A comprehensive review of 1,2,4-triazole fungicide toxicity in zebrafish (Danio rerio): A mitochondrial and metabolic perspective

In this critical review, we synthesize data from peer-reviewed literature reporting on triazole fungicide exposures in the zebrafish model. Based on their mode of action in plants (potent inhibitors of ergosterol synthesis), we focused attention on mechanisms related to cellular, lipid, and steroid metabolism. Evidence from several studies reveals that zebrafish exposed to triazoles present with impaired mitochondrial oxidative phosphorylation and oxidative stress, as well as dysregulation of lipid metabolism. Such metabolic disruptions are expected to underscore developmental delays, deformity, and aberrant locomotor activity and behaviors often observed following exposure. We begin by summarizing physiological and behavioral effects observed with triazole fungicide exposure in zebrafish. We then discuss mechanisms that may underlie adverse apical effects, focusing on mitochondrial bioenergetics and metabolism. Using computational approaches, we also identify novel biomarkers of triazole fungicide exposure. Extracting and analyzing data contained in the Comparative Toxicogenomics Database (CTD) revealed that transcriptional signatures responsive to different triazoles are related to metabolism of lipids and lipoproteins, biological oxidations, and fatty acid, triacylglycerol, and ketone body metabolism among other processes. Pathway and sub-network analysis identified several transcripts that are responsive in organisms exposed to triazole fungicides, several of which include lipid-related genes. Knowledge gaps and recommendations for future investigations include; (1) targeted metabolomics for metabolites in glycolysis, Krebs cycle, and the electron transport chain; (2) additional studies conducted at environmentally relevant concentrations to characterize the potential for endocrine disruption, given that studies point to altered cholesterol (precursor for steroid hormones), as well as altered estrogen receptor alpha and thyroid hormone expression; (3) studies into the potential role for lipid peroxidation and oxidation of lipid biomolecules as a mechanism of triazole-induced toxicity, given the strong evidence for oxidative damage in zebrafish following exposure to triazole fungicides.