title: Aroclor 1254-induced genotoxicity in male gonads through oxidatively damaged DNA and inhibition of DNA repair gene expression.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia, Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt, attiasm@yahoo.com.
authors.forename: Sabry Mohamed
authors.initials: SM
authors.lastname: Attia
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Sheikh Fayaz
authors.initials: SF
authors.lastname: Ahmad
authors.affiliation: Laboratory of Chemical and Clinical Pathology, Ministry of Health, Nasr City, Cairo, Egypt.
authors.forename: Radwa Mohamed
authors.initials: RM
authors.lastname: Okash
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Saleh Abdulrahman
authors.initials: SA
authors.lastname: Bakheet
mesh_terms: D000818:Animals; D020111:Chlorodiphenyl (54% Chlorine) / Q000633:toxicity*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects*; D006066:Gonads / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619352:Xrcc1 protein, mouse; D020111:Chlorodiphenyl (54% Chlorine); D011078:Polychlorinated Biphenyls; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase