Effects of acetaminophen and hydroxyurea on spermatogenesis and sperm chromatin structure in laboratory mice.
High doses of acetaminophen (400 mg/kg) or hydroxyurea (200 mg/kg) given intraperitoneally daily for 5 d caused reduction in relative testicular weight in mice (B6C3/F1/BOM M). Testicular atrophy of several tubules was seen in the hydroxyurea-treated mice 5 d after the last exposure, whereas acetaminophen did not lead to such changes. Exposure to acetaminophen caused neither a depletion of glutathione in the testis nor a marked increase in covalent binding. In contrast, significant decreases in the incorporation of thymidine into the testis were observed during the first 3 h following a single treatment with acetaminophen (100 to 400 mg/kg) or hydroxyurea (100 to 200 mg/kg). In mice treated with acetaminophen (400 mg/kg) or hydroxyurea (200 mg/kg) daily for 5 d, flow cytometric analysis revealed large reductions in one of the tetraploid populations of testicular cells (mostly early pachytene spermatocytes) on days 5 and 10. Changes in the populations of the various spermatid stages occurred later; thus, both compounds appeared to cause a delay in spermiogenesis. Indications of abnormal chromatin structure were seen in an increased frequency of vas deferens sperm on days 27 and 33 after the last exposure, when measured as increased susceptibility towards DNA denaturation in situ. In conclusion, high doses of acetaminophen or hydroxyurea inhibit DNA synthesis in the testis. The present data indicate that this leads to reduced testicular weight, a reduction in the number of early pachytene spermatocytes, changes in the proportions of the various spermatid stages, and an apparent alteration in sperm chromatin structure.
Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
R
R
Wiger
J K
JK
Hongslo
D P
DP
Evenson
P
P
De Angelis
P E
PE
Schwarze
J A
JA
Holme
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000165:Acridine Orange; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure*; D004247:DNA / Q000096:biosynthesis; D005434:Flow Cytometry; D006918:Hydroxyurea / Q000633:toxicity*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects / Q000648:ultrastructure*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013936:Thymidine / Q000378:metabolism; D014649:Vas Deferens / Q000378:metabolism / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002843:Chromatin; D013438:Sulfhydryl Compounds; D000082:Acetaminophen; D004247:DNA; D000165:Acridine Orange; D013936:Thymidine; D006918:Hydroxyurea