Abstract
The classification of the fungicide captan (CAS Number: 133-06-2) as a carcinogen agent is presently under discussion. Despite the mutagenic effect detected by the Ames test and carcinogenic properties observed in mice, the genotoxicity of this pesticide in humans is still unclear. New information is needed about its mechanism of action in mammalian cells. Here, we show that Chinese Hamster Ovary (CHO) cells exposed to captan accumulate Fpg-sensitive DNA base alterations. In CHO and HeLa cells, such DNA lesions require the XRCC1-dependent pathway to be repaired. Captan also induces a replicative stress that activated the ATR signaling response and resulted in double-strand breaks and micronuclei. The replicative stress is characterized by a dramatic decrease in DNA synthesis due to a reduced replication fork progression. However, impairment of the XRCC1-related repair process did not amplify the replicative stress, suggesting that the fork progression defect is independent from the presence of base modifications. These results support the involvement of at least two independent pathways in the genotoxic effect of captan that might play a key role in carcinogenesis. Environ. Mol. Mutagen. 60:286-297, 2019. © 2018 Wiley Periodicals, Inc.
Highlights
Captan is an agricultural fungicide that belongs to the phthalimide family
3.1 XRCC1 deficiency induces hypersensitivity to captan Since captan was reported to induce base substitution reversion in Ames test strains (TA102 and TA104) and WP2uvrA6 Escherichia coli strains used to detect base substitution mutagenesis, we first tested the effect of XRCC1 defect, a scaffold protein involved in base excision repair (BER) (Kubota et al 1996)
These results suggest that captan sensitivity is associated with the induction of DNA damage that is repaired by XRCC1
Summary
Captan is an agricultural fungicide that belongs to the phthalimide family. It was first registered in 1951 for tree fruit use and has been used commercially for over 60 years. In the United States, the Environmental Protection Agency (EPA) reclassified it in 2004 it from “probable human carcinogen” to “not likely carcinogenic to human” (Gordon 2007). It is classified in category 2 H351 (“suspected of causing cancer”) according to the European regulations (European Commission, EC Reg N°1272/2008). It is used mainly on fruits such as apples and is detected as pesticide residues in food in European countries (Crepet et al 2013; Lozowicka 2015)
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