Examining developmental toxicity of isopropylated phenyl phosphates (IPP) - Project abstract Organophosphate flame retardants (OPFRs) have become ubiquitous environmental contaminants following the phase-out of polybrominated diphenyl ethers (PBDEs). Among them, isopropylated phenyl phosphates (IPPs)—a complex mixture of structural isomers and a major component of the commercial mixture Firemaster 550—have emerged as a widespread yet poorly characterized class of OPFRs. IPPs are now frequently detected in indoor environments, firefighting gear, and human biosamples, including cord blood and toddler serum, raising concerns about their potential to disrupt development during sensitive windows. However, their toxicological impacts remain largely unexplored, particularly with respect to organ-specific developmental effects. Our preliminary work using zebrafish has revealed that embryonic exposure to IPP leads to significant disruption in visual behavior and ocular transcriptomes. Specifically, we observed striking upregulation of apolipoproteins apoa4b.2 and apobb.1, suggesting a novel connection between IPP exposure, metabolic imbalance, and ocular dysfunction. These findings challenge the current neurocentric paradigm of flame retardant toxicity and suggest the eye as a previously underappreciated, yet vulnerable, target of environmental toxicants. The goal of this R03 basic science pilot project is to define the mechanisms by which IPPs disrupt eye development and function, with a focus on the role of apolipoproteins as mediators of toxicity. Our central hypothesis is that IPP exposure disrupts visual function and eye physiology during development, and that this disruption is mediated, at least in part, by apolipoprotein dysregulation within the developing eye. We will pursue this objective through two aims. In aim 1, we will assess visual performance using a battery of behavioral assays (photomotor, optomotor, and optokinetic responses), quantify eye-specific neurotransmitters, and evaluate retinal structure and membrane potential using immunohistochemistry and fluorescence-based technqieus. In aim 2, we will use morpholino-mediated knockdown of apoa4b.2 and apobb.1, to evaluate their role in mediating visual and metabolic phenotypes following IPP exposure. This R03 will generate the first mechanistic insights into how IPPs disrupt eye development, establishing the eye as a sensitive and previously overlooked target of OPFR toxicity. The study will also establish apolipoproteins as novel mediators of environmental oculotoxicity. These findings will have broad implications for vision science, developmental toxicology, and environmental health policy, and will lay the groundwork for biomarker development and expanded investigation of OPFR mixtures.
