Research Progress on Genotoxicity and Molecular Mechanisms of Environmental Endocrine Disruptors

Genotoxicity can be transmitted across generations through germ cells, thereby substantially increasing long-term health risks. Environmental endocrine disruptors (EEDs) are ubiquitously present, resistant to degradation, and prone to biomagnification along food chains, ultimately leading to human exposure and multi-level genetic damage (from chromosomal aberrations to DNA strand breaks and base modifications). At first, this review outlines the five major sources of EEDs and summarizes current genotoxicological detection approaches, including the Ames test, comet assay, micronucleus test, γH2AX-DDR co-detection, error-corrected sequencing, and multi-omics technologies. Subsequently, based on classical animal and cellular models, we systematically evaluate the research progress and mechanistic insights into the genotoxicity of both traditional and emerging EEDs over the past fifteen years. Our review reveals that bisphenols, phthalates, polybrominated biphenyls (PBDEs), and some novel contaminants (e.g., BPA substitutes and PFAS alternatives) consistently induce DNA damage, chromosomal abnormalities, and micronucleus formation. The underlying core mechanisms converge on genotoxic insult driven by reactive oxygen species (ROS)-mediated oxidative stress, interference with DNA damage response (DDR) pathways, and epigenetic dysregulation. Notably, some novel BPA substitutes exhibit even greater toxicity than their parent compounds, and combined exposures, even at environmentally relevant low doses, can provoke significant genetic lesions and pose transgenerational risks. In light of current knowledge gaps, we propose that future research should leverage high-throughput screening, integrative multi-omics, and artificial intelligence to focus on low-dose, long-term, and co-exposure scenarios, thereby providing robust scientific evidence for genotoxicity risk assessment. This review not only supplies foundational data for evaluating the genotoxic hazards and health risks of EEDs to humans, but also delineates a forward-looking roadmap for environmental genetic toxicology research.