2,2-Dichloroacetamide exposure induces behavior and memory disorders in mice: Detrimental effects of long-term dietary restriction on neurotoxicity.

2, 2-dichloroacetamide (DCAcAm), a nitrogen-containing disinfection byproduct (DBPs), is commonly found in potable water. This study aimed to compare the neurotoxicity of DCAcAm in C57/BL6 mice at both environmentally relevant and higher doses through oral exposure over a 28-day period. Furthermore, the potential effects of dietary restriction (DR) on the cerebral toxicity induced by 20 ppb DCAcAm were examined. The findings indicated that DCAcAm exposure and DR treatment resulted in reduced memory retention and cognitive adaptability in mice. Additionally, higher doses of DCAcAm exposure induced severe brain inflammation and oxidative stress. Metabolic profiling revealed disruptions in fatty acid, energy, and amino acid metabolism in the brain. Remarkably, the negative impacts of 20 ppb DCAcAm on the mice brain were worsened by DR treatment. Analysis of 16S rRNA sequencing revealed notable changes in the composition and structure of intestinal microorganisms after exposure to DCAcAm. This study discovered that DCAcAm has both direct effects on the brain and indirect effects through the microbial-brain-intestinal axis, which collectively result in neurotoxicity and dietary restriction exacerbates these effects. This study provides emerging views on the assessment of the toxicity of nitrogen containing DBPs.