Decoding the underexplored biological impact of synthetic cathinones using C. elegans as a translational toxicity model

Background: The recreational use of New Psychoactive Substances (NPSs) represents a significant and growing public health concern. Among these, synthetic cathinones are increasingly consumed, yet their biotoxicological effects remain poorly characterized [1, 2]. In this context, in vivo models such as Caenorhabditis elegans, a suitable model for high-throughput toxicity screening that exhibits a high degree of conservation of molecular pathways with humans [3], are essential to elucidate the systemic and long-term effects of these substances on critical biological processes, which remain poorly understood. Objective: Using C. elegans as a discovery platform, this study aimed to evaluate the toxic effects of methylone and pentedrone on animal development, reproduction, and lifespan. Methods: Synchronized L1-stage animals of the DC19 strain [bus-5(br19)] (~200 animals/condition) were exposed, in liquid medium, to increasing concentrations of synthetic cathinones (0–10 mM) for 24–72 h. Survival rates were assessed by counting the number of live and dead worms. Using sublethal to low-lethal concentrations (0–2.5 mM), we further explored the impact of synthetic cathinones on (1) animal development, by measuring the body length using Fiji software; (2) reproductive behavior, by counting the total number of embryos laid by individual F0-exposed animals within a 24-h time window; and (3) lifespan, by monitoring exposed animals every two days throughout their lifespan. Results: Short-term exposure (24 h) of C. elegans to methylone or pentedrone did not affect animal survival rates at concentrations ≤1.0 mM, whereas higher concentrations (≥5.0 mM) significantly reduced viability. In contrast, prolonged exposure (72 h) significantly reduced animal survival rates at concentrations ≥1.0 mM, indicating enhanced toxicity over time. Sublethal concentrations of both compounds impaired animal development in a reversible manner and significantly reduced reproductive output, while progeny viability remained unaffected. Additionally, no significant effects on animal lifespan were observed, suggesting selective disruption of developmental and reproductive processes. Conclusions: These findings indicate that synthetic cathinones exhibit pronounced time-dependent toxicity in C. elegans. This highlights previously underexplored systemic risks and reinforces the value of C. elegans as a powerful in vivo platform to uncover the biological impact of psychoactive substances.