Gestational Trichloroacetic Acid Exposure Induces Miscarriage by Disrupting Iron Homeostasis in Trophoblasts via the KEAP1-NRF2 Pathway.

Abstract

Trichloroacetic acid (TCAA) is one of the most commonly detected non-volatile disinfection byproducts (DBPs) in public water supplies. Previous epidemiological studies have established associations between TCAA exposure and elevated risks of adverse pregnancy outcomes, yet its impacts on pregnancy maintenance remain poorly understood. In this study, we found that gestational TCAA exposure induced pregnancy loss in mice by disrupting trophoblast invasion and impairing the placental structure. Mechanistically, TCAA inhibited the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, which drove placental iron dyshomeostasis marked by an expanded labile iron pool (LIP) and subsequent reactive oxygen species (ROS) overaccumulation. The iron chelator deferoxamine (DFO) significantly alleviated TCAA-induced pregnancy loss by restoring iron metabolism, reducing oxidative stress, and enhancing trophoblast invasion. Taken together, our findings provided critical insights into the reproductive toxicity of TCAA and underscored the potential of targeting iron homeostasis as a therapeutic strategy.