Comparative glycolipid metabolic toxicities and mechanisms of the rubber-derived contaminants 6PPD and its derivative 6PPD-Q in zebrafish.

Emerging pollutants 6PPD and its oxidation product 6PPD-Q enter the environment via rubber product abrasion, with scarce toxicological data for risk assessment. This study compared their toxicity and mechanisms on zebrafish glucolipid metabolism at environmentally relevant and sublethal concentrations. Both induced developmental malformations dose-dependently, with 120hpf larvae LC50 of 991.6 μg/L (6PPD) and 165.2 μg/L (6PPD-Q), showing 6PPD-Q has higher teratogenicity and lethality. RNA-seq and bioinformatics revealed shared differentially expressed genes (DEGs) enrichment in ether lipid, glycerophospholipid, glycerolipid metabolism, and insulin signaling pathways, indicating common disruption of glucose-lipid homeostasis. Oil red o(ORO) staining and assays confirmed hepatic lipid accumulation (elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), reduced high-density lipoprotein cholesterol (HDL-C)) and glucose metabolism disorders (hyperglycemia, decreased insulin, lactate accumulation, etc.), suggesting insulin resistance and suppressed tricarboxylic acid cycle (TCA) cycle. Energy metabolism was dysfunctional (reduced adenosine triphosphate (ATP), impaired mitochondrial membrane potential (ΔΨm)), inhibiting swimming vitality, with more severe disturbances in 6PPD-Q group. PPI network analysis and RT-qPCR showed 6-PPD disrupts glucolipid metabolism via phospholipase A2(PLA2)-mediated pathways, while 6PPD-Q acts through PLA2, phospholipase D1(PLD1), and lysophosphatidylcholine acyltransferases (LPCATs). This study confirms their induction of glucolipid metabolic disorders with distinct mechanisms, providing a basis for environmental health risk assessment and related strategies.