What question did this study set out to answer?

This study aims to investigate the systemic effects of chronic 1-nitropyrene exposure and the efficacy of ferroptosis inhibition in rats.

March 16, 2026Open Access

Integrated microbiome-metabolome analysis reveals multiorgan toxicity of 1-nitropyrene and the limited efficacy of ferroptosis inhibitor Fer-1 in rats

Key Points

This study aims to investigate the systemic effects of chronic 1-nitropyrene exposure and the efficacy of ferroptosis inhibition in rats.
Chronic exposure to 1-nitropyrene was administered to rats.
Metabolic, immunological, hepatic, and microbiome changes were measured.
Ferroptosis inhibitor Fer-1 was tested for its mitigating effects.
Untargeted metabolomics and histopathology analyses were conducted.
Gut microbiota composition was assessed before and after exposure.
Chronic 1-nitropyrene exposure caused significant disruptions in glucose homeostasis.
Evidence of metabolic injury included decreased HDL levels and hepatocyte damage indicative of NAFLD.
Functional alterations in gut microbiota related to lipid metabolism and xenobiotic degradation were observed.
Ferroptosis inhibition by Fer-1 modified certain metabolic and microbial signatures but did not alleviate major toxic effects.

Abstract

Introduction 1-Nitropyrene (1-NP), a prevalent nitro-polycyclic aromatic hydrocarbon, is increasingly recognized as a potential metabolic disruptor, yet its systemic biological effects remain insufficiently characterized. Methods This study investigated the metabolic, immunological, hepatic, and microbiome alterations induced by chronic 1-NP exposure in rats and assessed whether ferroptosis inhibition via Fer-1 could mitigate these effects. Results Although body weight was not significantly altered overall, high-dose exposure impaired growth from week 4. Exposed groups exhibited progressively elevated fasting blood glucose and impaired glucose tolerance, indicating significant disruption of glucose homeostasis. Serum biochemistry revealed dose-dependent reductions in HDL and total cholesterol, while histopathology confirmed hepatocyte ballooning, inflammation, and steatosis consistent with NAFLD-like progression. Hematological changes, including shifts in neutrophil and lymphocyte populations, suggested chronic inflammatory activation. Untargeted metabolomics identified extensive alterations in pathways related to glycolysis, tryptophan metabolism, glycerophospholipid metabolism, and ABC transporters. Gut microbiota analysis demonstrated reduced richness and significant compositional shifts, with functional predictions linking dysbiosis to xenobiotic degradation, lipid metabolism, and phosphotransferase systems. Integrated microbiome–metabolome analysis revealed coordinated disruptions in host–microbial metabolic networks. Fer-1 intervention modified specific metabolic and microbial signatures but did not substantially alleviate major toxic outcomes. Conclusion Overall, chronic 1-NP exposure causes widespread metabolic injury driven by combined effects on host metabolism, immune regulation, hepatic function, and gut microbial ecology. These findings highlight 1-NP as a potent environmental metabolic disruptor and underscore the need for further mechanistic studies to inform mitigation strategies.

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