D051549:Glutathione S-Transferase pi / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006588:Hexanones / Q000008:administration & dosage / Q000633:toxicity; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013090:Spermatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012460:Sulfasalazine / Q000008:administration & dosage / Q000633:toxicity; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D005026:Ethylene Glycols; D018840:HSP70 Heat-Shock Proteins; D006588:Hexanones; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D012460:Sulfasalazine; D003520:Cyclophosphamide; C011269:2,5-hexanedione; D051549:Glutathione S-Transferase pi; C005219:methyl cellosolve