Molecular signatures associated with diuron exposure on rat urothelial mitochondria

Abstract

Diuron, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, is a worldwide used herbicide whose biotransformation gives rise to the metabolites, 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous studies indicate that diuron and/or its metabolites are toxic to the bladder urothelium of the Wistar rats where, under certain conditions of exposure, they may induce successively urothelial cell degeneration, necrosis, hyperplasia and eventually tumors. The hypothesis was raised that the molecular initiating event (MIE) of this Adverse Outcome Pathway is the mitochondrial toxicity of those compounds. Therefore, this study aimed to investigate in vitro the metabolic alterations resulting from urothelial mitochondria isolated from male Wistar rats exposure to diuron, DCPMU and DCA at 10 and 100 µM. A non-targeted metabolomic analysis using mass spectrometry showed discriminative clustering among groups and alterations in the intensity abundance of membrane-associated molecules phosphatidylcholine, phosphatidylinositol and phosphatidylserine, in addition to methylhexanoyl-CoA and, particularly for diuron 100 µM, dehydro-L-gulonate, all of them involved in critical mitochondrial metabolism. Collectively, these data indicate the mitochondrial dysfunction as an MIE that triggers cellular damage and death observed in previous studies.

Keywords:

• Herbicide
• DCA
• DCPMU
• mitochondrial dysfunction
• diuron toxicity

Acknowledgements

The authors are grateful to Paulo Roberto Cardoso and Paulo César Georgete for technical assistance.

Disclosure statement

This study is associated to the Botucatu Medical School, Unesp, SP, Brazil and after its completion, TRRL assumed 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; and 2019/05718-3 for JD]; the National Council for Scientific and Technological Development (CNPq) [Grant No. 167774/2018-2]; and by the Center for Evaluation of Environmental Impact on Human Health (TOXICAM), Unesp, Brazil.