Apoptotic response of spermatogenic cells to the germ cell mutagens etoposide, adriamycin, and diepoxybutane.
In testis, apoptosis is a way to eliminate damaged germ cells during their development. In this study, we evaluated the ability of three germ cell mutagens to induce apoptosis (or programmed cell death) at specific stages of rat seminiferous epithelial cycle. These chemicals include the cancer chemotherapy drugs etoposide and adriamycin and the butadiene metabolite diepoxybutane. According to our results, etoposide is a very potent inducer of apoptosis in male rat germ cells and the cell types most sensitive to it include all types of spermatogonia, zygotene, and early pachytene spermatocytes and meiotically dividing spermatocytes. Also, adriamycin causes an increase in apoptosis at specific stages of seminiferous epithelial cycle and the most sensitive cell types are type A3-4 spermatogonia, preleptotene, zygotene, and early pachytene spermatocytes. Diepoxybutane does not cause any significant increase in the frequency of apoptosis in rat testis. In addition, we studied whether p53 is taking part in the apoptotic response of spermatogenic cells by studying the levels of p53 protein in testis before and after chemical treatment. No accumulation of p53 in testis was seen after treatment with these three chemicals. The expression of two p53-regulated genes, p21WAF1 and mdm2, was also studied but no increase in the levels of mRNA of these genes was observed after treatment. The results indicate that apoptosis should be taken into consideration when the genotoxic effects of chemicals are evaluated in germ cells.
Sjöblom
T
T
Department of Medical Genetics, University of Turku, Finland. tiina.sjoblom@utu.fi
West
A
A
Lähdetie
J
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity; D004852:Epoxy Compounds / Q000494:pharmacology / Q000633:toxicity; D005047:Etoposide / Q000494:pharmacology / Q000633:toxicity; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D008297:Male; D009153:Mutagens / Q000494:pharmacology* / Q000633:toxicity; D009687:Nuclear Proteins; D016612:Paraffin Embedding; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000166:cytology* / Q000187:drug effects*; D013737:Testis / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004852:Epoxy Compounds; D009153:Mutagens; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C007366:diepoxybutane; D005047:Etoposide; D004317:Doxorubicin; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2