Transgenerational Aging Induced by Tris(1,3-dichloro-2-propyl)phosphate via Disruption of Lipid Homeostasis and Mitochondrial Function

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a widely used chlorinated flame retardant, is ubiquitous in dust, water, and biota. Parental exposure of Caenorhabditis elegans to environmentally relevant TDCPP (0.1–10 μg/L) reduced mean lifespan by 14.9–20.9% in parental nematodes and 8.07–28.2% in offspring. Multiomics analyses (transcriptomics and lipidomics) uncovered a previously unrecognized lipid-centered mechanism by which TDCPP impaired organismal health. Specifically, TDCPP suppressed the expression of daf-16 and downstream fatty acid desaturase (fat-5/6), leading to depletion of unsaturated lipid species, including triglycerides, diacylglycerols, lysophospholipids, and glycosphingolipids. This disruption was corroborated by phenocopy experiments showing that genetic deletion of fat-5/6 or dietary supplementation with saturated fatty acids (positive control) mimicked TDCPP-induced aging phenotypes. Moreover, TDCPP downregulated aak-2 and cpt-1, impairing mitochondrial β-oxidation and energy metabolism. These findings identified a novel daf-16–fat-6–AMPK–CPT-1 signaling axis, providing mechanistic insight into how the environmental pollutant TDCPP disrupts lipid homeostasis to promote aging and transgenerational toxicity.