Developmental susceptibility to PFOS toxicity in Drosophila shows genetic variation in toxicodynamics and rescue via enhanced muscle mitochondrial function

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Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants causing widespread concern for developmental toxicity in humans. PFAS can cause adverse developmental outcomes, yet factors determining PFAS susceptibility remain poorly understood. Whether PFAS resistance reflects generalized stress tolerance shared with other toxicants has not been explored. To address this, we assayed a panel of Drosophila melanogaster lines with established traits of resistance and susceptibility to methylmercury (MeHg) for developmental toxicity with several PFAS compounds, including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and hexafluoropropylene oxide dimer acid (GenX). With larval exposures, PFOS showed the greatest potency, producing failures in both pupariation and eclosion at concentrations as low as 5µM (2.5ppm) in food. PFOS and MeHg resistance profiles across the genotype panel did not correspond, indicating toxicant-specific mechanisms control susceptibility apart from generalized stress tolerance pathways. Accounting for PFOS body burden after exposure, resistant and susceptible lines displayed markedly different developmental outcomes at similar internal concentrations indicating that variation in susceptibility reflects toxicodynamic differences aside from variance in accumulation. Drawing on a prior role for mitochondrial dysfunction in the toxicity of both PFAS and heavy metals, we implemented neural and muscle-specific modulation of mitochondrial function via expression of dPGC-1 and ND1. Increased dPGC-1 or ND1 in muscle, compared to neural tissues, showed enhanced resistance to PFOS across all developmental outcomes. Notably, muscle-targeted overexpression of these mitochondria related genes conferred developmental protection without reducing PFOS accumulation, supporting a toxicodynamic basis of resistance. While PFOS toxicity arises through mechanisms distinct from MeHg, muscle mitochondria serve as a potential physiological nexus influencing developmental toxicity.