Diuron and its metabolites induce mitochondrial dysfunction-mediated cytotoxicity in urothelial cells

Abstract

In the environment, or during mammalian metabolism, the diuron herbicide (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is transformed mainly into 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous research suggests that such substances are toxic to the urothelium of Wistar rats where, under specific exposure conditions, they may induce urothelial cell degeneration, necrosis, hyperplasia, and eventually tumors. However, the intimate mechanisms of action associated with such chemical toxicity are not fully understood. In this context, the purpose of the current in vitro study was to analyze the underlying mechanisms involved in the urothelial toxicity of those chemicals, addressing cell death and the possible role of mitochondrial dysfunction. Thus, human 1T1 urothelial cells were exposed to six different concentrations of diuron, DCA, and DCPMU, ranging from 0.5 to 500 µM. The results showed that tested chemicals induced oxidative stress and mitochondrial damage, cell cycle instability, and cell death, which were more expressive at the higher concentrations of the metabolites. These data corroborate previous studies from this laboratory and, collectively, suggest mitochondrial dysfunction as an initiating event triggering urothelial cell degeneration and death.

Keywords:

• Mitotoxicants
• mitochondrial pathways
• toxicodynamics
• 1T1 cell culture
• diuron and metabolites

Acknowledgments

The authors are grateful to Vickeline Namba and Ana Paula Doria for assistance in the implementation of the cell culture model; Paulo Roberto Cardoso provided technical assistance.

Disclosure statement

This study is associated with the Botucatu Medical School, UNESP, SP, Brazil. After its completion, TRRL assumed a job position in a private company. The authors have no conflicts of interest to declare.

Additional information

Funding

This work was supported by the São Paulo Research Foundation (FAPESP) [Grant No. 2017/25402-5], the National Council for Scientific and Technological Development (CNPq) [Grant No. 167774/2018-2], and the Center for Evaluation of Environmental Impact on Human Health (TOXICAM), UNESP, Brazil.