Tris(1,3-dichloro-2-propyl)phosphate Reduces the Lifespan via Activation of an Unconventional Insulin/Insulin-Like Growth Factor-1 Signaling Pathway

Abstract

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an environmental contaminant which has attracted increasing concern due to its presence in environmental media and biological samples. Our previous study demonstrated that exposure to TDCPP reduced the lifespan of Caenorhabditis elegans (C. elegans), but the mechanisms, including the relevant signaling pathways, are unclear. The current study found that TDCPP exposure triggers an unconventional insulin/insulin-like growth factor signaling (IIS) pathway, not by disrupting the insulin like growth factor 1 receptor DAF-2/IGF1R, but by inhibiting the downstream tumor-suppressor factor DAF-18/PTEN. This inhibition reduces PI(3,4,5)P3 (PIP3) dephosphorylation, causing a buildup that increases activation of the Akt/Protein Kinase B (PKB) family of serine/threonine kinases. This activation induces DAF-16/FoxO phosphorylation and promotes the sequestration of DAF-16/FoxO in the cytoplasm, reducing the lifespan of nematodes. Our results have important diagnostic and therapeutic implications for controlling TDCPP-related diseases, especially those originating with IIS pathway components.