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Germline MET-2-LIN-3-LET-23 signaling axis governs nanoplastic-induced transgenerational reproductive toxicity in Caenorhabditis elegans
Summary
Scientists found that tiny plastic particles (nanoplastics), at levels comparable to real-world pollution, can damage the reproductive systems of worms—and this damage gets passed down to their offspring and grandoffspring, even though those descendants were never directly exposed. The researchers pinpointed the exact chain of molecular signals responsible, showing the plastic exposure triggers a self-destruct process in reproductive cells that carries forward across generations. While this study was done in worms, not humans, it's a warning sign: the ever-growing amount of nanoplastics in our food, water, and air could potentially affect fertility not just
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.