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

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.

Multiple Myeloma in an Agricultural Worker Exposed to Pesticides

“…Two of the most common cancers associated with pesticide use include non-Hodgkin lymphoma and leukemia [6,8]. While the etiology and pathogenesis of MM are still under investigation, recent studies have shown an elevated risk of MM with pesticide use [2,6,9-10]. For example, one case-control study collected extensive information, including occupational history from 573 persons with newly diagnosed multiple myeloma, and developed a job-exposure matrix for pesticide exposure.…”

“…There has been a great deal of debate worldwide regarding its toxicity. In the United States, the EPA or environmental protection agency classifies captan as “not likely carcinogenic to humans,” whereas the European commission classifies it as “suspected of causing cancer” [10]. Due to this controversy and given its extensive use, several recent studies have investigated the potential toxicity of captan and demonstrated a consistent increased risk of MM with captan exposure [5,10-12].…”

“…In the United States, the EPA or environmental protection agency classifies captan as “not likely carcinogenic to humans,” whereas the European commission classifies it as “suspected of causing cancer” [10]. Due to this controversy and given its extensive use, several recent studies have investigated the potential toxicity of captan and demonstrated a consistent increased risk of MM with captan exposure [5,10-12]. An analysis of three case-control studies comparing 547 patients with multiple myeloma and 2,700 controls found that less than 17.5 lifetime days of exposure to captan was associated with a more than three-fold increase in the risk of developing multiple myeloma [11].…”

Cytolethal Distending Toxin Promotes Replicative Stress Leading to Genetic Instability Transmitted to Daughter Cells

“…HeLa or U2OS cells were treated with CDT for 16 or 24 h, respectively, before sequential pulse labeling with 50 µM CldU (5-chlorodeoxyuridine, Sigma-Aldrich), then 100 µM IdU (5 iododeoxyuridine, Sigma-Aldrich) for 20 min each, followed by a chase with 200 µM thymidine (Sigma-Aldrich) for 1 h. Cells were then collected and DNA fiber assays were performed as described previously (Fernandez-Vidal et al, 2019). IdU and CldU were detected with monoclonal mouse (1/50, BD347583, Becton Dickinson) and rat anti-BrdU antibodies (1/75, OBT0030G, Bio-Rad), respectively, and subsequently single-strand DNA with mouse antibody (1/50, MAB3034, Millipore).…”

Cytological Effects of Herbicidal and Fungicidal Pesticides on Root Apex Meristem Cells of Triticum Aestivum

“…Pesticides have selective and targeted activity against mycopathogens and crop weeds. However, the selectivity of pesticide activity is not absolute: the evolutionary conservatism of many molecular-cellular events determines the activity of pesticides with respect to non-target organisms [16,17,18,19,20,21,22]. In this regard, cytogenetic studies of pesticides with respect to cereal crops, which are the main source in the nutritional structure of the world's population, are very important.…”