Evaluation of Diuron (3-[3,4-dichlorophenyl]-1,1-dimethyl urea) in a Two-stage Mouse Skin Carcinogenesis Assay

Abstract

-1,1-dimethyl urea) is an herbicide with carcinogenic activity in rats and mice, which have developed respectively urothelial and mammary gland tumors in long-term studies. Accordingly, diuron has been categorized as a ''likely human carcinogen'' by the U.S. Environmental Protection Agency. Although the carcinogenesis-initiating activity of diuron has been reported in an early initiation-promotion mouse skin study, its genotoxic potential has been disputed. It is necessary to clarify the mode of action through which it has caused rodent neoplasia and verify its relevance to humans. Herein, two experiments were developed to verify the initiating and promoting potentials of diuron in a twenty-threeand a twenty-one-week-long mouse skin carcinogenesis protocol. In one, dimethylsulfoxide (DMSO) was the solvent for the herbicide; in the other, acetone was the alternative solvent in order to verify whether DMSO had inhibitory influence on a potential cutaneous carcinogenic activity. The adopted schedule for the tumor-promoting agent 12-O-tetradecanoylphorbol 13-acetate (TPA) resulted in skin ulcers, which demonstrates the need for careful selection of TPA dose levels and frequency of application in this model. In both studies, diuron did not exert any influence on the skin carcinogenesis process, in contrast with results already reported in the literature.

Evaluation of Carcinogenic Potential of Diuron in a Rat Mammary Two-Stage Carcinogenesis Model

“…Although some reports in the literature suggest that Diuron is genotoxic (Agrawal et al 1996; Agrawal and Mehrota 1997; Bouilly et al 2007), studies performed in our laboratory indicated that the herbicide does not damage DNA in vivo and does not induce crosslinks in vitro (Nascimento et al 2006; da Rocha et al 2010) when tested by the comet (single-cell gel eletrophoresis) assay. Besides, Diuron did not exert initiating or promoting potentials in the liver of male Wistar rats or the skin of male Swiss mice (Ferrucio 2010; Grassi et al 2007). These observations are in line with others reported in the literature stating that Diuron is a nongenotoxic agent (Iyer 2002; Liu 2002; US EPA 2003).…”

“…It is not surprising that Diuron treatment alone did not initiate the carcinogenesis process in this organ. Although some reports in the literature suggest that Diuron is or promoting potentials in the liver of male Wistar rats or the skin of male Swiss mice (Ferrucio 2010;Grassi et al 2007). These observations are in line with others reported in the literature stating that Diuron is a nongenotoxic agent (Iyer 2002;Liu 2002;US EPA 2003).…”

Diuron exposure and Akt overexpression promote glioma formation through DNA hypomethylation

“…However, in gliomagenesis, the oncogenic effect is not due to itself since diuron needs to be associated to Akt overexpression to promote the gliomagenesis. The involvement of diuron in carcinogenesis is not new since diuron is already reported for the bladder [14, 15], urothelial [16], skin [17, 18], and mammary [15–19] carcinogenesis. Nevertheless, none of these publications mentioned an impact of diuron on the global level of DNA methylation and on the methylation level of certain gene promoters.…”

“…Despite its classification as a likely human carcinogen, little is known about the combination effect of oncogenic overexpression and the pesticide exposure on the glioma occurrence. More generally, little is known about the diuron-induced tumor molecular mechanism even if diuron has been already reported to promote the bladder [14, 15], urothelial [16], skin [17, 18], and mammary [15–19] carcinogenesis.…”

Distribution of Diuron in Coastal Seawater and Sediments from West Sea Area of Zhoushan Island

“…The APVMA suggested that the use of diuron be suspended except in anti-fouling paint, algae control, and as a buffer to continue the use of cotton defoliant [4][5][6]. The US Environmental Protection Agency has also categorized diuron as a "likely human carcinogen" [7]. The prevention and reduction of the environmental risks posed by diuron as well as the protection of human health should be prioritized by conducting research on the degradation and distribution features of diuron in the environment.…”