The present study aimed to examine if multiple exposure to Aroclor 1254, a commercial mixture of polychlorinated biphenyls, had any genotoxic potential on gonads of male mice; moreover, the molecular mechanism(s) underlying this deleterious effects were elucidated. In the standard comet assay, there were significant increases in the incidence of DNA strand breaks in sperm of mice killed after 3 and 24h of last treatment with 4 mg/kg/day Aroclor 1254 for 5 weeks, while no significant difference in the DNA strand breaks was found in mice treatment with 1 and 2 mg/kg/day Aroclor 1254. The same results were also observed with spermatocyte chromosomal analysis as obvious aberrant primary spermatocytes were noted with the highest dose of Aroclor 1254 when testes were examined at 24h after the last exposure. Moreover, digestion with EndoIII resulted in significantly increased levels of DNA damage at 3 and 24h after the last exposure to 2mg/kg/day Aroclor 1254; digestion with Fpg resulted in a significant increase in DNA damage at the 3-h sampling time only as detected by oxidative comet assays. The expression of DNA repair genes p53, PARP1 and BAX were up-regulated in testes of mice killed after 3 and 24h of last administration of 4 mg/kg/day Aroclor 1254. On the other hand, no significant alteration in the expression of XRCC1 gene was observed at both sampling times. It is noteworthy that the expression of OGG1 and APEX1 was significantly decreased at 3h after the last exposure to 4 mg/kg/day Aroclor 1254. On the other hand, only the expression level of APEX1 was recovered at the 24-h sampling times. The unrecovered OGG1 may suggest that inhibition of DNA repair can be considered as a potential mode of action of Aroclor 1254 gonadal toxicity and carcinogenesis.

The ability of the antineoplastic agent epirubicin to induce aneuploidy and meiotic delay in the somatic and germinal cells of male mice was investigated by fluorescence in situ hybridization assay using labeled DNA probes and BrdU-incorporation assay. Mitomycin C and colchicine were used as positive controls for clastogen and aneugen, respectively, and these compounds produced the expected responses. The fluorescence in situ hybridization assay with a centromeric DNA probe for erythrocyte micronuclei showed that epirubicin is not only clastogenic but also aneugenic in somatic cells in vivo. By using the BrdU-incorporation assay, it could be shown that the meiotic delay caused by epirubicin in germ cells was approximately 48 h. Disomic and diploid sperm were shown in epididymal sperm hybridized with DNA probes specific for chromosomes 8, X and Y after epirubicin treatment. The observation that XX- and YY-sperm significantly prevailed over XY-sperm indicates missegregation during the second meiotic division. The results also suggest that earlier prophase stages contribute less to epirubicin-induced aneuploidy. Both the clastogenic and aneugenic potential of epirubicin can give rise to the development of secondary tumors and abnormal reproductive outcomes in cured cancer patients and medical personnel exposed to epirubicin.

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