Nonylphenol exposure and cardiovascular toxicity: Mechanistic insights and integrated risk assessment from experimental models

Abstract

Nonylphenol (NP), a widespread environmental endocrine-disrupting chemical, has been extensively studied for its reproductive and neurological toxicity; however, its cardiovascular effects and underlying mechanisms remain poorly understood, and a systematic risk assessment is still lacking. This study investigated the effects of NP exposure on cardiac function in mice and its molecular mechanisms through subacute toxicity experiments, followed by a comprehensive risk analysis using the Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy. Kunming mice (equal numbers of males and females) were orally administered NP at doses of 75, 150, and 300 mg/kg daily for 28 days. Cardiac toxicity was evaluated via echocardiography, histopathology, cardiomyocyte contractility measurements, and transcriptomic analysis. Results showed that NP exposure significantly reduced left ventricular ejection fraction and fractional shortening in female mice, induced myocardial fibrosis and collagen deposition, and markedly decreased cardiomyocyte contractile amplitude as well as depolarization/repolarization rates. Transcriptomic analysis identified 242 differentially expressed genes, with abnormal activation of the relaxin signaling pathway potentially mediating NP-induced cardiotoxicity. Further TRAEC-based risk assessment classified NP as a medium-risk compound (score: 6.50), significantly higher than other alkylphenols such as butylphenol (2.43) and octylphenol (2.95), underscoring its heightened environmental and regulatory concern. This study systematically reveals the mechanisms by NP impairs cardiac contractility, induces fibrosis, and disrupts transcriptomic regulation, while clarifying its environmental risk level through the TRAEC framework. These findings provide critical scientific evidence for environmental policy formulation. Future research should prioritize human epidemiological validation and further exploration of NP's molecular targets.

Keywords: Cardiotoxicity; Nonylphenol; Risk assessment; Transcriptomics.