Molecular Toxicity Pathways and Transcriptomic Points of Departure (tPODs) of 6PPD-Quinone in Early-Life Stage Lake Trout (Salvelinus namaycush)

N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine-quinone
(6PPD-quinone) has been linked to acute mortality in select salmonid
species at concentrations found in surface waters after stormwater
runoff events. However, little is known about the specific mechanism
underlying the highly species-specific sensitivity to 6PPD-quinone,
limiting our ability to predict effects across fishes and develop
protective guidelines. This study aimed to characterize the molecular
toxicity pathways of 6PPD-quinone in lake trout (Salvelinus
namaycush), a species of significant ecological, cultural,
and economic importance in North America that is among the most sensitive
fishes to 6PPD-quinone exposure. Whole-transcriptome analysis of alevins
exposed to graded 6PPD-quinone concentrations (0.22–7.6 μg/L)
for 96 h revealed concentration-dependent dysregulation of pathways
related to inflammation, vascular integrity, oxidative stress, protein
homeostasis, and skeletal and craniofacial development. Notably, exposed
alevins showed early activation of proinflammatory cytokine signaling
and programmed cell death processes, including efferocytosis, necroptosis,
and ferroptosis. Benchmark concentration (BMC) modeling of the transcriptomic
data identified a transcriptomic BMC10th (the concentration
affecting the most sensitive 10th percentile of genes) of 0.211 μg/L,
closely aligning with the 45-day apical BMC10th and BMC20th values (0.161 and 0.252 μg/L, respectively). These
findings highlight that short-term transcriptomic responses in nonregulated
embryonic life stages offer mechanistic insights and provide predictive,
quantitative benchmarks that closely correspond with traditional apical
toxicity thresholds.