title: Induction of DNA damage and erroneous repair can explain genomic instability caused by endosulfan.
abstract: Endosulfan (ES) is an organochlorine pesticide, speculated to be associated with chromosomal abnormalities and diseases in humans. However, very little is known about the mechanism of its genotoxicity. Using in vivo, ex vivo and in vitro model systems, we show that exposure to ES induces reactive oxygen species (ROS) in a concentration and time-dependent manner. The generation of ROS results in DNA double-strand breaks either directly or in a replication-dependent manner, both in mice and human cells. Importantly, ES-induced DNA damage evokes DNA damage response, resulting in elevated levels of classical non-homologous DNA endjoining (NHEJ), the predominant double-strand break repair pathway in higher eukaryotes. Sequence analyses of NHEJ junctions revealed that ES treatment results in extensive processing of broken DNA, culminating in increased and long junctional deletions, thereby favoring erroneous repair. We also find that exposure to ES leads to significant increase in microhomology-mediated end joining (MMEJ), a LIGASE III-dependent alternative repair pathway. Therefore, we demonstrate that ES induces DNA damage and genomic instability, alters DNA damage response thereby promoting erroneous DNA repair.
authors: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors: Robin
authors: R
authors: Sebastian
authors: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India sathees@biochem.iisc.ernet.in.
authors: Sathees C
authors: SC
authors: Raghavan
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D059766:DNA End-Joining Repair / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects*; D004726:Endosulfan / Q000633:toxicity*; D042822:Genomic Instability / Q000187:drug effects*; D006801:Humans; D051379:Mice; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D004726:Endosulfan