Insights into cytotoxicity and redox modulation by the herbicide linuron and its metabolite, 3,4-dichloroaniline

Linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) is a phenylurea herbicide used to control the growth of grasses and weeds, thereby promoting the growth of crops such as soybeans. Both linuron and its metabolite, 3,4-dichloroaniline (DCA), have been identified as having toxic effects, including reproductive and developmental toxicity. However, the potential neurotoxic effects have not been thoroughly examined. This study investigates the toxic effects of linuron and DCA in neuronal cultures. A cell viability assay was used to evaluate cytotoxicity, while an iron and arachidonic acid-induced C11-BODIPY oxidation and ABTS assay were conducted to assess the potential redox modulatory activity of the tested compounds. Our results indicated that linuron and DCA were toxic to N27 cells (rat dopaminergic neurons) at higher concentrations, particularly above 50 μM. In contrast, these compounds did not demonstrate any considerable toxicity in HT-22 cells (mouse hippocampal neurons). We also examined whether linuron and DCA influence ferroptosis, a form of regulated cell death caused by lipid peroxidation. Our findings suggest that DCA significantly interferes with the process of ferroptosis and inhibits it due to its inherent radical-trapping antioxidant (RTA) activity. In conclusion, both linuron and its metabolite DCA showed modest cytotoxicity in N27 cells, and further experiments are needed to determine whether these agents cause neurotoxicity.