Dichloroacetonitrile Induces Protein Modifications in Cortical Astrocyte Cell Line CTX‐TNA2 and Alterations in Fetal Mouse Brain

Abstract

Epidemiological studies have shown an association between disinfection by‐products (DBP) of drinking water chlorination (DWC) and adverse pregnancy outcomes (APO) and indicated the involvement of DBP‐induced developmental toxicity on fetal brains. However, the precise mechanisms involved are not known. We report that dichloroacetonitrile (DCAN), a DBP of DWC, induces protein carbonylation in immortalized rat cortical astrocyte cells CTX‐TNA2 and pathological changes in the brains of fetuses of DCAN‐exposed pregnant albino mice. Exposure of cells to DCAN for 48 hr resulted in increased superoxide generation, decreased GSH/GSSG ratio, protein carbonylation, and inhibition of proteasomal activity. Oral administration of DCAN to pregnant mice resulted in low fetal body weight, neurodegeneration in the fetal cerebral cortex, redox imbalance and induction of apoptosis in the cerebral cortex and the cerebellum of the fetuses. Our data suggest that DCAN induces oxidative protein modifications and proteasomal inhibition which leads to accumulation of altered proteins in astrocytes, resulting in developmental pathological changes in fetal brains all of which result in APO. The findings provide insights toward understanding of the molecular basis of DCAN‐induced developmental pathologies and identify cellular pathways that can serve as tools for their prevention. (Supported by the Egyptian government)