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.

Quercetin ameliorates polychlorinated biphenyls-induced testicular DNA damage in rats

“…Excessive intracellular ROS production is well known to attack bases in nucleic acids, amino acid side chains in proteins and double bonds in unsaturated fatty acids which eventually leads to DNA, RNA, proteins and lipids damage (Wu et al ., ; Fedato & Maistro, ; Patlolla et al ., ). Moreover, oxidative damage to DNA has been suggested to be one of the most important factors responsible for PCBs‐induced gonadal cell genotoxicity and carcinogenic modes of action (Attia et al ., ). However, co‐treatment of quercetin with PCBs significantly ameliorated the fragmentation of DNA in the treated rats.…”

“…Furthermore, PCBs are well reported to exert their toxic effects by increasing free radicals generation, thus inducing oxidative stress (Murgesan et al ., ; Aly et al ., ; Atessahin et al ., ; Aly, ). Recent studies on PCBs toxicity demonstrated that PCB‐induced genotoxicity in male gonads through DNA oxidative damage and inhibition of DNA repair gene expression (Attia et al ., ). Increased ROS production in the cellular environment can damage DNA and oxidise cellular proteins (Patlolla et al ., ).…”

Tobacco Use Increases Oxidative DNA Damage in Sperm - Possible Etiology of Childhood Cancer

“…As sperm has a highly limited cytosolic antioxidants and limited base exicision repair mechanisms by virtue of it being transcriptionally and translationally inert, the DNA damage borne in sperm DNA persists (Attia et al, 2014). DOI:http://dx.doi.org/10.7314/APJCP.2015.16.16.6967 Tobacco Use Increases Oxidative DNA Damage in Sperm -Possible Etiology of Childhood Cancer A study from our lab documented that significantly lower levels of PARP1 and OGG1 in mature sperm of infertile men Thilagavathi et al, 2013).…”

The mutagenic effect of tobacco smoke on male fertility

“…Although ROS is required for physiological processes (Haque et al 2014), the abnormal accumulation thereof can lead to DNA strand breaks, peroxidation of unsaturated lipids, disruption of mitochondrial function, and oxidative damage to DNA (Fullston et al 2017;Roychoudhury et al 2017). Spermatozoa are vulnerable to ROS due to the presence of limited cytoplasmic antioxidants and limited repair mechanisms (Attia et al 2014). Due to the translational and transcriptional inert nature of DNA, the DNA damage borne in sperm DNA persists (Attia et al 2014).…”