Polystyrene microplastics induce nephrotoxicity through DDIT4-mediated autophagy and apoptosis

Area of Science:

• Environmental Health
• Developmental Biology
• Toxicology

Background:

• Microplastics (MPs) are pervasive environmental contaminants with potential health risks.
• While MPs accumulate in organs like kidneys, their specific impact on kidney development and underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the nephrotoxic effects of polystyrene microplastics (PS-MPs) on kidney development using a human pluripotent stem cell-derived 3D kidney organoid model.
• To elucidate the molecular pathways involved in PS-MP-induced kidney toxicity.

Main Methods:

• Human pluripotent stem cell-derived kidney organoids were exposed to 1 μm PS-MPs (1.25–10 μg/mL for 24 h).
• Assessed organoid size, nephron-specific markers, autophagy (LC3-II), apoptosis (cleaved caspase-3), and gene expression via transcriptomics.
• Investigated the role of DNA damage-inducible transcript 4 (DDIT4) by silencing it.

Main Results:

• PS-MPs significantly reduced organoid size and impaired proximal and distal tubule formation.
• Enhanced autophagy and apoptosis were observed in nephron progenitor cells (NPCs) with increased LC3-II and cleaved caspase-3.
• Transcriptomic analysis identified DDIT4 as a mediator linking PS-MP exposure to mTOR signaling inhibition; DDIT4 silencing reduced PS-MP-induced toxicity.

Conclusions:

• PS-MPs induce nephrotoxicity by disrupting kidney organoid development, promoting autophagy and apoptosis in NPCs.
• DDIT4 plays a critical role in mediating PS-MP-induced nephrotoxicity by inhibiting mTOR signaling.
• Findings highlight the need for further research on the developmental and long-term health impacts of microplastic exposure.