Germline MET-2-LIN-3-LET-23 signaling axis governs nanoplastic-induced transgenerational reproductive toxicity in...

Chronic exposure to low concentrations of polystyrene nanoparticles (PS-NPs) can induce reproductive toxicity across multiple generations, yet the underlying molecular mechanisms remain poorly defined. Our previous studies showed that the parental germline EGF ligand LIN-3 could transgenerationally regulate PS-NPs-induced reproductive toxicity by targeting intestinal LET-23-DAF-16 or neuronal LET-23-DBL-1/DAF-7 signaling in the offspring. However, the offspring germline signaling cascade mediated by parental LIN-3 remained unclear. Using Caenorhabditis elegans as a model, the present study demonstrates that a germline MET-2-initiated, LIN-3-EGF-MAPK-LIN-1-mediated transgenerational signaling cascade is crucial for regulating PS-NPs-induced reproductive toxicity. Exposure to 1-10 μg/L PS-NPs caused dose-dependent defects in reproductive output and gonadal development in subsequent generations. RNA interference of key EGF pathway components, including lin-3, let-23, let-60, lin-45, mpk-1, and lin-1, significantly alleviated PS-NPs-induced reproductive toxicity. Moreover, parental germline LIN-3, epigenetically regulated by the H3K9 histone methyltransferase MET-2, transgenerationally activated the offspring germline EGF receptor LET-23, thereby modulating reproductive outcomes. Downstream, LIN-1 transmitted signals from the LET-23-LET-60-LIN-45-MPK-1 cascade and regulated the pro-apoptotic factors HUS-1 and EGL-1, leading to germline apoptosis in response to PS-NPs exposure. In summary, low-dose PS-NPs induce transgenerational reproductive toxicity by promoting germline apoptosis through activation of the MET-2-LIN-3-LET-23-LET-60-LIN-45-MPK-1-LIN-1-HUS-1/EGL-1 signaling axis, providing mechanistic insight into the multigenerational reproductive risks posed by nanoplastics in the range of μg L^-1.