| Summary: | As the areca nut market is expanding, there is a growing concern regarding areca nut toxicity. Areca nut alkaloids are the major risky components in betel nuts, and their toxic effects are not fully understood. Here, we investigated the parental and transgenerational toxicity of varied doses of areca nut alkaloids in <i>Caenorhabditis elegans</i>. The results showed that the minimal effective concentration of arecoline is 0.2–0.4 mM. First, arecoline exhibited transgenerational toxicity on the worms’ longevity, oviposition, and reproduction. Second, the redox homeostasis of <i>C. elegans</i> was markedly altered under exposure to 0.2–0.4 mM arecoline. The mitochondrial membrane potential was thereafter impaired, which was also associated with the induction of apoptosis. Moreover, antioxidant treatments such as lycopene could significantly ameliorate the toxic effects caused by arecoline. In conclusion, arecoline enhances the ROS levels, inducing neurotoxicity, developmental toxicity, and reproductive toxicity in <i>C. elegans</i> through dysregulated oxidative stress, cell apoptosis, and DNA damage-related gene expression. Therefore, the drug-induced production of reactive oxygen species (ROS) may be crucial for its toxic effects, which could be mitigated by antioxidants.
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