Cetewayo Rashid Pilot Scope: Organophospate Flame Retardants Promote Steatosis Development Independent of Halogenation

Abstract Organophosphate flame retardants (OPFRs) are used in automobiles, mattresses, and upholstery to meet federal and state-mandated flammability standards. Studies from the National Health and Nutrition Examination Survey (NHANES) indicate that >95% of the American population have detectable OPFR body burdens. Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) and the non-halogenated OPFR triphenyl phosphate (TPhP) are both associated with metabolic syndrome3, obesity1, steatosis 1; 4, and insulin resistance1. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30% of the American population and is a key risk factor for chronic conditions such as type 2 diabetes. NHANES studies show a 100% and 74% increased risk of MASLD in people with the highest quartile of TDCPP, and TPhP exposure, respectively compared to the lowest quartile of exposure 1. However, despite their similar chemical structure, it is unknown whether shared or disparate mechanisms mediate the associated metabolic deficits. The mechanisms by which TDCPP and TPhP, either individually and in combination, regulate hepatocyte lipid metabolism remain largely unknown and will be explored in the current study. To ensure translationally relevancy, we will use primary human hepatocytes to determine the effect of OPFR exposure on lipid accumulation, oxidative stress, lipid metabolism, lipid synthesis, and VLDL secretion. Finally, RNAseq will be performed to identify mechanisms of disruption and the combined influence of OPFR co-exposure. These results will inform our understanding of halogenation on OPFR-induced metabolic disruption and uncover targets with the potential to mitigate their harmful effects.