Effects of captan on dna and dna metabolic processes in human diploid fibroblasts

Abstract

The fungicide Captan has been examined for its effects on DNA and DNA processing in order to better understand the genotoxicity associated with this agent. Captan treatment resulted in production of DNA single strand breaks and DNA-protein cross-links and elicited an excision repair response in human diploid fibroblasts. Captan was also shown to inhibit cellular DNA synthesis and to form stable adducts in herring sperm and human cellular DNA. Misincorporation of nucleotides into Captan-treated synthetic DNA templates was significantly elevated in an in vitro assay using E. coli DNA polymerase I, suggesting that DNA adduct formation by Captan could have mutagenic consequences. In sum, these studies demonstrate that Captan is capable of interacting with DNA at a number of levels and that these interactions could provide the basis for Captan's genotoxicity. The extreme cytotoxicity of this fungicide, however, could be due to other cellular effects since at the IC50 for cell killing, approximately 0.8 microM, none of the above genotoxic events could be detected by the methods employed.

Exposure to the Fungicide Captan Induces DNA Base Alterations and Replicative Stress in Mammalian Cells

“…DNA strand breaks and micronuclei are induced as a consequence of RS, which in turn leads to genomic instability. Our study demonstrates that captan exposure in mammalian cells induces various genotoxic effects, corroborating previous in vivo reports (Legator ; Feng and Lin ; Snyder ) and suggesting that these mechanisms could play a role in carcinogenesis. Moreover, our in vitro results on human peripheral lymphocytes, showing DNA damage with alkaline comet assay after captan treatment (Supporting Information Fig.…”

“…However, the mutagenic potency of captan has long been reported in Ames strains TA1535 and TA104 and also in the Escherichia coli WP2 uvrA strain (Bridges ; Barrueco and de la Pena ; Ohta et al ), revealing base‐change substitution on AT or GC base pairs, as well as in mammalian cellular mutation assays (O'Neill et al ; Edgar et al ). In addition to its mutagenic activity, the genotoxic potential of captan is supported by the induction of DNA breaks leading to chromosomal aberrations in mammalian cells (Swenberg et al ; Tezuka et al ; Snyder ). Finally, a direct interaction of captan with DNA and/or proteins linked to chromatin such as histones, polymerases or topoisomerase II, has been suggested (Anderson and Rosenkranz ; Couch and Siegel ; Couch et al ; Selsky and Matheson ; Dillwith and Lewis ; Pritchard and Lappin ; Snyder ; Grilli et al ; Provan et al ; Provan and Eyton‐Jones ; Rahden‐Staron ).…”

“…In addition to its mutagenic activity, the genotoxic potential of captan is supported by the induction of DNA breaks leading to chromosomal aberrations in mammalian cells (Swenberg et al ; Tezuka et al ; Snyder ). Finally, a direct interaction of captan with DNA and/or proteins linked to chromatin such as histones, polymerases or topoisomerase II, has been suggested (Anderson and Rosenkranz ; Couch and Siegel ; Couch et al ; Selsky and Matheson ; Dillwith and Lewis ; Pritchard and Lappin ; Snyder ; Grilli et al ; Provan et al ; Provan and Eyton‐Jones ; Rahden‐Staron ).…”

Urine mutagenicity and lymphocyte DNA damage in fruit growers occupationally exposed to the fungicide captan

“…21 22 Captan is able to interact with DNA, especially to form DNA adducts and DNA-protein crosslinks 23 and more specifically inducing mutation through base-pair substitution mechanisms including those detected by TA102 or TA104 Salmonella typhimurium strains. 24 25 Recent studies have confirmed the ability of captan to be highly mutagenic on strains detecting base-pair mutations, 26 27 and not on strains sensitive to frameshift mutations such as *Including farmers without any protective devices (4 for mixing and 7 for application), with protective clothes alone (1 for mixing and 1 for application), with mask alone (3 for mixing and 1 for application).…”

Comparative evaluation of genotoxicity of captan in amphibian larvae (Xenopus laevis andPleurodeles waltl) using the comet assay and the micronucleus test

“…Although the mechanism underlying the genotoxic effects is not well known, several reports have suggested that captan may interact with DNA (Anderson and Rosenkranz, 1974;SCC, 1981) and induce DNA repair (Swenberg et al, 1976;Ahmed et al, 1977;Simmon et al, 1977). Snyder (1992) indicated that captan induces a type of DNA damage recognized by the excision repair system in human fibroblasts and that captan-induced DNA damage may be at least partially repaired via a long-patch repair system. The DNA-damaging and repair-inducing character of captan has been verified using the nick translation assay (Nose and Okamoto, 1983;Snyder and Matheson, 1985).…”