Work

Multigenerational developmental and skeletal toxicity from benzo[a]pyrene exposure in F0 and F2 medaka: metabolic trade-offs and survival costs

Year: 2026

Type: article

Abstract: Benzo[a]pyrene is a ubiquitous emerging contaminant; however, whether and how it disrupts fish development and skeletal health across multiple generations, particularly at the metabolomic level, remains unclear. The latent effects of embryonic benzo[a]pyrene exposure at environmentally relevant levels (2.5–80 μg/L) on developmental toxicity and skeletal integrity were assessed over three generations (F0–F2) of medaka. The F1 and F2 offspring were reared in clean water to isolate the inherited impacts. Untargeted metabolomic analysis (Variable Importance in Projection > 1.0, p < 0.05 in Student's t-test, and ratio ≥ 1.5 or ≤ 0.67) of F0 and F2 embryos identified 233 (86) and 254 (752) differentially abundant metabolites in the F0 (F2) embryos exposed ancestrally to benzo[a]pyrene at 2.5 and 20 μg/L. Benzo[a]pyrene exposure induced multigenerational impairments, including reduced survivorship and hatching success in F0 embryos, altered morphometrics (e.g., reduced body length, smaller eye pit, and larger pericardial cavity) in F0–F1 larvae, and elevated skeletal malformation frequency (e.g., craniofacial and spinal deformities) in F0–F2 larvae. Metabolomic perturbations were linked to four major biological processes: (1) metabolic activation and oxidative stress; (2) disruption of energy metabolism and redox balance, evidenced by a triad of elevated 3-hydroxybutyric acid, oxoglutaric acid, and depleted 2-hydroxyglutarate; (3) dysregulation of cell signaling and developmental programming, including energy crisis (elevated AMP), impaired vascular development (reduced prostaglandin I2), and disrupted efferocytosis; and (4) impairment of neurological and sensory functions. These findings demonstrate that F0 embryonic benzo[a]pyrene exposure induces lasting multigenerational toxicity by disrupting metabolic, signaling, and sensory pathways, ultimately leading to developmental impairment and osteotoxicity. While F2 larvae showed partial morphological recovery, this may represent a survival trade-off, where metabolic resources were redirected from skeletal development to support the formation of essential organs. This study identifies the metabolomic basis for the multigenerational developmental and skeletal toxicity induced by embryonic benzo[a]pyrene exposure.

Source: New Contaminants

DOI: 10.48130/newcontam-0025-0022