Early-life exposure to the mycotoxin zearalenone causes aberrant lipid metabolism requiring mitochondrial fission in Caenorhabditis elegans: Mechanistic insights from in vivo genetic and in silico analyses.

Zearalenone, a mycotoxin commonly detected in food and the environment, is an underestimated global public health concern, especially as climate change may worsen its prevalence and effects. Although zearalenone has been associated with various adverse health outcomes, the exact mechanistic links to obesogenic effects, mitochondrial dysfunction, and related molecular pathways remain unclear. This research explored the impact of early-life zearalenone exposure on lipid accumulation and its potential relationship to mitochondrial dysfunction in the nematode Caenorhabditis elegans. Multiple lipid indicators, including Nile Red, Oil Red O, lipid droplet-associated fluorescent protein DHS-3, and triglyceride assays, showed that zearalenone exposure (0.3-50 μM) significantly increased worm lipid content. At 50 μM, zearalenone significantly upregulated lipogenesis genes (fasn-1, fat-6, fat-7, pod-2), β-oxidation genes (acs-2, ech-1), and transcription factors (nhr-49, sbp-1). Oil Red O assays using nhr-49 and sbp-1 mutant backgrounds revealed their essential roles in zearalenone-induced obesogenic effects. Exposure to 50 μM zearalenone significantly decreased mitochondrial content, potentially linked to upregulation of the mitochondrial fission gene drp-1. Oil Red O assays using drp-1 RNAi worms suggested that zearalenone's obesogenic effects depended on drp-1. Molecular docking analysis indicated possible spontaneous binding of zearalenone to DRP-1 and its homologues across species. This study offers mechanistic insights into the obesogenic effects of early-life zearalenone exposure, involving interconnected lipid metabolism (sbp-1 and nhr-49) and mitochondrial fission (drp-1), both of which are evolutionarily conserved.