ToxCast chemical library screen identifies diethanolamine as an activator of Wnt signaling

Abstract

Numerous autism spectrum disorder (ASD) risk genes are associated with Wnt signaling, suggesting that brain development may be especially sensitive to genetic perturbation of this pathway. Additionally, valproic acid, which modulates Wnt signaling, increases risk for ASD when taken during pregnancy. We previously found that an autism-linked gain-of-function UBE3AT485A mutant construct hyperactivated canonical Wnt signaling, providing a genetic means to elevate Wnt signaling above baseline levels. To identify environmental use chemicals that enhance or suppress Wnt signaling, we screened the ToxCast Phase I and II libraries in cells expressing this autism linked UBE3AT485 gain-of-function mutant construct. Using structural comparisons, we identify classes of chemicals that stimulated Wnt signaling, including ethanolamines, as well as chemicals that inhibited Wnt signaling, such as agricultural pesticides, and synthetic hormone analogs. To prioritize chemicals for follow-up, we leveraged predicted human exposure data, and identified diethanolamine (DEA) as a chemical that both stimulates Wnt signaling in UBE3AT485A-transfected cells and has a high potential for prenatal exposure in humans. DEA also enhanced proliferation in two primary human neural progenitor cell lines. Overall, this study identifies chemicals with the potential for human exposure that influence Wnt signaling in human cells.