Abstract
p, p′-Dichlorodiphenyldichloroethylene (DDE), the major metabolite of Dichlorodiphenyltrichloroethane (DDT), is an organochlorine pollutant and associated with cancer progression. The present study investigated the possible effects of p,p′-DDE on colorectal cancer and the involved molecular mechanism. The results indicated that exposure to low concentrations of p,p′-DDE from 10−10 to 10−7 M for 96 h markedly enhanced proliferations of human colorectal adenocarcinoma cell lines. Moreover, p,p′-DDE exposure could activate Wnt/β-catenin and Hedgehog/Gli1 signaling cascades, and the expression level of c-Myc and cyclin D1 was significantly increased. Consistently, p,p′-DDE-induced cell proliferation along with upregulated c-Myc and cyclin D1 were impeded by β-catenin siRNA or Gli1 siRNA. In addition, p,p′-DDE was able to activate NADPH oxidase, generate reactive oxygen species (ROS) and reduce GSH content, superoxide dismutase (SOD) and calatase (CAT) activities. Treatment with antioxidants prevented p,p′-DDE-induced cell proliferation and signaling pathways of Wnt/β-catenin and Hedgehog/Gli1. These results indicated that p,p′-DDE promoted colorectal cancer cell proliferation through Wnt/β-catenin and Hedgehog/Gli1 signalings mediated by oxidative stress. The finding suggests an association between p,p′-DDE exposure and the risk of colorectal cancer progression.
Highlights
Dichlorodiphenyltrichloroethane (DDT) was the most used organochlorine pesticide in the world
The results demonstrated that p,p’-DDE exposure promoted colorectal adenocarcinoma cell proliferation through activated Wnt/b-catenin and Hedgehog/Gli1 signalings, which were mediated by oxidative stress
Treatment with 1029 M p,p’-DDE resulted in the biggest increase in cell viability and viable cell counts. These results indicated that low concentrations of p,p’-DDE (10212 to 1027 M) markedly promote colorectal adenocarcinoma cell proliferation
Summary
Dichlorodiphenyltrichloroethane (DDT) was the most used organochlorine pesticide in the world. DDT became banned in the 1970s in most western countries because of its adverse effects on wildlife. DDT is still being used to prevent malaria and typhoid in some developing countries [1,2]. DDT has generally been restricted for use over decades, the metabolites exposure still exists mainly through metabolic conversion in the body. P, p’Dichlorodiphenyldichloroethylene (p, p’-DDE) is DDT’s major metabolite with high persistence and lipophilicity. P’-DDE levels are usually found in human blood and tissues [3,4,5,6]. Accumulated evidences indicate that p, p’-DDE exposure is related to repercussions in human health, such as neurotoxicity, immunotoxicity and cancinogenesis. Investigations involved in adverse effects of p, p’-DDE on human health, especially its link with cancer, are receiving more and more attentions
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