Dichlorodiphenyltrichloroethane metabolites inhibit DNMT1 activity which confers methylation-specific modulation of the sex determination pathway

Dichlorodiphenyltrichloroethane (DDT) poses a significant health risk to humans which is associated with genomic DNA hypomethylation. However, the mechanism and biological consequences remain poorly understood. In vitro assays confirmed that the DDT metabolites 2,2-bis(p-chlorophenyl)-acetic acid (DDA) and 1-chloro-2,2-bis-(p-chlorophenyl)ethylene (DDMU), but not other DDT metabolites, significantly inhibited DNA methyltransferase 1 (DNMT1) activity, leading to genomic hypomethylation in cell culture assays. DNMT1 as a target for DNA hypomethylation induced by DDT metabolites was also confirmed using cell cultures in which DNMT1 was silenced or highly expressed. DDA and DDMU can modify methylation markers in the promoter regions of sexual development-related genes, and change the expression of Sox9 and Oct4 in embryonic stem cells. Molecular docking indicated that DDA and DDMU bound to DNMT1 with high binding affinity. Molecular dynamic simulation revealed that DDA and DDMU acted as allosteric modulators that reshaped the conformation of the catalytic domain of DNMT1. These findings provide a new insight into DDT-induced abnormalities in sexual development and demonstrate that selective binding to DNMT1 by DDA and DDMU can interfere with human DNMT1 activity and regulate the expression of the Sox9 and Oct4 genes. (c) 2021 Elsevier Ltd. All rights reserved.

Automated summary

The study found that DDT metabolites DDA and DDMU induce DNA hypomethylation by inhibiting DNMT1 activity, leading to changes in the expression of sexual development-related genes.