Molecular mechanisms underlying multi-generational skeletal abnormalities in marine medaka induced by the quinolone antibiotic norfloxacin (NOR)

Abstract

Norfloxacin (NOR), a quinolone antibiotic, has caused substantial environmental pollution and exhibits toxicity to the reproductive, immune, and endocrine systems of organisms. Proper skeletal function is crucial for overall health. This study demonstrates the toxic effects of NOR on the skeletal maturation of multiple generations of marine medaka (Oryzias melastigma) and explores the underlying mechanisms. NOR impaired skeletal formation throughout the full life cycles of the F0 and F1 generations and during the early growth phases of the F2 generation, leading to deformities. Proteomic analysis and validation experiments identified the STKR proteins-mediated BMP signaling pathway as critical in the skeletal toxicity observed in the F0 generation. Analyses of enzyme concentration and gene expression revealed that NOR disrupted key enzymes and genes involved in skeletal formation. Furthermore, DNA hypermethylation in the BMP pathway, along with transgenerational contaminant transmission, contributed to toxicity in subsequent generations. In conclusion, NOR disrupts the BMP pathway by interfering with the STKR proteins and induces DNA hypermethylation, resulting in skeletal deformities across multiple generations. These findings offer valuable insights for future research on the ecotoxicological effects of QNs.

Keywords: Marine medaka; Norfloxacin; Proteomic analysis; Transgenerational mechanism; Validation experiment.